ORCID Profile
0000-0002-5895-2253
Current Organisation
University of Wollongong
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In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Biochemistry and Cell Biology | Biochemistry and Cell Biology not elsewhere classified | Organic Chemistry | Analytical Spectrometry | Biomedical Instrumentation | Optical Properties of Materials | Organic Chemical Synthesis | Nanochemistry and Supramolecular Chemistry | Synchrotrons; Accelerators; Instruments and Techniques | Proteins and Peptides | Food Sciences | Protein Trafficking | Proteomics and Intermolecular Interactions (excl. Medical Proteomics) | Systems Physiology | Other Physical Sciences | Analytical Biochemistry | Medical Biochemistry: Lipids | Other Food Sciences | Medical Biochemistry: Proteins and Peptides (incl. Medical Proteomics) | Cell Development, Proliferation and Death
Expanding Knowledge in the Biological Sciences | Endocrine organs and diseases (incl. diabetes) | Expanding Knowledge in the Medical and Health Sciences | Expanding Knowledge in the Chemical Sciences | Infectious diseases | Cardiovascular system and diseases | Biological sciences | Chemical sciences | Scientific instrumentation | Expanding Knowledge in Technology | Expanding Knowledge in the Physical Sciences | Preventive medicine | Nutrition |
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.BRAINRES.2009.02.075
Abstract: Tyrosine hydroxylase is the rate-limiting enzyme in the synthesis of dopamine, a key neurotransmitter in the regulation of food intake. This study examined tyrosine hydroxylase mRNA expression in obese mice fed a high-fat diet. After 8 week feeding of high-fat diet mice were classified as diet-induced obese and obese-resistant according to body weight gain. They were then placed on different dietary interventions including a high-fat diet, a low-fat diet and an energy-restricted high-fat diet for six weeks. The control group was fed a low-fat diet. The results revealed that tyrosine hydroxylase mRNA expression was significantly decreased in the ventral tegmental area (VTA), ventromedial hypothalamic nucleus (VMH), and substantia nigra (SN) of the high-fat diet-induced obese (-29%, -26% and -26%) and obese-resistant mice (-21%, -24% and -18%) compared to controls. After switching the diet from high to low-fat diet tyrosine hydroxylase mRNA was increased in the VTA, VMH, and SN of the diet-induced obese mice and in the VMH, and SN of the obese-resistant mice. Energy restriction, even with high-fat feeding, reduced tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN compared to controls. In addition, tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN showed a significant negative correlation with plasma leptin levels. This study suggests that the up- or down-regulation of tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN is mainly due to the intake of macronutrient type rather than body weight.
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.SCHRES.2013.04.035
Abstract: Many genes associated with dopamine (DA) and norepinephrine (NE) systems influence cognitive deficits of schizophrenia patients, but one key enzyme is dopamine beta-hydroxylase (DBH), which converts DA to NE and whose activity and levels are under strong genetic control. This study examines the association of the 19 bp insertion/deletion (Ins/Del) polymorphism in the 5' flank of the DBH gene with cognitive deficits in first-episode schizophrenic patients (FEP). We assessed the cognitive function in 195 FEP and 304 healthy controls using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The 19 bp Ins/Del polymorphism of DBH gene was genotyped. Our results showed that the allelic and genotypic frequencies of the 19 bp Ins/Del polymorphism significantly differed between FEP and healthy controls (both p < 0.05). Cognitive test scores were significantly lower in FEP than healthy controls on all scales (all p 0.05). Immediate memory abilities significantly differed by genotype (p<0.05) but not genotype×diagnosis. Immediate memory score was lower in FEP with DBH5'-Del/Del genotype (61.3 ± 17.2) than those with DBH5'-Ins/Ins genotype (68.6 ± 16.2 p < 0.05). The 19 bp Del allele was associated with poorer immediate memory performance than the Ins allele in FEP (p < 0.05). However, healthy controls did not show any differences in cognitive function indices between the Ins and Del for either the allele or genotype of the 19 bp Ins/Del polymorphism. Our findings suggest that the DBH5'-Ins/Del polymorphism may play a role in susceptibility to FEP. The DBH5'-Ins/Del polymorphism may also influence immediate memory in FEP. Moreover, FEP had poorer cognitive function than healthy controls in all examined cognitive domains except for the visuospatial/constructional index.
Publisher: Oxford University Press (OUP)
Date: 10-02-2009
Publisher: Springer Science and Business Media LLC
Date: 12-2018
Publisher: Elsevier BV
Date: 11-2003
DOI: 10.1016/J.BRAINRES.2003.08.019
Abstract: The melanocortinergic system plays an important role in promoting negative energy balance and preventing excessive fat deposition. This study has investigated the levels of mRNA expression of proopiomelanocortin (POMC), agouti-related protein (AgRP) and the melanocortin-4 receptor (MC4-R) in diet-induced obese (DIO) and diet-resistant (DR) mice. Thirty C57 mice were used in this study. Twenty-four mice were fed with a high-fat diet (HF: 40% of calories from fat, 20% from saturated fat) for 4 weeks and then classified as DIO and DR according to their body weight gain. Six mice were placed on a low-fat diet (LF: 10% of calories from fat, 1% from saturated fat) and were used as controls. After 22 weeks of feeding, visceral fat deposits were more than twice as heavy in the DIO mice as in the DR and LF mice, while the latter two groups had no significant difference. Using quantitative in situ hybridization techniques, this study found that the DIO mice had a significantly lower level of Arc POMC (-29%) and AgRP (-31%) mRNA expression than the DR and LF mice, respectively. The mice on high-fat diets had higher levels of AgRP mRNA expression in the bed nucleus of stria terminalis (BST), and ventral part of the lateral septal nucleus (LSV) than the LF mice. Furthermore, the DIO mice had a 40% higher level of MC4-R mRNA expression in the ventromedial hypothalamic nucleus (VMH) and posterodorsal part of the medial amygdaloid nucleus (MePD) than the LF mice. In conclusion, this study has demonstrated that differential expression of POMC, AgRP and MC4-R mRNA levels exists in DIO, DR and LF mice. These differences were shown to occur in the specific nuclei of the hypothalamus and other parts of the limbic system. These findings may assist in understanding the involvement of the melanocortinergic system in the regulation of body weight via the autonomic and limbic systems.
Publisher: Wiley
Date: 29-11-2010
DOI: 10.1002/JCB.22905
Abstract: Colorectal cancer is the third most common cancer with a 5-year survival rate of less than 10%. It is caused by alterations of multiple signal pathways which are affected by both genetic and environmental factors. In some cases, EGFR is important in the carcinogenesis of colorectal cancer suggesting anti-EGFR therapy may be a potential treatment option. However, in other cases it is not effective, which may be related to its down-stream targeted gene mutations. KRAS is highly emphasized in the literature but other mutations like Src, PIK3CA, and BRAF may also be important. Furthermore, obesity may decrease the effectiveness of anti-EGFR treatment as it increases the risk factors for colorectal cancer. Using next-generation sequencing technology, it may be possible to identify all gene mutations in an in idual with colorectal cancer. Therefore, gene mutations affecting anti-EGFR therapy in colorectal cancer patients can be identified.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2017
DOI: 10.1038/SREP42525
Abstract: Deficits in neurite outgrowth, possibly involving dysregulation of risk genes neuregulin-1 (NRG1) and disrupted in schizophrenia 1 (DISC1) have been implicated in psychiatric disorders including schizophrenia. Electrical stimulation using conductive polymers has been shown to stimulate neurite outgrowth of differentiating human neural stem cells. This study investigated the use of the electroactive conductive polymer polypyrrole (Ppy) to counter impaired neurite outgrowth of primary pre-frontal cortical (PFC) neurons from NRG1-knock out (NRG1-KO) and DISC1-locus impairment (DISC1-LI) mice. Whereas NRG1-KO and DISC1-LI exhibited reduced neurite length and number of neurite branches compared to wild-type controls, this was not apparent for cultures on electroactive Ppy. Additionally, the use of the Ppy substrate normalised the synaptophysin and PSD95 protein and mRNA expression whereas both are usually reduced by NRG1-KO or DISC1-LI. Our findings support the utility of Ppy mediated electrical stimulation to prevent the reduction of neurite outgrowth and related synaptic protein expression in the primary PFC neurons from NRG1-KO and DISC1-LI mice, providing proof-of-concept for treating neurodevelopmental diseases including schizophrenia.
Publisher: Informa UK Limited
Date: 07-11-2013
DOI: 10.3109/00207454.2013.853058
Abstract: The N-methyl-d-aspartate (NMDA) system closely interacts with the dopaminergic system and is strongly implicated in the pathophysiological mechanisms and therapeutic paradigms of Parkinson's disease. This study aims to systematically investigate the changes of NMDA receptors in a wide range of brain structures 3 weeks after unilateral medial forebrain bundle lesion by 6-hydroxydopamine (6-OHDA). NMDA receptor distributions and alterations in the post-mortem rat brain were detected by [(3)H] MK-801 binding autoradiography. In the 6-OHDA-induced Parkinsonian rat model, nigrostriatal dopaminergic neuron loss significantly mediated the decreased [(3)H] MK-801 binding, predominantly in the hippoc us (-22.4%, p < 0.001), caudate putamen (-14.1%, p < 0.01), accumbens nucleus (-13.8%, p < 0.05), cingulate cortex (-13.4%, p < 0.001), posteromedial cortical amygdala (-14.5%, p < 0.01) and piriform cortex (-9%, p < 0.05) compared to the controls, while there was a profound reduction of tyrosine hydroxylase (TH) immunohistochemistry in the substantia nigra pars compacta. Alterations in [(3)H] MK-801 in the specific brain regions related to cognitive functions may indicate that cognitive dysfunctions caused by 6-OHDA lesion were via the NMDA system. The downregulation of NMDA receptor binding in the present study provides indirect evidence for plasticity in the NMDA system in the rat brain. The present study improves our understanding of the critical roles of the NMDA receptors in treating neurodegenerative disorders, and implicates NMDA receptors as a novel therapeutic target in the treatment of Parkinson's disease.
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.SCHRES.2016.10.028
Abstract: Long-term antipsychotic treatment for schizophrenia is associated with the development of tar e dyskinesia (TD), which is involved in increased cognitive impairment. Dopamine beta-hydroxylase (DBH) gene associated with dopamine and norepinephrine systems influences cognition. Schizophrenia with TD have higher DBH activity than those without TD. This study examined whether DBH5'-insertion/deletion (-Ins/Del) polymorphism could influence cognitive function in schizophrenia with and without TD. The presence of DBH5'-Ins/Del polymorphism was determined in 345 schizophrenia with TD and 397 schizophrenia without TD. The Abnormal Involuntary Movement Scale and Repeatable Battery for Assessment of Neuropsychological Status (RBANS) were used to assess TD severity and cognition. The allele and genotype frequencies of DBH5'-Ins/Del polymorphism did not differ between patients with and without TD (both p>0.05). RBANS total score and subscales did not differ by DBH5'-Ins/Del genotype groups in patients with TD (all p>0.05). However, attention score significantly differed by DBH5'-Ins/Del genotype groups in those without TD (p<0.05). Patients without TD who were Del homozygous had significantly lower attention score than those without TD who were Ins alleles (p<0.05). Immediate memory and attention scores were lower in patients with TD than without TD (both p<0.05). This study indicated that DBH5'-Ins/Del polymorphism may not play a role in the susceptibility to TD and cognitive deficits in schizophrenia with TD, but it may influence cognitive function in schizophrenia with non-TD. Moreover, schizophrenia with TD experienced greater cognitive deficits than those with non-TD, especially in immediate memory and attention.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.BBR.2009.07.003
Abstract: Weight regain after weight loss is a major hurdle for combating obesity. The aim of this study is to examine orexigenic and anorectic neuropeptides of the hypothalamic arcuate nucleus (Arc) in response to weight loss after chronic energy intake restriction. Thirty mice were fed with a high-fat diet for 8 weeks and then classified as diet-induced obese (DIO n=10) or diet-resistant (DR n=10) mice according to the highest and lowest body weight gainers. Five mice from DIO and DR groups were placed on an energy restricted diet or continued on their high-fat diet ad libitum for 6 weeks. An additional five mice were on a LF diet throughout the course of this study as controls. Results showed that a six-week energy restricted diet completely reversed the increased body weight, fat mass and leptin in the DIO mice to the levels of the LF and DR mice. Arc neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expression in DIO mice after obesity reversal were significantly higher than DIO mice without obesity reversal (17%, 47%, both p<0.05), while the Arc pro-opiomelanocortin (POMC) and cocaine- and hetamine-regulated transcript (CART) mRNA showed no difference. Both NPY and AgRP expression in DIO mice were negatively correlated with plasma leptin (R=-0.78, p<0.05 R=-0.72, p<0.05). In conclusion, while chronic energy restriction will lead to weight loss, it can up-regulate hypothalamic orexigenic peptides, which may be an important contributing factor to weight regain after a weight loss program from an energy restricted diet.
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.JPSYCHIRES.2012.02.016
Abstract: Numerous studies report dysfunctional dopaminergic and noradrenergic neurotransmission in the pathogenesis of schizophrenia. Dopamine beta-hydroxylase (DBH) is an intracellular enzyme catalyzing the conversion of dopamine to noradrenaline. Functional polymorphisms have been reported in the promoter region of DBH gene, including a 19 bp insertion/deletion polymorphism. The purpose of this study was to investigate whether there was an association between the functional polymorphism (DBH5'-Ins/Del) and schizophrenia in a Han Chinese population. This polymorphism was genotyped in 221 first-episode schizophrenics, 360 chronic schizophrenics and 318 healthy controls using a case-control design. We assessed their psychopathology using the Positive and Negative Syndrome Scale (PANSS). We showed that the DBH5'-Ins/Del deletion (Del) allelic and genotypic frequencies were significantly lower in controls than first-episode of schizophrenics (FES) (both p < 0.001), but controls were not different from chronic schizophrenics. Furthermore, the PANSS positive symptom and total scores were significantly higher in FES with the Del/Del genotype than those with Ins/Del and Ins/Ins genotypes (all p < 0.05). The DBH5'-Ins/Del polymorphism may play a role in susceptibility to the positive symptoms of FES and to these FES not progressing on to chronic schizophrenia.
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.PUHE.2008.05.010
Abstract: Emerging evidence suggests that chronic sleep restriction contributes to obesity. Targeting short sleep duration may therefore offer a novel and effective method of preventing and treating obesity. However, this area of research is only in its infancy, and a complete understanding of how chronic sleep restriction and obesity are linked is currently lacking. The aim of this paper is to briefly review epidemiological evidence for an association between chronic sleep restriction and obesity in adults, and outline the key methodological limitations of these studies. Particular attention is paid to the methods used to measure sleep and obesity, as well as the need to control for potential confounding variables. Methodological recommendations are provided for future studies that will facilitate a more complete understanding of how chronic sleep restriction and obesity are linked in the general population. This has implications for the development of public health programmes that target sleep as a modifiable risk factor for obesity.
Publisher: Springer Science and Business Media LLC
Date: 11-06-2011
DOI: 10.1007/S00213-011-2342-0
Abstract: The interactions between Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) during chronic treatment, and at equivalent doses, are not well characterised in animal models. The aim of this study is to examine whether the behavioural effects of THC, and blood and brain THC levels are affected by pre-treatment with equivalent CBD doses. Adolescent rats were treated with ascending daily THC doses over 21 days (1 then 3 then 10 mg/kg). Some rats were given equivalent CBD doses 20 min prior to each THC injection to allow examination of possible antagonistic effects of CBD. During dosing, rats were assessed for THC and CBD/THC effects on anxiety-like behaviour, social interaction and place conditioning. At the end of dosing, blood and brain levels of THC, and CB(1) and 5-HT(1A) receptor binding were assessed. CBD potentiated an inhibition of body weight gain caused by chronic THC, and mildly augmented the anxiogenic effects, locomotor suppressant effects and decreased social interaction seen with THC. A trend towards place preference was observed in adolescent rats given CBD/THC but not those given THC alone. With both acute and chronic administration, CBD pre-treatment potentiated blood and brain THC levels, and lowered levels of THC metabolites (THC-COOH and 11-OH-THC). CBD co-administration did not alter the THC-induced decreases in CB(1) receptor binding and no drug effects on 5-HT(1A) receptor binding were observed. CBD can potentiate the psychoactive and physiological effects of THC in rats, most likely by delaying the metabolism and elimination of THC through an action on the CYP450 enzymes that metabolise both drugs.
Publisher: Springer Science and Business Media LLC
Date: 10-06-2009
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.PNPBP.2011.04.002
Abstract: Evidence from genetic, transgenic and post-mortem studies has strongly supported the critical role that neuregulin 1 (NRG1) and its ErbB4 receptor plays in the pathophysiology of schizophrenia. This article aims to review current evidence regarding the effects of antipsychotic treatment on NRG1-ErbB4 signalling. NRG1 and ErbB4 knockout mice display abnormal behaviours relevant to certain features of schizophrenia, which could be improved by antipsychotic (clozapine/haloperidol) treatment. In contrast to most NRG1/ErbB4 knockout mice with a decreased NRG1-ErbB4 signalling, the majority post-mortem studies showed an increased NRG1-ErbB4 signalling in schizophrenic patients. These differences could be due to degrees of alteration in risk genes (subtle variations in patients vs pronounced alteration in mutant mice) or the duration of the modification on NRG1 signalling. Various antipsychotics have different effects on NRG1 and ErbB4 expression and signalling that are dependent on treatment duration. Current evidence suggests that a chronic (12weeks) antipsychotic treatment, at least in animal models, could downregulate NRG1-ErbB4 signalling, although an upregulation is seen for a short-term treatment. These effects may be due to multiple binding profiles with various G-coupled protein receptors (e.g. dopamine, and serotonin receptors) of antipsychotics. Studies are needed to investigate the interactions between NRG1-ErbB4 and the other signalling pathways (such as glutamatergic, GABAergic and dopaminergic). Furthermore, the interactions between NRG1/ErbB4 and other schizophrenia suspensibility genes under antipsychotic treatment also require investigation.
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.LFS.2016.05.005
Abstract: Cannabinoid 1(CB1) receptors are closely correlated to the dopaminergic system and involved in cognitive function. Since statins have been used to regulate the progression of Parkinson's disease (PD) via its anti-inflammation and neuroprotective effects, we asked if statins affect the CB1 receptors in the 6-hydroxydopamine (6-OHDA) lesioned rat. The PD rat model was established by injecting 6-OHDA into the unilateral medial forebrain bundle while rats were orally pre-treated with simvastatin (1 or 10mg/kg/day), or saline for 5days before surgery, and the same treatments for each group were continued for 3weeks post-surgery. [(3)H] SR141716A binding autoradiography was adopted to investigate the alterations in CB1 receptor density in the brains. The 6-OHDA induced a remarkable downregulation of CB1 receptor density in the prefrontal cortex, caudate putamen, nucleus accumbens, cingulate cortex, hippoc us, and substantia nigra while simvastatin (10mg/kg/day) significantly ameliorated this downregulation in those regions. Furthermore, simvastatin (1mg/kg/day) reversed the 6-OHDA-induced downregulation of CB1 receptors in the substantia nigra and hippoc us. Simvastatin showed minimal changes in [(3)H] SR141716A binding in the examined regions in sham rats, but did reveal a significant down-regulation of binding density within the striatum, prefrontal cortex and substantia nigra. Alterations in the [(3)H] SR141716A binding in the examined brain areas may represent the specific regions that mediate motor and cognitive dysfunctions in PD via the endocannabinoid system. Our data suggest a critical role of CB1 receptors in treating PD with simvastatin, and implicate CB1 receptors as a potential therapeutic target in the treatment of PD.
Publisher: Springer Science and Business Media LLC
Date: 05-06-2017
DOI: 10.1038/S41598-017-02884-W
Abstract: Chronic treatment with second-generation antipsychotic drugs (SGAs) has been associated with an increased risk of metabolic syndrome. To evaluate the longitudinal changes in glucose-lipid homeostasis after SGA use, we studied the time-dependent effects of olanzapine (OLZ) (3 mg/kg, b.i.d.) or clozapine (CLZ) (20 mg/kg, b.i.d.) treatment on metabolic profiles for 9 weeks in rats. Although only OLZ significantly increased body weight in rats, both OLZ and CLZ elevated blood lipid levels. Chronic OLZ treatment induced significant weight gain leading to a higher fasting insulin level and impaired glucose tolerance, whereas CLZ lowered fasting insulin levels and impaired glucose tolerance independent of weight gain. Treatment with both drugs deranged AKT/GSK phosphorylation and up-regulated muscarinic M3 receptors in the rats’ livers. Consistent with an elevation in lipid levels, both OLZ and CLZ significantly increased the protein levels of nuclear sterol regulatory element-binding proteins (SREBPs) in the liver, which was associated with improvement in hepatic histamine H1R. However, enhanced carbohydrate response element binding protein (ChREBP) signalling was observed in only CLZ-treated rats. These results suggest that SGA-induced glucose-lipid metabolic disturbances could be independent of weight gain, possibly through activation of SREBP/ChREBP in the liver.
Publisher: Public Library of Science (PLoS)
Date: 08-2014
Publisher: Elsevier BV
Date: 09-2020
Publisher: MDPI AG
Date: 12-02-2014
DOI: 10.3390/NU6020650
Publisher: Frontiers Media SA
Date: 14-05-2020
Publisher: Elsevier BV
Date: 07-1998
DOI: 10.1016/S0006-8993(98)00541-1
Abstract: This study examined c-fos-like immunoreactivity (FLI) in the brain of obese (ob/ob) and lean (+/+) mice during states of satiety and hunger. The results demonstrated that there is an altered neural activity primarily in the hypothalamus of the obese mouse brain. Most interestingly, only obese mice had an increased FLI in the dorsomedial and supramammillary nuclei. Conversely, only lean mice showed increase in FLI in the medial part of perifornical nucleus following food deprivation for 24 h.
Publisher: Springer Science and Business Media LLC
Date: 04-2009
Publisher: Hindawi Limited
Date: 2010
DOI: 10.1155/2010/821710
Abstract: A growing number of studies have identified chronic sleep restriction as a potential risk factor for obesity. This could have important implications for how obesity is prevented and managed, but current understanding of the processes linking chronic sleep restriction to obesity is incomplete. In this paper, we examined some of the pathways that could underlie the relationship between chronic sleep restriction and obesity. This involved exploring some of the potential environmental, health, behavioral, and sociodemographic determinants of chronic sleep restriction, which require further investigation in this context. Three pathways that could potentially link chronic sleep restriction to obesity were then examined: (1) altered neuroendocrine and metabolic function, (2) impaired glucose regulation, and (3) waking behavior. The selected pathways linking chronic sleep restriction to obesity reviewed in this paper are presented in a schematic representation this may be used to guide future research in this area. This area of research is important because it may lead to more effective interventions and strategies to combat the present obesity epidemic.
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.NEUROSCIENCE.2006.02.068
Abstract: The aim of this study was to examine the influence of different fat diets on serotonin receptor and transporter binding. Male Sprague-Dawley rats were fed a diet of either high saturated fat, omega-6 polyunsaturated fatty acid, omega-3 polyunsaturated fatty acid or low fat (control) for eight weeks. Using Beta-Imager quantification techniques, [(3)H]ketanserin, [(3)H]mesulergine and [(3)H]paroxetine binding to serotonin (5-HT)(2A), 5-HT(2C) receptors and 5-HT transporters (5-HTT) was measured throughout the brain in all four groups. All three high fatty acid diets influenced serotonin receptor binding, however the most pronounced effects were that compared with the low fat control group, i) 5-HT(2A) receptor binding was increased in the caudate putamen, but reduced in the mammillary nucleus in high saturated fat and high omega-6 polyunsaturated fatty acid diet groups ii) 5-HT(2C) receptor binding was reduced in the mamillary nucleus of saturated fat group and reduced in prefrontal cortex of the omega-6 polyunsaturated fatty acid and omega-3 polyunsaturated fatty acid groups and iii) 5-HTT binding was reduced in the hippoc us in the omega-6 polyunsaturated fatty acid group. Overall, the omega-6 polyunsaturated fatty acid diet exerted the most influence on serotonin receptor and transporter binding. These results may be of importance in relation to neuropsychiatric diseases such as schizophrenia, where associations between altered fatty acid levels and the serotonergic system have been made.
Publisher: Wiley
Date: 10-2009
Publisher: Elsevier BV
Date: 08-2010
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.NPEP.2006.01.002
Abstract: Using quantitative in situ hybridization, this study examined regional changes in rat brain mRNA levels encoding neuropeptide Y (NPY) following olanzapine, clozapine and haloperidol administration (1.2, 1.5 and 2.0 mg/kg, oral) for 36 days. The NPY mRNA expression levels and patterns were examined after the last drug administration at both time points enabling the measurement of immediate effect at 2h and the effects after 48 h of drug administration. It was found that all these drugs had an immediate effect on NPY mRNA expression, while virtually all these changes normalized 48 h after the drug treatments. A similarity in altered NPY mRNA expression patterns was seen between the olanzapine and clozapine groups however, haloperidol was very different. Olanzapine and clozapine administration decreased NPY mRNA levels in the nucleus accumbens, striatum and anterior cingulate cortex (from -60% to -77%, p<0.05). Haloperidol decreased NPY mRNA expression in the amygdala and hippoc us (-69%, -64%, p<0.05). In the lateral septal nucleus, NPY mRNA levels significantly decreased in the olanzapine group (-66%, p<0.05), a trend toward a decrease was observed in the clozapine group, and no change was found in the haloperidol treated group. These results suggest that the different effects of atypical and typical antipsychotics on NPY systems may reflect the neural chemical mechanisms responsible for the differences between these drugs in their effects in treating positive and negative symptoms of schizophrenia. The immediate decrease of NPY mRNA levels suggests an immediate reduction of NPY biosynthesis in response to these drugs.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.PSYNEUEN.2013.07.010
Abstract: Based on clinical and animal studies, this review suggests a tri-phasic effect of second-generation antipsychotics (SGAs) on circulating ghrelin levels: an initial increase exerted by the acute effect of SGAs followed by a secondary decrease possibly due to the negative feedback from the SGA-induced body weight gain or hyperphagia and a final re-increase to reach the new equilibrium. Moreover, the results can also vary depending on in idual SGAs, other hormonal states, dietary choices, and other confounding factors including medical history, co-treatments, age, gender, and ghrelin measurement techniques. Interestingly, rats treated with olanzapine, an SGA with high weight gain liabilities, are associated with increased hypothalamic ghrelin receptor (GHS-R1a) levels. In addition, expressions of downstream ghrelin signalling parameters at the hypothalamus, including neuropeptide Y (NPY)/agouti-related peptide (AgRP) and proopiomelanocortin (POMC) are also altered under SGA treatments. Thus, understanding the role of ghrelin signalling in antipsychotic drug-induced weight gain should offer potential novel pharmacological targets for tackling the obesity side-effect of SGAs and its associated metabolic syndrome.
Publisher: Elsevier BV
Date: 09-2000
DOI: 10.1016/S0006-8993(00)02580-4
Abstract: A high fat diet leads to progressive development of obesity and leptin resistance in C57 mice with a middle stage of peripheral, but not central, leptin resistance. This stage is characterized by increased fat accumulation despite relative hypophagia. At a later stage central leptin resistance ensues along with hyperphagia, rapid weight and fat gain. The aim of this study is to characterize the mRNA levels of leptin receptor (LR), neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) in high fat (HFF) and low fat (LFF) fed groups of mice. The hypothalamic arcuate nucleus (Arc) was investigated, as was the choroid plexus (ChP) in the case of the leptin receptor. No differences between groups were seen in LR, NPY or POMC mRNA levels after 1 week of feeding. After 8 and 19 weeks, the HFF mice, compared to LFF controls, demonstrated a +45% (P<0. 003) and +84% (P<0.0001) increase in the ratio of visceral fat to body weight and +223% (P<0.0001) and +468% (P<0.0001) elevation in plasma leptin levels, respectively. At 8 weeks, LR mRNA expression showed a +98% (P<0.016) and +66% (P<0.0001) increase in ChP and Arc, respectively, while Arc NPY mRNA showed down-regulation by -45% (P<0. 006). Arc POMC mRNA showed no significant changes between groups at 8 weeks. However, after long-term (19 weeks) feeding, the HFF mice displayed significantly -26% (P<0.039) and -33% (P<0.0015) reduced LR mRNA in the ChP and Arc, respectively, with Arc POMC and NPY mRNAs down by -55% (P<0.004) and -32% (P<0.009), respectively. The present results suggest that in the middle stage of development of high fat-induced obesity, when central leptin sensitivity is maintained, the increased leptin receptor expression may play a role to defend against obesity which is overwhelmed as central leptin insensitivity develops. In this later stage the down-regulation of the POMC system may be important in the final breakdown of weight homeostasis.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.PSYCHRES.2014.12.014
Abstract: Neuregulin-1 (NRG1) and ErbB4 genes have been identified as candidate genes for schizophrenia. Post-mortem studies indicated that NRG1-ErbB4 signalling is impaired in schizophrenia subjects. This study investigated whether short- or long-term antipsychotic treatment has different effects on the expression of NRG1 and ErbB4 receptors. Female Sprague-Dawley rats were treated orally with either aripiprazole (0.75 mg/kg), haloperidol (0.1 mg/kg), olanzapine (0.5 mg/kg), or vehicle, 3 times/day for 1 or 12 weeks. Western blotting was performed to examine the expression of NRG1 isoforms (135 kDa, 70 kDa and 40 kDa) and ErbB4 receptors. Both 1-week haloperidol and olanzapine treatment increased NRG1-70kDa expression in the hippoc us haloperidol also up-regulated ErbB4 levels in the prefrontal cortex (PFC). In the 12-week group, aripiprazole decreased the expression of all three NRG1 isoforms and ErbB4 receptors in the PFC, NRG1-70 kDa and -40 kDa in the cingulate cortex (Cg), and NRG1-135 kDa, -70 kDa and ErbB4 receptors in the hippoc us haloperidol reduced NRG1-135 kDa in the PFC, NRG1-40 kDa in all three brain regions, and ErbB4 receptor levels in the PFC and hippoc us NRG1-40 kDa in the PFC and Cg was also down-regulated by olanzapine. These results suggest that the time-dependent and region-specific effects of antipsychotics on NRG1-ErbB4 signalling may contribute to the efficacy of antipsychotics to treat schizophrenia.
Publisher: Elsevier BV
Date: 10-2009
Publisher: Springer Science and Business Media LLC
Date: 02-10-2020
DOI: 10.1186/S40168-020-00920-Y
Abstract: “Western” style dietary patterns are characterized by a high proportion of highly processed foods rich in fat and low in fiber. This diet pattern is associated with a myriad of metabolic dysfunctions, including neuroinflammation and cognitive impairment. β-glucan, the major soluble fiber in oat and barley grains, is fermented in the lower gastrointestinal tract, potentially impacting the microbial ecosystem and thus may improve elements of cognition and brain function via the gut-brain axis. The present study aimed to evaluate the effect of β-glucan on the microbiota gut-brain axis and cognitive function in an obese mouse model induced by a high-fat and fiber-deficient diet (HFFD). After long-term supplementation for 15 weeks, β-glucan prevented HFFD-induced cognitive impairment assessed behaviorally by object location, novel object recognition, and nesting building tests. In the hippoc us, β-glucan countered the HFFD-induced microglia activation and its engulfment of synaptic puncta, and upregulation of proinflammatory cytokine (TNF-α, IL-1β, and IL-6) mRNA expression. Also, in the hippoc us, β-glucan significantly promoted PTP1B-IRS-pAKT-pGSK3β-pTau signaling for synaptogenesis, improved the synaptic ultrastructure examined by transmission electron microscopy, and increased both pre- and postsynaptic protein levels compared to the HFFD-treated group. In the colon, β-glucan reversed HFFD-induced gut barrier dysfunction increased the thickness of colonic mucus (Alcian blue and mucin-2 glycoprotein immunofluorescence staining), increased the levels of tight junction proteins occludin and zonula occludens-1, and attenuated bacterial endotoxin translocation. The HFFD resulted in microbiota alteration, effects abrogated by long-term β-glucan supplementation, with the β-glucan effects on Bacteroidetes and its lower taxa particularly striking. Importantly, the study of short-term β-glucan supplementation for 7 days demonstrated pronounced, rapid differentiating microbiota changes before the cognitive improvement, suggesting the possible causality of gut microbiota profile on cognition. In support, broad-spectrum antibiotic intervention abrogated β-glucan’s effects on improving cognition, highlighting the role of gut microbiota to mediate cognitive behavior. This study provides the first evidence that β-glucan improves indices of cognition and brain function with major beneficial effects all along the gut microbiota-brain axis. Our data suggest that elevating consumption of β-glucan-rich foods is an easily implementable nutritional strategy to alleviate detrimental features of gut-brain dysregulation and prevent neurodegenerative diseases associated with Westernized dietary patterns.
Publisher: Elsevier BV
Date: 07-2004
Publisher: Public Library of Science (PLoS)
Date: 07-08-2012
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.BBI.2015.09.014
Abstract: Brain-derived neurotrophic factor (BDNF) interacts with cytokines. Although both BDNF and cytokines occur at abnormal levels in schizophrenia patients, their interactions have not yet been examined. We therefore compared serum BDNF, TNF-α, interleukin (IL)-2, IL-6, and IL-8 levels in 92 chronically medicated schizophrenia patients and 60 healthy controls. We correlated these serum levels within these subject groups with each other and with clinical symptoms assessed according to the Positive and Negative Syndrome Scale (PANSS). Compared to the control group, the schizophrenia patients had significantly lower BDNF and TNF-α levels, and higher IL-2, IL-6, and IL-8 levels. The patients also showed a significant positive correlation between BDNF and both IL-2 and IL-8 levels, and low BDNF and TNF-α levels together were associated with poor performance on the PANSS cognitive factor. Thus, an interaction between cytokines and neurotrophic factors may be implicated in the pathophysiology of chronic schizophrenia. In particular, the cytokine TNF-α may interact with BNDF causing cognitive impairment.
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.PNPBP.2014.02.003
Abstract: Excessive weight gain has been identified as a serious metabolic side-effect of second-generation antipsychotics (SGAs), including olanzapine. While hyperphagia has been suggested to be the main contributor for this side-effect in the short term, reduced energy expenditure, in particular thermogenesis and locomotor activity, has been considered to contribute to the maintenance of heavy weight under long-term SGA treatments. Recent studies have identified metabolically active brown adipose tissues (BAT) in adult humans, suggesting potential clinical significance for the involvement of BAT thermogenesis in SGA-induced weight gain. However, to date there has been little research elucidating the central neuronal pathways affecting BAT thermogenesis or the morphological changes of the BAT. The present study aimed to investigate the role of BAT thermogenesis and locomotor activity in olanzapine-induced weight gain during the prolonged time courses of olanzapine treatment in an established female rat model. Although short- to mid-term olanzapine treatment had no effect on BAT temperature, we observed that long-term olanzapine treatment (from day 18 to 34) induced a significant reduction in BAT temperature, with an acute effect being observed between 45 and 150 min post-treatment in the long-term cohort. Additionally, in the long-term olanzapine group, the reduced BAT temperature was accompanied by decreased UCP1 and PGC-1α expressions in the BAT. Moreover, TH mRNA expressions in both hypothalamus and brainstem were also downregulated after mid- to long-term olanzapine treatment. Further, olanzapine led to reduced percentage of brown adipocytes in BAT during mid- to long-term treatments. Finally, locomotor activity was reduced throughout the three treatment cohorts. In summary, our results suggest that the reduction of BAT thermogenesis plays an important role during the long-term of olanzapine-induced weight gain, which was accompanied by an earlier onset of BAT adipocyte morphological changes and biochemical changes in the hypothalamus and the brainstem, while locomotor activity contributes to the entire olanzapine treatment courses.
Publisher: Elsevier
Date: 2003
Publisher: Springer Science and Business Media LLC
Date: 05-2000
Abstract: To investigate the development of high fat diet-induced obesity and leptin resistance. Two experiments were carried out in this study. Firstly, we fed the mice with a high- or low-fat diet for up to 19 weeks to examine a progressive development of high fat diet-induced obesity. Secondly, we examined peripheral and central exogenous leptin sensitivity in mice fed high- or low-fat diets for 1, 8 or 19 weeks. A total of 168 C57BL/6J mice (3 weeks old) were used in this study. In the first experiment, we measured the body weight, energy intake, adipose tissue mass, tibia bone length, and plasma leptin in mice fed either a high- or low-fat diet for 1, 8, 15 and 19 weeks. In the second experiment, body weight change and cumulative energy intake were measured at 6 h intervals for 72 h after leptin injection in mice fed a high- or low-fat diet for 1, 8 or 19 weeks. The results from the first experiment suggested that the development of high fat diet-induced obesity in mice could be ided into early, middle and late stages. Compared with the mice fed a low-fat diet, the mice fed a high-fat diet showed a gradually increased body weight (+5.2%), fat storage (epididymal plus perirenal +6.7%) and plasma leptin (+18%) at 1 week +11.4%, +68.1%, and +223%, respectively, at 8 weeks and +30.5%, +141%, and +458%, respectively, at 19 weeks. Energy intake of high fat diet-fed mice was equal to that of low fat diet-fed controls for the first 3 weeks it fell below control levels over the next 5 week period, but began to increase gradually after 8 weeks of high-fat diet feeding and then increased dramatically from 15 weeks to be 14% higher than that of controls after 19 weeks. The results from our second experiment showed that: (1) after 1 week of feeding, the mice fed a high-fat diet were sensitive to a 2 microg/g (body weight) intraperitoneal (i. p.) injection of leptin, with no differences in body weight change or cumulative energy intake post-injection (2) after 8 weeks of feeding, the mice fed a high-fat diet were insensitive to 2 microg/g (body weight) i.p. leptin, but were sensitive to a 0.1 microg intracerebroventricular (i.c.v.) injection of leptin (3) after 19 weeks of feeding, the mice fed a high-fat diet were insensitive to 0. 1 microg i.c.v. leptin, but were sensitive to a high dose of 2 microg i.c.v. leptin. The present study demonstrated that the development of high fat diet-induced obesity (19 weeks) in C57 B1/6J mice could be ided into three stages: (1) an early stage in response to high-fat diet that mice were sensitive to exogenous leptin (2) a reduced food intake stage when mice had an increase in leptin production and still retained central leptin sensitivity and (3) an increased food intake stage, accompanied by a reduction of central leptin sensitivity.
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.PNPBP.2009.11.009
Abstract: Atypical antipsychotics such as olanzapine and clozapine are effective at treating the multiple domains of schizophrenia, with a low risk of extra-pyramidal side-effects. However a major downfall to their use is metabolic side-effects particularly weight gain/obesity, which occurs by unknown mechanisms. The present paper explores the potential candidature of histaminergic neurotransmission in the mechanisms of atypical antipsychotic-induced weight gain, with a focus on the histaminergic H1 and H3 receptors. Olanzapine and clozapine have a high affinity for the H1 receptor, and meta-analyses show a strong correlation between risk of weight gain and H1 receptor affinity. In addition, olanzapine treatment decreases H1 receptor binding and mRNA expression in the rat hypothalamus. Furthermore, a complex role is emerging for the histamine H3 receptor in the control of hunger. The H3 receptor is a pre-synaptic autoreceptor that inhibits the synthesis and release of histamine, and a heteroreceptor that inhibits other neurotransmitters such as serotonin (5-HT), noradrenaline (NA) and acetylcholine (ACh), which are also implicated in the regulation of food intake. Thus, the H3 receptor is in a prime position to regulate food intake, both through its control of histamine and its influence on other feeding pathways. We proposed that a mechanism for atypical antipsychotic-induced weight gain may be partly through the H3 receptor, as a drug-induced decrease in H1 receptor activity may decrease histamine tone through the H3 autoreceptors, compounding the weight gain problem. In addition, atypical antipsychotics may affect food intake by influencing 5-HT, NA and ACh release via interactions with the H3 heteroreceptor.
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.PSYNEUEN.2008.01.018
Abstract: The present study investigated body weight gain, food intake, open-field activity and brain histamine H1 receptor mRNA and protein expression in rats treated with three types of antipsychotics. Rats were ided into eight groups and treated with aripiprazole (2.25mg/kg/day), olanzapine (1.5mg/kg/day), haloperidol (0.3mg/kg/day) or vehicle (as control) for 1 or 12 weeks. Administration of olanzapine for 1 week led to a threefold increase in body weight gain and a 35% increase in fat deposits compared to controls (p<0.05). In the 12-week olanzapine treatment group, accumulative food intake was significantly higher in the first 7 weeks of treatment compared to controls (p<0.018), while body weight gain was significantly greater in the first 8 weeks compared to controls (p<0.045). Using in situ hybridization, we found that olanzapine treatment, but not aripiprazole or haloperidol treatment, significantly reduced H1 receptor mRNA expression in the arcuate hypothalamic nucleus (Arc: -18%, p=0.006, 1 week -20%, p=0.008, 12 weeks) and ventromedial hypothalamic nucleus (VMH: -22%, p=0.006, 1 week -19%, p=0.042, 12 weeks) compared to controls. The quantitative autoradiography data showed a reduction in VMH H1 receptor binding density after 1 (-12%, p=0.040) and 12 (-10%, p=0.094) weeks of olanzapine treatment. There were significant negative correlations between the levels of H1 receptor mRNA expression, and body weight gain and energy efficiency in the Arc and VMH after 1- and 12-week antipsychotic treatments in all groups. In addition, H1 receptor mRNA expression in the Arc showed a significant negative correlation with food intake and fat mass in all groups. Furthermore, there were negative correlations between H1 receptor binding density in the VMH and total fat mass and body weight gain after 1 week of antipsychotic treatment. The present study suggests that downregulated VMH and Arc H1 receptor expression may be a key factor contributing to olanzapine-induced obesity.
Publisher: Frontiers Media SA
Date: 13-01-2020
DOI: 10.3389/FNINS.2020.589650
Abstract: The antipsychotic drug olanzapine is associated with serious obesity side effects. Hypothalamic astrocytes and associated toll-like receptor-4 (TLR4) signaling play an essential role in obesity pathogenesis. This study investigated the effect of olanzapine on astrocytes and TLR4 signaling both in vitro and in the rat hypothalamus and their potential role in olanzapine-induced weight gain. We found that olanzapine treatment for 24 h dose-dependently increased cell viability, increased the protein expression of astrocyte markers including glial fibrillary acidic protein (GFAP) and S100 calcium binding protein B (S100B), and activated TLR4 signaling in vitro . In rats, 8- and 36-day olanzapine treatment caused weight gain accompanied by increased GFAP and S100B protein expression and activated TLR4 signaling in the hypothalamus. These effects still existed in pair-fed rats, suggesting that these effects were not secondary effects of olanzapine-induced hyperphagia. Moreover, treatment with an endoplasmic reticulum (ER) stress inhibitor, 4-phenylbutyrate, inhibited olanzapine-induced weight gain and ameliorated olanzapine-induced changes in hypothalamic GFAP, S100B, and TLR4 signaling. The expression of GFAP, S100B, and TLR4 correlated with food intake and weight gain. These findings suggested that olanzapine-induced increase in hypothalamic astrocytes and activation of TLR4 signaling were related to ER stress, and these effects may be related to olanzapine-induced obesity.
Publisher: Springer Science and Business Media LLC
Date: 04-02-2021
DOI: 10.1186/S12967-021-02724-6
Abstract: Long-term high fat (HF) diet intake can cause neuroinflammation and cognitive decline through the gut-brain axis. (1, 3)/(1, 6)-β-glucan, an edible polysaccharide isolated from medical mushroom, Lentinula edodes ( L. edodes ), has the potential to remodel gut microbiota. However, the effects of L. edodes derived β-glucan against HF diet-induced neuroinflammation and cognitive decline remain unknown. This study aimed to evaluate the neuroprotective effect and mechanism of dietary L edodes β-glucan supplementation against the obesity-associated cognitive decline in mice fed by a HF diet. C57BL/6J male mice were fed with either a lab chow (LC), HF or HF with L. edode s β-glucan supplementation diets for 7 days (short-term) or 15 weeks (long-term). Cognitive behavior was examined blood, cecum content, colon and brain were collected to evaluate metabolic parameters, endotoxin, gut microbiota, colon, and brain pathology. We reported that short-term and long-term L. edodes β-glucan supplementation prevented the gut microbial composition shift induced by the HF diet. Long-term L. edodes β-glucan supplementation prevented the HF diet-induced recognition memory impairment assessed by behavioral tests (the temporal order memory, novel object recognition and Y-maze tests). In the prefrontal cortex and hippoc us, the β-glucan supplementation ameliorated the alteration of synaptic ultrastructure, neuroinflammation and brain-derived neurotrophic factor (BDNF) deficits induced by HF diet. Furthermore, the β-glucan supplementation increased the mucosal thickness, upregulated the expression of tight junction protein occludin, decreased the plasma LPS level, and inhibited the proinflammatory macrophage accumulation in the colon of mice fed by HF diet. This study revealed that L. edodes β-glucan prevents cognitive impairments induced by the HF diet, which may occur via colon-brain axis improvement. The finding suggested that dietary L. edodes β-glucan supplementation may be an effective nutritional strategy to prevent obesity-associated cognitive decline.
Publisher: Springer Science and Business Media LLC
Date: 31-03-2007
DOI: 10.1007/S00702-007-0668-X
Abstract: Phencyclidine (PCP) is an antagonist of the NMDA subtype of glutamate receptor. PCP treatment induces psychosis in normal humans, which provides a valuable model of schizophrenia. PCP administration also models some of the symptoms of schizophrenia in experimental animals. NMDA hypofunction has been hypothesized to explain these schizophrenia-like symptoms. Acute or chronic administration of the NMDA receptor antagonist PCP has been shown to induce several short or long-term effects in both humans and experimental animals. In an attempt to clarify the neurochemical substrates of these effects in the present study, we used quantitative autoradiography to examine the effects of chronic (14 days) PCP treatment on NMDA receptor binding in mouse brain following both a short- (1 and 24 h) and long-term (14 days) delay after the last PCP treatment. NMDA receptors were targeted using [(3)H]MK801. Chronic PCP treatment increased [(3)H]MK801 binding consistently in the hippoc us in the short-term (p < 0.01). Conversely in the long-term, there were widespread reductions in NMDA receptor binding and this effect was most evident in the hippoc us where a 35% reduction of binding was found (p < 0.001). These results suggest that the hippoc us has a strong involvement in both the short and long-term effects of PCP treatment and that reduced NMDA receptor function might be one of the neurochemical substrates of the long lasting actions of PCP or PCP-induced psychosis. Importantly, this study shows that the long-term delay following chronic PCP treatment more accurately represents a state of NMDA hypofunction than the short-term PCP model.
Publisher: KARGER
Date: 2005
DOI: 10.1159/000088222
Publisher: Elsevier BV
Date: 04-2010
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.PSYNEUEN.2014.06.010
Abstract: Olanzapine is widely used to treat schizophrenia and other disorders, but causes adverse obesity and other metabolic side-effects. Both animal and clinical studies have shown that co-treatment with betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for ameliorating olanzapine-induced weight gain/obesity. To reveal the mechanisms underlying these effects, this study investigated the effects of co-treatment of olanzapine and betahistine (O+B) on expressions of histaminergic H1 receptor (H1R), AMP-activated protein kinase (AMPK), neuropeptide Y (NPY), and proopiomelanocortin (POMC) in the hypothalamus associated with reducing olanzapine-induced weight gain. Olanzapine significantly upregulated the mRNA and protein expressions of H1R, while O+B co-treatment significantly downregulated the H1R levels, compared to the olanzapine-only treatment group. The NPY mRNA expression was significantly enhanced by olanzapine, but it was significantly reversed by O+B co-treatment. The hypothalamic H1R expression was positively correlated with total food intake, and NPY expression. Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation (pAMPKα)/AMPKα ratio compared with controls, whereas O+B co-treatment decreased the pAMPKα/AMPKα ratio, compared with olanzapine only treatment. The pAMPKα/AMPKα ratio was positively correlated with total food intake and H1R expression. Although olanzapine administration decreased the POMC mRNA level, this level was not affected by O+B co-treatment. Therefore, these results suggested that co-treatment with betahistine may reverse olanzapine-induced body weight gain via the H1R-NPY and H1R-pAMPKα pathways.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2006
Publisher: Public Library of Science (PLoS)
Date: 10-07-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-1998
DOI: 10.1097/00001756-199803090-00032
Abstract: Brain neuropeptide Y (NPY) subtype-5 (Y5 receptor) mRNA expression in lean (+/+) and obese (ob/ob) C57Bl/6 mice was examined using a non-radioactive in situ hybridization detection method. Significant decreases in Y5 receptor mRNA expression were found in the ventromedial, dorsomedial and arcuate hypothalamic nuclei, midline thalamic nuclei, piriform, cingulate and retrosplenial granular cortices of the obese mouse brain. There were minor changes in the amount of Y5 receptor mRNA expression in the hippoc al formation and medial habenular nucleus. Results indicated that Y5 receptor mRNA expression is downregulated in hereditary obese (ob/ob) mice. This is possibly due to over-expression of hypothalamic NPY which occurs in this phenotype.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2018
DOI: 10.1038/S41598-018-27784-5
Abstract: Deficits in neurite outgrowth and synaptogenesis have been recognized as an underlying developmental aetiology of psychosis. Electrical stimulation promotes neuronal induction including neurite outgrowth and branching. However, the effect of electrical stimulation using 3D electrodes on neurite outgrowth and synaptogenesis has not been explored. This study examined the effect of 3D electrical stimulation on 3D primary cortical neuronal cultures. 3D electrical stimulation improved neurite outgrowth in 3D neuronal cultures from both wild-type and NRG1-knockout (NRG1-KO) mice. The expression of synaptophysin and PSD95 were elevated under 3D electrical stimulation. Interestingly, 3D electrical stimulation also improved neural cell aggregation as well as the expression of PSA-NCAM. Our findings suggest that the 3D electrical stimulation system can rescue neurite outgrowth deficits in a 3D culturing environment, one that more closely resembles the in vivo biological system compared to more traditionally used 2D cell culture, including the observation of cell aggregates as well as the upregulated PSA-NCAM protein and transcript expression. This study provides a new concept for a possible diagnostic platform for neurite deficits in neurodevelopmental diseases, as well as a viable platform to test treatment options (such as drug delivery) in combination with electrical stimulation.
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.NUMECD.2009.04.007
Abstract: Decreasing energy intake relative to energy expenditure is the indisputable tenet of weight loss. In addition to caloric restriction modification of the type of dietary fat may provide further benefits. The aim of the present study was to examine the effect of energy restriction alone and with dietary fat modification on weight loss and adiposity, as well as on risk factors for obesity related disease. One-hundred and fifty overweight men and women were randomized into a 3month controlled trial with four low fat (30% energy) dietary arms: (1) isocaloric (LF) (2) isocaloric with 10% polyunsaturated fatty acids (LF-PUFA) (3) low calorie (LF-LC) (-2MJ) (4) low calorie with 10% PUFA (LF-PUFA-LC). Primary outcomes were changes in body weight and body fat and secondary outcomes were changes in fasting levels of leptin, insulin, glucose, lipids and erythrocyte fatty acids. Changes in dietary intake were assessed using 3day food records. One-hundred and twenty-two participants entered the study and 95 completed the study. All groups lost weight and body fat (P<0.0001 time effect for both), but the LC groups lost more weight (P=0.026 for diet effect). All groups reduced total cholesterol levels (P<0.0001 time effect and P=0.017 intervention effect), but the LC and PUFA groups were better at reducing triacylglycerol levels (P=0.056 diet effect). HDL increased with LF-LC and LF-PUFA but not with LF-PUFA-LC (0.042 diet effect). The LF and LF-LC groups reported greater dietary fat reductions than the two PUFA groups (P=0.043). Energy restriction has the most potent effect on weight loss and lipids, but fat modification is also beneficial when energy restriction is more modest.
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1016/J.MOLBRAINRES.2004.12.013
Abstract: The present study examined brain dopamine D2 and D4 receptor and tyrosine hydroxylase (TH) mRNA expression in chronic high-fat diet-induced obese (cDIO) and obese-resistant (cDR) mice. Twenty-eight mice were fed a high-fat diet (HF: 40% of calories from fat) for 6 weeks and then classified as cDIO (n = 8) or cDR (n = 8) mice according to the highest and lowest body weight gainers, respectively. Seven mice were fed a low-fat diet (LF: 10% of calories from fat) and used as controls. After 20 weeks of feeding, visceral fat per gram of initial body weight was significantly higher in the cDIO group (ratio: 0.25, 0.09, and 0.04 P < 0.01 cDIO vs. cDR and LF, respectively). Using quantitative in situ hybridization techniques, the levels of D2 and D4 receptor and tyrosine hydroxylase (TH) mRNAs were measured in multiple brain sections. The cDIO mice had a significantly higher level of D2 receptor mRNA expression in the core of the nucleus accumbens (AcbC, +16%) and ventral parts of caudate putamen (CPu, 21% and 24%) compared to the cDR and LF mice. The levels of D2 receptor mRNA expression in the AcbC and ventromedial part of the CPu were positively related to the final body weight. This study is the first to systematically examine the D4 mRNA expression in the mouse brain using in situ hybridization method. D4 receptor mRNA expression in the ventromedial hypothalamic nucleus (VMH) and the ventral part of the lateral septal nucleus were also significantly higher in the cDIO mice compared to the cDR and LF mice (+31% and +60% P < 0.05). TH mRNA expression was significantly higher in the ventral tegmental area (+17%, P </= 0.05) and locus caeruleus (+15%, P </= 0.05) of the cDIO mice compared to cDR mice. In conclusion, this study has demonstrated differentially regulated levels of D2 and D4 receptor and TH mRNA expression in specific brain regions of cDIO and cDR mice. It provides evidence that D4 receptors may play an important role influencing satiety via the mesohypothalamic pathway while the D2 receptor may regulate reward and motor centers via mesolimbic and nigrostriatal pathways. These findings contribute to the understanding of the role of these receptors in susceptibility, or resistance, to diet-induced obesity.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2018
DOI: 10.1007/S11064-018-2584-X
Abstract: Dysfunction of the glutamatergic system is believed to underlie many neurodevelopmental disorders including autism, Rett syndrome and schizophrenia. Metabotropic glutamate receptor (mGluR5) positive allosteric modulators (PAM) potentiate glutamatergic signaling, particularly indirectly via the NMDA receptor. Preclinical studies report mGluR5 PAMs can improve schizophrenia-relevant behaviours. Furthermore, adolescent administration has shown to prevent cognitive induced deficits in adult rodents. However, there is limited understanding of the short- and long-term neurochemical effects of mGluR5 PAMs, which may underlie their therapeutic effects. We examined the effect of 7-day adolescent (PN28-34) treatment with the mGluR5 PAM, CDDPB (30 mg/kg), on glutamatergic receptor expression at adolescence (PN35) and adulthood (PN96). Immunoblot analysis revealed that 7-day adolescent CDPPB treatment increased protein expression of glutamatergic receptors including the NMDA receptor subunits, NR1 and NR2A and the AMPA subunits (GluA1 and GluA2) in the adolescent hippoc us, changes that did not extend to adulthood. In contrast, there were no changes in the adolescent frontal cortex, however elevated mGluR5 protein expression was observed at adulthood following adolescent CDPPB treatment. The present study indicates adolescent CDPPB treatment may cause brain region dependent effects on the glutamatergic system, which do not persist into adulthood. These findings may have implications for the preclinical development of mGluR5 PAMs for the treatment of neurodevelopmental disorders.
Publisher: Elsevier BV
Date: 10-08-2006
DOI: 10.1016/J.BBR.2006.03.040
Abstract: This study examined regional changes in rat brain mRNA levels encoding 5-HT(2A) and 5-HT(2C) receptors following chronic olanzapine treatment. The immediate effect (2h after the last treatment) was a down-regulation of 5-HT(2A) receptor mRNA expression, predominantly in the hypothalamus, limbic system and striatum, while a rebound effect was observed 48 h later. 5-HT(2C) receptor mRNA expressions were decreased in the substantia nigra. Correlations between 5-HT(2A) receptor mRNA expression and total food intake, weight gain and energy efficiency were observed.
Publisher: Elsevier BV
Date: 12-2010
Publisher: Springer Science and Business Media LLC
Date: 19-05-2006
DOI: 10.1007/S00221-006-0503-X
Abstract: The posterior cingulate cortex (PCC) has recently been implicated in the pathophysiology of schizophrenia, through both animal and human studies. We have recently shown abnormal glutamate, GABA, and muscarinic receptor binding in the PCC in schizophrenia. In addition, there is evidence for an abnormal endogenous cannabinoid system in schizophrenia. The endogenous cannabinoid system, including CB1 receptors, is proposed to play a role in modulating neurotransmission via affecting the release of a variety of neurotransmitters, (e.g. GABA). In the present study, we used quantitative autoradiography to investigate the binding of [(3)H]CP-55940 to CB1 receptors in the PCC in schizophrenia subjects compared to controls. A significant 25% increase in CB1 binding was found in the superficial layers (layer I, II) of the PCC of schizophrenia subjects compared to controls, none of whom had recently used cannabis. There was no statistical difference in CB1 binding in the deeper layers (layers III-VI) between the two groups. There were no significant correlations between CB1 binding density and age, PMI, pH, brain weight, freezer storage time, or final recorded antipsychotic drug dose. These results show an increase in CB1 receptor density in the PCC in schizophrenia, and therefore provide support for a role of the endogenous cannabinoid system in schizophrenia.
Publisher: Wiley
Date: 09-11-2017
DOI: 10.1111/OBR.12638
Abstract: Second generation antipsychotics (SGAs), notably atypical antipsychotics including olanzapine, clozapine and risperidone, can cause weight gain and obesity side effects. Antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling have been identified as a main cause of SGA induced obesity. Here we review the pivotal regulatory role of the 5-HT2cR in ghrelin-mediated appetite signalling. The 5-HT2cR dimerizes with GHSR1a to inhibit orexigenic signalling, while 5-HT2cR antagonism reduces dimerization and increases GHSR1a-induced food intake. Dimerization is specific to the unedited 5-HT2cR isoform. 5-HT2cR antagonism by SGAs may disrupt the normal inhibitory tone on the GHSR1a, increasing orexigenic signalling. The 5-HT2cR and its interaction with the GHSR1a could serve as the basis for discovering novel approaches to preventing and treating SGA-induced obesity.
Publisher: Springer Science and Business Media LLC
Date: 17-03-2015
DOI: 10.1007/S00401-015-1411-6
Abstract: Knockout of genes encoding metabotropic glutamate receptor 5 (mGluR5) or its endogenous regulators, such as Norbin, induce a schizophrenia-like phenotype in rodents, suggesting dysregulation of mGluR5 in schizophrenia. Human genetic and pharmacological animal studies support this hypothesis, but no studies have explored mGluR5 dysfunction at the molecular level in the postmortem schizophrenia brain. We assessed mGluR5 mRNA and protein levels in the dorsolateral prefrontal cortex (DLPFC) using a large cohort of schizophrenia and control subjects (n = 37/group), and additionally measured protein levels of recently discovered mGluR5 endogenous regulators, Norbin (neurochondrin), Tamalin (GRASP-1), and Preso1 (FRMPD4), which regulate mGluR5 localization, internalization and signaling. While mGluR5 mRNA expression was unchanged, mGluR5 protein levels were significantly higher in schizophrenia subjects compared to controls (total: +22% dimer: +54% p < 0.001). Conversely, mGluR5 regulatory proteins were expressed at lower levels in schizophrenia subjects compared to controls (Norbin -37%, p < 0.001 Tamalin -30%, p = 0.084 Preso1 -29%, p = 0.001). mGluR5 protein was significantly associated with mGluR5 mRNA and mGluR5 endogenous regulators in control subjects, but these associations were lost in schizophrenia subjects. Lastly, there were no associations between protein measures and lifetime antipsychotic history in schizophrenia subjects. To confirm no antipsychotic influence, all proteins were measured in the prefrontal cortex of rats exposed to haloperidol or olanzapine there were no effects of antipsychotic drug treatment on mGluR5, Norbin, Tamalin or Preso1. The results from our study provide compelling evidence that mGluR5 regulation is altered in schizophrenia, likely contributing to the altered glutamatergic signaling that is associated with the disorder.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.PNPBP.2019.109666
Abstract: The mainstay treatment for schizophrenia is antipsychotic drugs (APDs), which are mostly effective against the positive symptoms (e.g. hallucinations), but provide minimal benefits for the negative symptoms (e.g. social withdrawal) and cognitive deficits. We have recently shown that treatment with the non-intoxicating phytocannabinoid, cannabidiol (CBD), can improve cognition and social interaction deficits in a maternal immune activation (MIA) model relevant to the aetiology of schizophrenia, however, the mechanisms underlying this effect are unknown. An imbalance in the main excitatory (glutamate) and inhibitory (GABA) neurotransmitter systems in the brain plays a role in the pathophysiology of schizophrenia. Therefore, the endocannabinoid system could represent a therapeutic target for schizophrenia as a regulator of glutamate and GABA release via the CB1 receptor (CB1R). This study investigated the effects of chronic CBD treatment on markers of glutamatergic, GABAergic and endocannabinoid signalling in brain regions implicated in social behaviour and cognitive function, including the prefrontal cortex (PFC) and hippoc us (HPC). Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg, i.v.) or saline (control) on gestational day 15. Male offspring were injected with CBD (10 mg/kg, i.p.) or vehicle twice daily from postnatal day 56 for 3 weeks. The prefrontal cortex (PFC) and hippoc us (HPC) were collected for post-mortem receptor binding and Western blot analyses (n = 8 per group). CBD treatment attenuated poly I:C-induced deficits in cannabinoid CB1 receptor binding in the PFC and glutamate decarboxylase 67, the enzyme that converts glutamate to GABA, in the HPC. CBD treatment increased parvalbumin levels in the HPC, regardless of whether offspring were exposed to poly I:C in utero. Conversely, CBD did not affect N-methyl-d-aspartate receptor and gamma-aminobutyric acid (GABA) A receptor binding or protein levels of fatty acid amide hydrolase, the enzyme that degrades the endocannabinoid, anandamide. Overall, these findings show that CBD can restore cannabinoid/GABAergic signalling deficits in regions of the brain implicated in schizophrenia pathophysiology following maternal poly I:C exposure. These findings provide novel evidence for the potential mechanisms underlying the therapeutic effects of CBD treatment in the poly I:C model.
Publisher: Elsevier BV
Date: 10-2008
DOI: 10.1016/J.JCHEMNEU.2008.06.004
Abstract: Phencyclidine (PCP), a non-competitive NMDA/glutamate receptor antagonist, is a psychotomimetic drug that produces a syndrome in normal humans that resembles schizophrenia. The present study investigated the mechanisms of PCP actions by examining the density of glutamate and muscarinic receptors in the rat brain 4h after a single injection of PCP. We used receptor autoradiography and [3H]MK801, [3H]AMPA, [3H]pirenzepine and [3H]AFDX384 to target glutamate NMDA, glutamate AMPA and muscarinic M1 and M2 receptors, respectively. The major outcome from the present study was an overall decrease in levels of the glutamate AMPA receptor density (F=14.5, d.f.=1, p<0.001) in the PCP treated rats. More specifically, PCP-treated animals displayed decreased AMPA receptor density in hippoc us CA1 (-16%), hippoc us CA2 (-25%), dentate gyrus (-27%), parietal cortex layers III-VI (-19%), central nucleus of the amygdala (-40%), and basolateral amygdala (-19%). Other brain regions examined were unaffected. PCP administration did not significantly affect glutamate NMDA, muscarinic M1 and M2 receptor density. The present study demonstrates the limbic system as the anatomical locus of alterations in AMPA receptor density after acute administration of PCP and may have implications for models of schizophrenia that focus on glutamatergic dysfunction in limbic cortical regions.
Publisher: Springer Science and Business Media LLC
Date: 17-02-2009
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.PSYNEUEN.2019.03.017
Abstract: Antipsychotics are the most important treatment for schizophrenia. However, antipsychotics, particularly olanzapine and clozapine, are associated with severe weight gain/obesity side-effects. Although numerous studies have been carried out to identify the exact mechanisms of antipsychotic-induced weight gain, it is still important to consider other pathways. Endoplasmic reticulum (ER) stress signaling and its associated inflammation pathway is one of the most important pathways involved in regulation of energy balance. In the present study, we examined the role of hypothalamic protein kinase R like endoplasmic reticulum kinase- eukaryotic initiation factor 2α (PERK-eIF2α) signaling and the inflammatory IkappaB kinase β- nuclear factor kappa B (IKKβ-NFκB) signaling pathway in olanzapine-induced weight gain in female rats. In this study, we found that olanzapine significantly activated PERK-eIF2α and IKKβ-NFκB signaling in SH-SY5Y cells in a dose-dependent manner. Olanzapine treatment for 8 days in rats was associated with activated PERK-eIF2α signaling and IKKβ-NFκB signaling in the hypothalamus, accompanied by increased food intake and weight gain. Co-treatment with an ER stress inhibitor, 4-phenylbutyrate (4-PBA), decreased olanzapine-induced food intake and weight gain in a dose- and time-dependent manner. Moreover, 4-PBA dose-dependently inhibited olanzapine-induced activated PERK-eIF2α and IKKβ-NFκB signaling in the hypothalamus. These results suggested that hypothalamic ER stress may play an important role in antipsychotic-induced weight gain.
Publisher: Wiley
Date: 02-10-1995
Abstract: The primary aim of this study was to provide a comprehensive account of the morphology, topography, and frequency of tyrosine hydroxylase- and substance P-like (TH-LI, SP-LI) immunoreactive neurons of the human intermediate reticular zone (IRt), the putative autonomic zone of the medullary reticular formation. A further aim is to examine the IRt from a three-dimensional perspective using computer reconstruction techniques and compare its relationship with other structures in the rest of the medullary reticular formation. Six adult human brains were obtained from in iduals with no sign of cerebral disease and were perfusion fixed. Free-floating transverse sections were immunostained with monoclonal antibodies against tyrosine hydroxylase and substance P by the avidin-biotin-peroxidase technique. The entire IRt displays TH-LI cell bodies and fibers, and thus it is readily distinguishable from the neighbouring gigantocellular and parvicellular reticular nuclei. In contrast, SP-LI cells are restricted to the external part of the IRt that is found in the open medulla, while SP-LI fibers are more widely distributed. The IRt displays TH-LI neurons which are fusiform, oval, and round in shape. The SP-LI neurons of the IRt are primarily oval and fusiform. In preparations stained for Nissl substance, IRt cells were classified as pigmented and nonpigmented. A characteristic feature of the IRt is that its cells are larger (20 +/- 4 micrograms) than those of the laterally adjoining parvicellular (12 +/- 2 micrograms) and clearly smaller than those of the medially adjoining gigantocellular nuclei (33 +/- 6 micrograms). The shape of the IRt is in keeping with the radial organization of the medulla with zones emanating from the fourth ventricle. Three-dimensional computer reconstructions of the cell plots show that 1) TH-LI neurons extend through the entire IRt and densely packed in the rostral part of the ventrolateral IRt and 2) SP-LI neurons are found only in the rostral half of the medulla oblongata.
Publisher: Springer Science and Business Media LLC
Date: 19-09-2017
DOI: 10.1038/S41598-017-12027-W
Abstract: Using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), previous study showed significant gender differences for cognitive deficits in immediate and delayed memory in schizophrenia patients. However, RBANS does not include reasoning and problem solving, and social cognition. These cognitive functions can significantly affect the outcomes and daily life in patients. This study examined the gender differences of cognition using the measurement and treatment research to improve cognition in schizophrenia (MATRICS) consensus cognitive battery (MCCB), especially focusing on reasoning and problem solving, and social cognition in schizophrenia patients. The results showed that healthy controls exemplified better cognition than patients in both genders in all examined MCCB scores. Male healthy controls had better reasoning and problem solving and working memory than females, but these gender differences were not presented in schizophrenia patients. Also, male schizophrenia patients showed worse cognition than females on social cognition, processing speed, verbal learning and visual learning. Our results support that male schizophrenia patients had more cognitive impairment than females on reasoning and problem solving, social cognition, processing speed, working memory, verbal learning and visual learning.
Publisher: Elsevier BV
Date: 04-2010
Publisher: Elsevier BV
Date: 12-2013
Publisher: Elsevier BV
Date: 09-2006
DOI: 10.1016/J.BBRC.2006.07.090
Abstract: Obesity has been proposed to be a result of an imbalance in the physiological system that controls and maintains the body energy homeostasis. Several G-protein coupled receptors (GPCRs) are involved in the regulation of energy homeostasis. To investigate the importance of GPCR12, mice deficient of this receptor (GPCR12 KO) were studied regarding metabolism. Expression of GPCR12 was found primarily in the limbic and sensory systems, indicating its possible involvement in motivation, emotion together with various autonomic functions, and sensory information processing. GPCR12 KO mice were found to have higher body weight, body fat mass, lower respiratory exchange ratio (RER), hepatic steatosis, and were dyslipidemic. Neither food intake nor energy in faeces was affected in the GPCR12 KO mice. However, lower energy expenditure was found in the GPCR12 KO mice, which may explain the obesity. In conclusion, GPCR12 is considered important for the energy balance since GPCR12 KO mice develop obesity and have lower energy expenditure. This may be important for future drugs that target this receptor.
Publisher: Springer Science and Business Media LLC
Date: 10-2008
Publisher: Public Library of Science (PLoS)
Date: 16-03-2012
Publisher: Wiley
Date: 28-10-2009
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.NEUROSCIENCE.2009.01.078
Abstract: Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) are closely associated with the regulation of energy homeostasis, but their roles in diet-induced obesity have not been explored. Using dietary interventions, this study examined regional changes of BDNF and TrkB mRNA expression in different brain regions of diet-induced obese (DIO) and resistant (DR) mice in response to high-fat (HF), energy-restricted pair-feeding and low fat (LF) diets. Using in situ hybridization, DIO mice had significantly decreased levels of BDNF mRNA expression (-32% to -37%) and TrkB (-21% to -23%) in the hippoc us compared to DR mice on an HF diet, but not on energy-restricted pair-feeding and LF diets. In the ventromedial hypothalamic nucleus (VMH), BDNF expression was decreased in DIO mice on HF (-23%) and energy-restricted pair-feeding (-21%) diets. Furthermore, the VMH BDNF expression was negatively correlated with blood glucose but positively correlated with plasma adiponectin. These findings suggest that decreased hippoc al BDNF and TrkB expression plays an important role in high-fat diet induced obesity. A lower baseline BDNF mRNA expression in the VMH of DIO mice after normalization of body weight may indicate their intrinsic nature or an elevated body weight set point to drive body weight gain.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.CBI.2016.07.013
Abstract: High-fat (HF) diet-induced obesity is associated with hypothalamic leptin resistance and low grade chronic inflammation, which largely impairs the neuroregulation of negative energy balance. Neuroregulation of negative energy balance is largely controlled by the mediobasal and paraventricular nuclei regions of the hypothalamus via leptin signal transduction. Recently, a derivative of oleanolic acid, bardoxolone methyl (BM), has been shown to have anti-inflammatory effects. We tested the hypothesis that BM would prevent HF diet-induced obesity, hypothalamic leptin resistance, and inflammation in mice fed a HF diet. Oral administration of BM via drinking water (10 mg/kg daily) for 21 weeks significantly prevented an increase in body weight, energy intake, hyperleptinemia, and peripheral fat accumulation in mice fed a HF diet. Furthermore, BM treatment prevented HF diet-induced decreases in the anorexigenic effects of peripheral leptin administration. In the mediobasal and paraventricular nuclei regions of the hypothalamus, BM administration prevented HF diet-induced impairments of the downstream protein kinase b (Akt) pathway of hypothalamic leptin signalling. BM treatment also prevented an increase in inflammatory cytokines, tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) in these two hypothalamic regions. These results identify a potential novel neuropharmacological application for BM in preventing HF diet-induced obesity, hypothalamic leptin resistance, and inflammation.
Publisher: Physicians Postgraduate Press, Inc
Date: 16-02-2016
DOI: 10.4088/JCP.14M09629
Publisher: Public Library of Science (PLoS)
Date: 11-12-2013
Publisher: Oxford University Press (OUP)
Date: 07-02-2008
Publisher: Springer Science and Business Media LLC
Date: 22-06-2012
Abstract: Olanzapine is an atypical antipsychotic drug with high clinical efficacy, but which can cause severe weight gain and metabolic disorders in treated patients. Blockade of the histamine 1 (H 1 ) receptors is believed to play a crucial role in olanzapine induced weight gain, whereas the therapeutic effects of this drug are mainly attributed to its favourable serotoninergic 2A and dopamine 2 (5HT 2A /D 2 ) receptor binding affinity ratios. We have synthesized novel olanzapine analogues 8a and 8b together with the already known derivative 8c and we have examined their respective in vitro affinities for the 5HT 2A , D 2 , and H 1 receptors. We suggest that thienobenzodiazepines 8b and 8c with lower binding affinity for the H 1 receptors, but similar 5HT 2A /D 2 receptor binding affinity ratios to those of olanzapine. These compounds may offer a better pharmacological profile than olanzapine for treating patients with schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 16-12-2016
DOI: 10.1007/S12020-016-1197-X
Abstract: The estrogen levels in the pre and post menstrual phases interact with brain-derived neurotrophic factor in a complex manner, which influences the overall state of the body. To study the role of oestradiol and brain-derived neurotrophic factor in modulating obesity related type 2 diabetes and the interactions between two factors, we enrolled 15 diabetic premenopausal women and 15 diabetic postmenopausal women respectively, the same number of healthy pre and postmenopausal women were recruited as two control groups. The fasting blood glucose, insulin, lipids, estrogen, and brain-derived neurotrophic factor levels were measured through clinical tests. Additionally, we set up obese female mouse model to mimic human trial stated above, to verify the relationship between estrogen and brain-derived neurotrophic factor. Our findings revealed that there is a moderately positive correlation between brain-derived neurotrophic factor and oestradiol in females, and decreased brain-derived neurotrophic factor may worsen impaired insulin function. The results further confirmed that high fat diet-fed mice which exhibited impaired glucose tolerance, showed lower levels of oestradiol and decreased expression of brain-derived neurotrophic factor mRNA in the ventromedial hypothalamus. The level of brain-derived neurotrophic factor reduced on condition that the level of oestradiol is sufficiently low, such as women in postmenopausal period, which aggravates diabetes through feeding-related pathways. Increasing the level of brain-derived neurotrophic factor may help to alleviate the progression of the disease in postmenopausal women with diabetes.
Publisher: Hindawi Limited
Date: 2011
DOI: 10.1155/2011/258051
Abstract: High-fat diet (HFD) induces obesity. This study examined the effects of Shiitake mushroom on the prevention of alterations of plasma lipid profiles, fat deposition, energy efficiency, and body fat index induced by HFD. Rats were given a low, medium, and high (7, 20, 60 g/kg = LD-M, MD-M, HD-M) Shiitake mushroom powder in their high-fat (50% in kcal) diets for 6 weeks. The results showed that the rats on the HD-M diet had the lowest body weight gain compared to MD-M and LD-M groups ( P 0.05 ). The total fat deposition was significantly lower (−35%, P 0.05 ) in rats fed an HD-M diet than that of HFD group. Interestingly, plasma triacylglycerol (TAG) level was significantly lower (−55%, P 0.05 ) in rats on HD-M than HFD. This study also revealed the existence of negative correlations between the amount of Shiitake mushroom supplementation and body weight gain, plasma TAG, and total fat masses.
Publisher: Frontiers Media SA
Date: 19-11-2020
DOI: 10.3389/FPSYT.2020.537280
Abstract: Objective: The present study aimed to examine whether insulin resistance and oxidative stress are associated with cognitive impairment in first-episode drug-free schizophrenia (SZ) patients. Methods: Ninety first-episode SZ patients and 70 healthy controls were enrolled. Fasting insulin (FINS) and markers of oxidative stress [oxidized glutathione (GSSG), superoxide dismutase (SOD), nitric oxide (NO) and uric acid (UA) levels] were measured in serum before pharmacological treatment was initiated. Psychiatric symptoms and cognitive function were assessed with the Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB), respectively. In addition, the homeostatic model assessment of insulin resistance (HOMA-IR) was also studied. Results: HOMA-IR and serum levels of GSSG and NO were significantly higher in SZ patients than in healthy controls ( P & 0.001), while the serum levels of SOD were significantly lower than in healthy controls ( P & 0.001). HOMA-IR, GSSG and NO levels were significantly correlated to the total cognitive function scores of the patient group ( r = −0.345,−0.369,−0.444, respectively, P & 0.05). But these factors were not co-related to the cognitive functions in the healthy control group. And, levels of SOD, UA were not associated with the total cognitive function scores in both the patient and the healthy control groups. NO was positively correlated with general pathological and the total score in the PANSS, and was negatively correlated with six cognitive domains ( r = −0.316 to −0.553, P & 0.05). Conclusions: The levels of insulin resistance and oxidative stress are elevated, and correlated with the severity of cognitive impairment in drug-naïve, first-episode SZ patients. Treatment approaches targeting on reducing insulin resistance and oxidative stress may improve cognitive function in SZ patients.
Publisher: Wiley
Date: 11-11-2018
DOI: 10.1111/CNS.12776
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.NEUROSCIENCE.2008.04.026
Abstract: Statins are increasingly being used for the treatment of a variety of conditions beyond their original indication for cholesterol lowering. We previously reported that simvastatin affected the dopaminergic system in the rat brain. This study aims to investigate regional changes of muscarinic M1/4 receptors in the rat brain after 4-week administration of simvastatin (1 or 10 mg/kg/day). M1/4 receptor distribution and alterations in the post-mortem rat brain were detected by [(3)H]pirenzepine binding autoradiography. Simvastatin (1 mg/kg/day) increased [(3)H]pirenzepine binding, predominantly in the prefrontal cortex (171%, P<0.001), primary motor cortex (153%, P=0.001), cingulate cortex (109%, P<0.001), hippoc us (138%, P<0.001), caudate putamen (122%, P=0.002) and nucleus accumbens (170%, P<0.001) compared with controls while lower but still significant increases of [(3)H]pirenzepine binding were observed in the examined regions following simvastatin (10 mg/kg/day) treatment. Our results also provide strong evidence that chronic simvastatin administration, especially at a low dosage, up-regulates M1/4 receptor binding, which is likely to be independent of its muscarinic agonist-like effect. Alterations in [(3)H]pirenzepine binding in the examined brain areas may represent the specific regions that mediate the clinical effects of simvastatin treatment on cognition and memory via the muscarinic cholinergic system. These findings contribute to a better understanding of the critical roles of simvastatin in treating neurodegenerative disorders, via muscarinic receptors.
Publisher: Elsevier BV
Date: 19-07-2007
DOI: 10.1016/J.BBR.2007.03.028
Abstract: This experiment aimed to examine the role of the CB1 and Opioid mu receptors on fat preference by administering the CB1 inverse agonist AM 251 (5mg/kg i.p.) and the opioid mu antagonist beta-Funaltrexamine (15mg/kg s.c.) for 4 days to fat-preferring C57BL/6 mice fed a two-choice high-fat/low-fat diet. Both drugs were found to significantly reduce total energy intake, high-fat diet intake and fat preference during treatment.
Publisher: Wiley
Date: 2007
DOI: 10.1002/JNR.21247
Abstract: Phencyclidine (PCP) is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Several studies have demonstrated that chronic NMDA receptor antagonist treatment in humans and animals can cause long-term behavioral changes that are reminiscent of negative and cognitive schizophrenia-like symptoms. The muscarinic cholinergic system, which is associated with cognitive functions, has been hypothesized to contribute to PCP's mechanism of action. No study, however, has examined the status of M1/4 receptors in the PCP model of schizophrenia. The aim of the present study was to investigate the effects of chronic (14 day) PCP treatment on mouse brain M1/4 receptors in the short term (1 hr and 24 hr) and long term (14 days) after last PCP administration. [(3)H]pirenzepine was used to target M1/4 receptors. In the short term following chronic PCP treatment, M1/4 binding was significantly increased in regions of the limbic system, caudate-putamen, cortex, and thalamus (ranging from 56% to 368%), compared with saline-treated mice. There were no differences in binding between mice treated with PCP for 14 days and sacrificed 1 hr or 24 hr after the final PCP treatment. In the long term following chronic PCP treatment, M1/4 binding was significantly decreased in all of the above-mentioned brain regions (ranging from 31% to 72%), except in the thalamus, which showed no change. These findings in the long-term group are similar to those reported in post-mortem studies of patients suffering from schizophrenia.
Publisher: SAGE Publications
Date: 21-10-2014
Abstract: The metabolic side-effects of olanzapine have undermined drug compliance and increased concern for this otherwise-effective treatment for schizophrenia. As obesity and type 2 diabetes are associated with low-grade inflammation, and olanzapine-induced weight gain has three typical stages, the current study investigated the inflammatory effects of olanzapine in three treatment stages. Female Sprague-Dawley rats were treated orally with olanzapine (1 mg/kg three times daily) or vehicle for one week, two weeks, and five weeks. Olanzapine significantly increased body weight and white visceral fat deposition in all three treatment stages compared to control. Olanzapine enhanced average adipocyte size and level of macrophage infiltration in white adipose tissue (WAT) compared to control, with levels of macrophage infiltration increased over time. There was a high correlation between adipocyte size and macrophage infiltration rate. Olanzapine also caused increased macrophage infiltration in brown adipose tissue (BAT), but not liver. Additionally, pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin (IL)-1β, and IL-6 were upregulated by olanzapine in the hypothalamus, WAT, and BAT compared to control, but not the liver. Finally, plasma triglycerides were elevated by olanzapine compared to control, but not total cholesterol, high density lipoprotein (HDL) or low density lipoprotein (LDL). These findings indicate that olanzapine-induced inflammation and adiposity are closely related, and that peripheral low-grade inflammation develops during olanzapine treatment.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2014
DOI: 10.1038/TP.2013.121
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.BRAINRESBULL.2013.06.003
Abstract: High-fat (HF) diet and obesity are risk factors for a number of mental health problems including depression, cognitive dysfunction, dementia, and neurodegenerative diseases. Histamine H1 receptors (H1Rs) are involved in many of these conditions. This study examined H1R receptor binding density in the brain of male rats fed a high-saturated fat (HF) diet, as well as the effect of docosahexaenoic acid (DHA), galacto-oligosaccharide (GOS) and resistant starch (RS) supplementation of HF diet. Alterations of H1R expression in the post-mortem rat brain were detected by [(3)H]-pyrilamine binding autoradiography. We found that HF diet significantly decreased H1R binding densities in the substantia nigra (SN), caudate putamen (CPu), hypothalamic arcuate nucleus (Arc), ventral tegmental area (VTA), piriform cortex (Pir) and primary motor cortex (M1), compared with low-fat fed rats, and the suppression of receptor binding density ranged from 31% to 48%. Interestingly, supplementing the HF diet with 0.5% n-3 polyunsaturated docosahexaenoic acid (DHA) prevented reduction of H1R binding densities in the SN and CPu. Addition of galacto-oligosaccharide (GOS) and resistant starch (RS) to the diet blunted HF induced reduction of H1R ligand binding in the SN and Pir, respectively. In conclusion this study showed that HF diet can alter H1R binding densities in various brain regions, and many of these changes can be prevented by adding DHA, GOS or RS to the diet.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.PSYNEUEN.2014.01.018
Abstract: Although second-generation antipsychotics induce severe weight gain and obesity, there is a lack of detailed knowledge about the progressive development of antipsychotic-induced obesity. This study examined the hypothalamic histamine H1 receptor and AMP-activated protein kinase (H1R-AMPK) signaling at three distinctive stages of olanzapine-induced weight gain (day 1-12: early acceleration, day 13-28: middle new equilibrium, and day 29-36: late heavy weight maintenance). At the early acceleration stage, the rats were hyperphagic with an underlying mechanism of olanzapine-increased H1R mRNA expression and AMPK phosphorylation (pAMPK), in which pAMPK levels positively correlated with H1R mRNA expression and food intake. At the middle stage, when the rats were no longer hyperphagic, the changes in H1R-AMPK signaling vanished. At the late stage, olanzapine increased H1R mRNA expression but decreased pAMPK which were positively and negatively correlated with weight gain, respectively. These data suggest a time-dependent change of H1R-AMPK signaling, where olanzapine activates AMPK by blocking the H1Rs and causing hyperphagia in the acute phase. The chronic blockade of H1R may contribute to the late stage of olanzapine-induced heavy weight maintenance. However, pAMPK was no longer elevated and actually decreased. This indicates that AMPK acts as an energy sensor and negatively responds to the positive energy balance induced by olanzapine. Furthermore, we showed that an H1R agonist, 2-(3-trifluoromethylphenyl) histamine, can significantly inhibit olanzapine-induced hyperphagia and AMPK activation in the mediobasal hypothalamus in a dose dependent manner. Therefore, lowering H1R-AMPK signaling is an effective treatment for the olanzapine-induced hyperphagia associated with the development of obesity.
Publisher: Springer Science and Business Media LLC
Date: 06-2009
Publisher: Springer Science and Business Media LLC
Date: 17-04-2017
DOI: 10.1007/S00406-017-0802-1
Abstract: Brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB) signaling plays a key role in the brain neurodevelopment. The exposure of pregnant mice to polyinosinic-polycytidylic acid [poly(I:C)] causes cognitive deficits in adult offspring. Supplementation with a TrkB agonist, 7,8-dihydroxyflavone, in poly(I:C)-treated pregnant mice from pregnancy to weaning could prevent the onset of cognitive deficits and reduced BDNF-TrkB signaling in the prefrontal cortex of their adult offspring. These findings suggest that supplementation with a TrkB agonist in pregnant women with an ultra-high risk of psychosis may reduce the development of psychosis in their offspring.
Publisher: Elsevier BV
Date: 10-2169
DOI: 10.1016/S0306-4522(01)00533-4
Abstract: Abnormalities in the anterior cingulate cortex have been reported in patients with schizophrenia, and have been implicated in the pathophysiology of this disorder. In the present study, we have examined antipsychotic-sensitive binding sites in the left anterior cingulate cortex of schizophrenia patients and controls. Using quantitative autoradiography and [(3)H]spiperone as a ligand, both saturation and competition experiments were performed in post-mortem brain tissue obtained from six schizophrenia and six control cases. Saturation experiments revealed that the maximum number of [(3)H]spiperone binding sites was significantly reduced by 31% in the schizophrenia group as compared to the control group (65.3+/-5.6 fmol/mg tissue versus 94.2+/-7.3 fmol/mg tissue). Increased dissociation constant was also observed in the schizophrenia group (2.2+/-0.4 nM versus 1.3+/-0.2 nM), but was not statistically significant (P=0.07). Competition experiments were performed in order to examine the pharmacological profile of [(3)H]spiperone binding, and revealed that: (i) displacement of [(3)H]spiperone binding by clozapine and mianserin was significantly reduced in the schizophrenia group as compared to the control group (-26% and -16% respectively) (ii) the order of displacement potency of the drugs tested was: haloperidol>mianserin>butaclamol approximately risperidone>clozapine>2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene. Our results suggest a reduction of antipsychotic-sensitive binding sites in the anterior cingulate cortex of patients with schizophrenia. Such abnormality could lead to an imbalance in neurotransmitter regulation in the anterior cingulate cortex which may contribute to the emergence of some symptoms of schizophrenia.
Publisher: Elsevier BV
Date: 06-1999
DOI: 10.1016/S0361-9230(99)00049-0
Abstract: High-fat diet can induce obesity. However, it is not known if the neural activity of the hypothalamus is altered under high-fat diet. The aim of the present study is to search for the altered hypothalamic neuronal activity in C57BI/6J mice fed a high-fat diet for 15 weeks. Hypothalamic c-Fos-like immunoreactivity (FLI) and serum leptin were measured after mice were fed a high-fat diet for 15 weeks. Our results demonstrate that increased body weight and serum leptin are accompanied by an elevated neuronal c-Fos-like immunoreactivity in the lateral hypothalamus, the lateral part of the dorsomedial hypothalamic and perifornical nuclei of diet-induced obese mice. Fasting increases FLI neurons in the arcuate hypothalamic nucleus and decreases FLI neurons in the lateral hypothalamic area and dorsomedial hypothalamic nucleus of both diet-induced obese and lean mice. The current data suggest that constantly activated status of these neurons in the hypothalamus may be responsible for differences in body weight and serum leptin between obese and lean mice.
Publisher: Springer Science and Business Media LLC
Date: 08-09-2015
DOI: 10.1038/MP.2015.137
Abstract: The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a s le of 616 affected families and five independent replication s les totaling 4017 affected and 4704 unaffected in iduals (odds ratio=1.1 P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2014
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.JELEKIN.2005.10.007
Abstract: The aim of the present study was to determine how the intra-muscular segments of three shoulder muscles were coordinated to produce isometric force impulses around the shoulder joint and how muscle segment coordination was influenced by changes in movement direction, mechanical line of action and moment arm (ma). Twenty male subjects (mean age 22 years range 18-30 years) with no known history of shoulder pathologies, volunteered to participate in this experiment. Utilising an electromyographic technique, the timing and intensity of contraction within 19 muscle segments of three superficial shoulder muscles (Pectoralis Major, Deltoid and Latissimus Dorsi) were studied and compared during the production of rapid (e.g. approximately 400ms time to peak) isometric force impulses in four different movement directions of the shoulder joint (flexion, extension, abduction and adduction). The results of this investigation have suggested that the timing and intensity of each muscle segment's activation was coordinated across muscles and influenced by the muscle segment's moment arm and its mechanical line of action in relation to the intended direction of shoulder movement (e.g. flexion, extension, abduction or adduction). There was also evidence that motor unit task groups were formed for in idual motor tasks which comprise motor units from both adjacent and distant muscles. It was also confirmed that for any particular motor task, in idual muscle segments can be functionally classified as prime mover, synergist or antagonist - classifications which are flexible from one movement to the next.
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.NUTRES.2011.12.004
Abstract: The purpose of this study was to examine the hypothesis that serum levels of phospholipid (PL) fatty acids (FA) and minerals are associated with the components of metabolic syndrome (MetS) in the Chinese population and the profiles of changes may differ from patients with MetS from Western countries. The levels of serum PL, FA, and minerals were examined in 201 subjects (52 with MetS and 149 healthy controls without any MetS components) in China. The saturated FA proportion in serum was significantly higher, whereas the proportion of total polyunsaturated FA (PUFA), n-3 and n-6 PUFA (22:6n-3: -16%, P = .006 20:4n-6: -36%, P < .001), and estimated δ-5 desaturase were significantly lower in the MetS group compared with those that are not MetS. Subjects with MetS had higher levels of serum Zn (P = .037) and Mg (P < .001) than subjects without MetS. The proportion of n-3 PUFA was significantly negatively correlated with body mass index and waist circumference. In conclusion, serum PL FA composition and serum minerals in Chinese men with MetS differed significantly from that of healthy in iduals, reflecting a decrease in n-3 and n-6 PUFA, especially 22:6n-3 and 20:4n-6, and an increase in saturated FA, magnesium, and zinc. These changes may reflect improper dietary intake in subjects with MetS, and dietary modification could be useful to prevent MetS and as an adjunctive therapy.
Publisher: Springer Science and Business Media LLC
Date: 09-03-2016
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/549352
Abstract: Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of bardoxolone methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α ), and uncoupling protein 2 (UCP2) proteins. Overall, BARD induces preventive effect in HFD mice through regulation of mesenteric adipose tissue.
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.PNPBP.2012.07.010
Abstract: Schizophrenic patients have cognitive impairments, but gender differences in these cognitive deficits have had limited study. This study assessed cognitive functioning in 471 subjects including 122 male and 78 female schizophrenic patients and 141 male and 130 female healthy controls. We found that immediate memory, language, delayed memory and total RBANS scores were significantly decreased in schizophrenia compared with healthy controls for both genders. Male patients had significant lower immediate memory, delayed memory and total RBANS scores than female patients, and healthy controls showed a similar gender difference. The RBANS showed modest correlations with PANSS scores, duration of illness and antipsychotic dose (chlorpromazine equivalents). Almost all RBANS scores in the schizophrenics and healthy controls showed significant positive correlations with education. Thus, patients of both sexes with schizophrenia experienced more deteriorated performance than healthy controls on cognitive domains of immediate memory, language and delayed memory. Furthermore, male schizophrenic patients had more serious cognitive deficits than female patients in immediate and delayed memory, but not in language, visuospatial and attention indices.
Publisher: Springer Science and Business Media LLC
Date: 22-09-2017
DOI: 10.1038/S41598-017-12156-2
Abstract: A high-fat (HF) diet alters gut microbiota and promotes obesity related inflammation and cognitive impairment. Teasaponin is the major active component of tea, and has been associated with anti-inflammatory effects and improved microbiota composition. However, the potential protective effects of teasaponin, against HF diet-induced obesity and its associated alteration of gut microbiota, inflammation and cognitive decline have not been studied. In this study, obesity was induced in C57BL/6 J male mice by feeding a HF diet for 8 weeks, followed by treatment with oral teasaponin (0.5%) mixed in HF diet for a further 6 weeks. Teasaponin treatment prevented the HF diet-induced recognition memory impairment and improved neuroinflammation, gliosis and brain-derived neurotrophic factor (BDNF) deficits in the hippoc us. Furthermore, teasaponin attenuated the HF diet-induced endotoxemia, pro-inflammatory macrophage accumulation in the colon and gut microbiota alterations. Teasaponin also improved glucose tolerance and reduced body weight gain in HF diet-induced obese mice. The behavioral and neurochemical improvements suggest that teasaponin could limit unfavorable gut microbiota alterations and cognitive decline in HF diet-induced obesity.
Publisher: American Physiological Society
Date: 06-2002
DOI: 10.1152/AJPENDO.00230.2001
Abstract: Some, but not all, fats are obesogenic. The aim of the present studies was to investigate the effects of changing type and amount of dietary fats on energy balance, fat deposition, leptin, and leptin-related neural peptides: leptin receptor, neuropeptide Y (NPY), agouti-related peptide (AgRP), and proopiomelanocortin (POMC), in C57Bl/6J mice. One week of feeding with a highly saturated fat diet resulted in ∼50 and 20% reduction in hypothalamic arcuate NPY and AgRP mRNA levels, respectively, compared with a low-fat or an n-3 or n-6 polyunsaturated high-fat (PUFA) diet without change in energy intake, fat mass, plasma leptin levels, and leptin receptor or POMC mRNA. Similar neuropeptide results were seen at 7 wk, but by then epididymal fat mass and plasma leptin levels were significantly elevated in the saturated fat group compared with low-fat controls. In contrast, fat and leptin levels were reduced in the n-3 PUFA group compared with all other groups. At 7 wk, changing the saturated fat group to n-3 PUFA for 4 wk completely reversed the hyperleptinemia and increased adiposity and neuropeptide changes induced by saturated fat. Changing to a low-fat diet was much less effective. In summary, a highly saturated fat diet induces obesity without hyperphagia. A regulatory reduction in NPY and AgRP mRNA levels is unable to effectively counteract this obesogenic drive. Equally high fat diets emphasizing PUFAs may even protect against obesity.
Publisher: Elsevier BV
Date: 02-2010
Publisher: Springer Science and Business Media LLC
Date: 11-08-2017
DOI: 10.1038/S41598-017-08204-6
Abstract: Methylglyoxal (MG) accumulation has been observed in human cerebrospinal fluid and body tissues under hyperglycaemic conditions. Recent research has demonstrated that MG-induces neuronal cell apoptosis, which promotes the development of diabetic encephalopathy. Our previous animal study has shown that luteolin, a natural flavonoid, attenuates diabetes-associated cognitive dysfunction. To further explore the neuroprotective properties of luteolin, we investigated the inhibitive effect of luteolin on MG-induced apoptosis in PC12 neuronal cells. We found that MG inhibited cell viability in a dose-dependent manner and induced apoptosis in PC12 cells. Pretreatment with Luteolin significantly elevated cell viability, reduced MG-induced apoptosis, inhibited the activation of the mTOR/4E-BP1 signaling pathway, and decreased pro-apoptotic proteins, Bax, Cytochrome C as well as caspase-3. Furthermore, we found that pretreatment with the mTOR inhibitor, rapamycin, significantly reduced the expression of the pro-apoptotic protein Bax. Therefore, these observations unambiguously suggest that the inhibitive effect of Luteolin against MG-induced apoptosis in PC12 cells is associated with inhibition of the mTOR/4E-BP1 signaling pathway.
Publisher: Elsevier BV
Date: 09-2006
DOI: 10.1016/J.PNPBP.2006.05.008
Abstract: The amygdala has a role in the modulation of moods and emotion, processes that are known to be affected in people with psychiatric disorders such as schizophrenia and depression. The tachykinin NK(1) receptor is known to be expressed in the amygdala. However to date, there is limited knowledge of the distribution of the NK(1) receptor in this region. This study used immunohistochemistry to analyse the distribution of the NK(1) receptor in fixed human amygdala tissue in control subjects with no history of psychiatric illness and matched subjects with a diagnosis of schizophrenia (n=4 pairs). The NK(1) receptor was observed sparsely distributed in cell bodies in all amygdaloid nuclei with the basolateral and lateral having a greater relative density of NK(1) receptor-immunoreactive cell bodies than the other nuclei. Double labelling with antibodies to microtubule associated protein and the NK(1) receptor revealed that the NK(1) receptor is expressed by large pyramidal, small stellate and large bipolar neurons. Interestingly, the basal nucleus of Meynert, which is just dorsal to the amygdala, was observed to have a significantly higher relative density of NK(1) receptor-immunoreactive cell bodies compared to any of the amygdaloid nuclei. Preliminary analysis of the density of NK(1) receptor-immunoreactive cell bodies in the major amygdaloid nuclei and the basal nucleus of Meynert revealed no significant differences between schizophrenia and control subjects. Real-time PCR showed that the mRNA for both the short and long isoforms of the NK(1) receptor was expressed at low levels in fresh frozen human amygdala tissue from control subjects and that this was not different in matched subjects with schizophrenia (n=11 pairs). In conclusion, this study has demonstrated that the NK(1) receptor is widely distributed in the amygdala, and has shown for the first time a high relative density of NK(1) receptor-immunoreactive cell bodies in the basal nucleus of Meynert.
Publisher: Public Library of Science (PLoS)
Date: 22-06-2011
Publisher: Springer Science and Business Media LLC
Date: 21-09-2012
DOI: 10.1007/S00213-011-2492-0
Abstract: Developmental vitamin D (DVD) deficiency is a candidate risk factor for developing schizophrenia in humans. In rodents DVD deficiency induces subtle changes in the way the brain develops. This early developmental insult leads to select behavioural changes in the adult, such as an enhanced response to hetamine-induced locomotion in female DVD-deficient rats but not in male DVD-deficient rats and an enhanced locomotor response to the N-methyl-D: -aspartate (NMDA) receptor antagonist, MK-801, in male DVD-deficient rats. However, the response to MK-801-induced locomotion in female DVD-deficient rats is unknown. Therefore, the aim of the current study was to further examine this behavioural finding in male and female rats and assess NMDA receptor density. DVD-deficient Sprague Dawley rats were assessed for locomotion, ataxia, acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR to multiple doses of MK-801. The NMDA receptor density in relevant brain regions was assessed in a drug-naive cohort. DVD deficiency increased locomotion in response to MK-801 in both sexes. DVD-deficient rats also showed an enhanced ASR compared with control rats, but PPI was normal. Moreover, DVD deficiency decreased NMDA receptor density in the caudate putamen of both sexes. These results suggest that a transient prenatal vitamin D deficiency has a long-lasting effect on NMDA-mediated signalling in the rodent brain and may be a plausible candidate risk factor for schizophrenia and other neuropsychiatric disorders.
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.PNPBP.2005.04.034
Abstract: This review addresses the relationship between modifications in membrane phospholipid composition (MPC) and alterations in dopaminergic, serotonergic and cholinergic neurotransmitter systems in schizophrenia. The main evidence in support of the MPC hypothesis of schizophrenia comes from post-mortem and platelet studies, which show that in schizophrenia, certain omega-3 and omega-6 polyunsaturated fatty acid (PUFA) levels are reduced. Furthermore, examination of several biochemical markers suggests abnormal fatty acid metabolism may be present in schizophrenia. Dietary manipulation of MPC with polyunsaturated fatty acid diets has been shown to affect densities of dopamine, serotonin and muscarinic receptors in rats. Also, supplementation with omega-3 fatty acids has been shown to improve mental health rating scores, and there is evidence that the mechanism behind this involves the serotonin receptor complex. This suggests that a tight relationship exists between essential fatty acid status and normal neurotransmission, and that altered PUFA levels may contribute to the abnormalities in neurotransmission seen in schizophrenia.
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.PNPBP.2010.07.025
Abstract: Statins have been widely used for the treatment of a variety of medical conditions including psychoneurological disorders beyond their original use in lowering cholesterol. Histamine receptors play an important role in the regulation of neural activity, however, it is unknown whether statins act on histamine receptors, particularly for their neural regulatory effects. This study examined the effects of simvastatin and 6-hydroxydopamine (6-OHDA) lesions on histamine H1 receptors using [(3)H] pyrilamine binding autoradiography. Compared to the saline group, simvastatin (1 mg/kg/day) significantly decreased H1 receptor bindings in the primary motor cortex (M1), ventromedial hypothalamic nucleus (VMH), caudate putamen (CPu), accumbens core (AcbC) and prefrontal cortex (PfC) (all p<0.05) however 10 mg/kg/day simvastatin increased H1 receptor density only in the medial amygdaloid nucleus (Mep) (p<0.05), but had no significant effect in other regions examined. The 6-OHDA lesion did not alter H1 receptor binding density in most brain areas, except a trend decrease in the hippoc us (p=0.07) and a trend increase in the cingulate cortex (p=0.06). These results suggested that simvastatin has different effects on the H1 receptors in different rat brain regions depending on the doses. Therefore, simvastatin can modulate histaminergic neurotransmission in the brain, and support the role of H1 receptors in psychoneurological disorders.
Publisher: Elsevier BV
Date: 05-2007
DOI: 10.1016/J.PNPBP.2007.02.009
Abstract: In this study, we investigated the effects of antipsychotic drugs, olanzapine and haloperidol, on the density of the muscarinic M2 receptors in the dorsal vagal complex (DVC) and hypoglossal nucleus (HN). Female Sprague Dawley rats were treated with olanzapine, haloperidol or vehicle (control) for 1 (short-term) or 12 weeks (long-term). Quantitative autoradiography was used to investigate the M2 receptor density in the DVC and HN using a muscarinic antagonist [(3)H] AF-DX384. Olanzapine, but not haloperidol, treatment induced a significant decrease in the binding density of M2 receptors in the DVC compared to control groups. Although the HN showed a higher density of [(3)H] AF-DX384 binding than the DVC, treatment with both olanzapine and haloperidol did not induce any significant changes in [(3)H] AF-DX384 binding in the HN. These results suggest that olanzapine-induced body weight gain may be associated with functional changes in the muscarinic neurotransmission in the DVC.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2016
DOI: 10.1038/SREP30040
Abstract: Aripiprazole is a D 2 -like receptor (D 2 R) partial agonist with a favourable clinical profile. Previous investigations indicated that acute and short-term administration of aripiprazole had effects on PKA activity, GSK3β-dependent pathways, GABA A receptors, NMDA receptor and CREB1 in the brain. Since antipsychotics are used chronically in clinics, the present study investigated the long-term effects of chronic oral aripiprazole treatment on these cellular signalling pathways, in comparison with haloperidol (a D 2 R antagonist) and bifeprunox (a potent D 2 R partial agonist). We found that the Akt-GSK3β pathway was activated by aripiprazole and bifeprunox in the prefrontal cortex NMDA NR2A levels were reduced by aripiprazole and haloperidol. In the nucleus accumbens, all three drugs increased Akt-GSK3β signalling in addition, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3, β-catenin and GABA A receptors, NMDA receptor subunits, as well as CREB1 phosphorylation levels. The results suggest that chronic oral administration of aripiprazole affects schizophrenia-related cellular signalling pathways and markers (including Akt-GSK3β signalling, Dvl-GSK3β-β-catenin signalling, GABA A receptor, NMDA receptor and CREB1) in a brain-region-dependent manner the selective effects of aripiprazole on these signalling pathways might be associated with its unique clinical effects.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.CBI.2015.11.018
Abstract: Obesity caused by the consumption of a high-fat (HF) diet is a major risk factor for the development of associated complications, such as heart and kidney failure. A semi-synthetic triterpenoid, bardoxolone methyl (BM) was administrated to mice fed a HF diet for 21 weeks to determine if it would prevent the development of obesity-associated cardiac and renal pathophysiologies. Twelve week old male C57BL/6J mice were fed a lab chow (LC), HF (40% fat), or a HF diet supplemented with 10 mg/kg/day BM in drinking water. After 21 weeks, the left ventricles of hearts and cortex of kidneys of mice were collected for analysis. Histological analysis revealed that BM prevented HF diet-induced development of structural changes in the heart and kidneys. BM prevented HF diet-induced decreases in myocyte number in cardiac tissue, although this treatment also elevated cardiac endothelin signalling molecules. In the kidneys, BM administration prevented HF diet-induced renal corpuscle hypertrophy and attenuated endothelin signalling. Furthermore, in both the hearts and kidneys of mice fed a HF diet, BM administration prevented HF diet-induced increases in fat accumulation, macrophage infiltration and tumour necrosis factor alpha (TNFα) gene expression. These findings suggest that BM prevents HF diet-induced developments of cardiac and renal pathophysiologies in mice fed a chronic HF diet by preventing inflammation. Moreover, these results suggest that BM has the potential as a therapeutic for preventing obesity-induced cardiac and renal pathophysiologies.
Publisher: Wiley
Date: 22-05-2018
DOI: 10.1002/MED.21512
Abstract: Although antipsychotic drugs are mainly used for treating schizophrenia, they are widely used for treating various psychiatric diseases in adults, the elderly, adolescents and even children. Today, about 1.2% of the worldwide population suffers from psychosis and related disorders, which translates to about 7.5 million subjects potentially targeted by antipsychotic drugs. Neurites project from the cell body of neurons and connect neurons to each other to form neural networks. Deficits in neurite outgrowth and integrity are implicated in psychiatric diseases including schizophrenia. Neurite deficits contribute to altered brain development, neural networking and connectivity as well as symptoms including psychosis and altered cognitive function. This review revealed that (1) antipsychotic drugs could have profound effects on neurites, synaptic spines and synapse, by which they may influence and regulate neural networking and plasticity (2) antipsychotic drugs target not only neurotransmitter receptors but also intracellular signaling molecules regulating the signaling pathways responsible for neurite outgrowth and maintenance (3) high doses and chronic administration of antipsychotic drugs may cause some loss of neurites, synaptic spines, or synapsis in the cortical structures. In addition, confounding effects causing neurite deficits may include elevated inflammatory cytokines and antipsychotic drug-induced metabolic side effects in patients on chronic antipsychotic therapy. Unraveling how antipsychotic drugs affect neurites and neural connectivity is essential for improving therapeutic outcomes and preventing aversive effects for patients on antipsychotic drug treatment.
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.SCHRES.2013.01.018
Abstract: Metabotropic glutamate receptor 5 (mGluR5) has been identified as a potential therapeutic target for schizophrenia, primarily due to its ability to indirectly modulate glutamatergic signalling through the NMDA receptor (NMDAR). Despite its potential, molecular studies characterising mGluR5 in schizophrenia are limited. We therefore aimed to determine if the mGluR5 binding site or protein levels were altered in schizophrenia or by current antipsychotics. Using in-situ radioligand binding and immunoblot, we measured [(3)H]MPEP binding to mGluR5 and mGluR5 protein density in the post-mortem dorsolateral prefrontal cortex (DLPFC BA46) of 37 schizophrenia and 37 matched control subjects. Subsequently, we measured [(3)H]MPEP binding in rat brains following typical (haloperidol) or atypical (olanzapine) antipsychotic treatment (n = 6/group). Subjects with schizophrenia showed no significant alteration in mGluR5 binding density or mGluR5 protein levels. Furthermore, mGluR5 binding in the rat cortex, thalamus, hippoc us and striatum was unaltered by short-, medium- and long-term antipsychotic treatment. Our data suggests that there are no alterations in mGluR5 in schizophrenia subjects. The lack of alteration in mGluR5 binding and protein in schizophrenia is advantageous because its ability to modulate the NMDAR is potentially unhindered, thereby supporting the development of novel antipsychotic agents that work through the mGluR5/NMDAR complex.
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.PNPBP.2013.08.005
Abstract: Olanzapine is widely used in treating multiple domains of schizophrenia symptoms but induces serious metabolic side-effects. Recent evidence has showed that co-treatment of betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for preventing olanzapine-induced weight gain/obesity, however it is not clear whether this co-treatment affects on the primary therapeutic receptor binding sites of olanzapine such as serotonergic 5-HT2A receptors (5-HT2AR) and dopaminergic D2 receptors (D2R). Therefore, this study investigated the effects of this co-treatment on 5-HT2AR, 5-HT transporter (5-HTT) and D2R bindings in various brain regions involved in antipsychotic efficacy. Female Sprague Dawley rats were administered orally (t.i.d.) with either olanzapine (1mg/kg), betahistine (2.7 mg/kg), olanzapine plus betahistine (O+B), or vehicle (control) for 2 weeks. Quantitative autoradiography was used to detect the density of [(3)H]ketanserin, [(3)H]paroxetine and [(3)H]raclopride binding site to 5-HT2AR, 5-HTT and D2R. Compared to the controls, olanzapine significantly decreased [(3)H]ketanserin bindings to 5-HT2AR in the prefrontal cortex, cingulate cortex, and nucleus accumbens. Similar changes in 5-HT2AR bindings in these nuclei were also observed in the O+B co-treatment group. Olanzapine also significantly decreased [(3)H]paroxetine binding to 5-HTT in the ventral tegmental area and substantia nigra, however, both olanzapine only and O+B co-treatment did not affect [(3)H]raclopride binding to D2R. The results confirmed the important role of 5-HT2AR in the efficacy of olanzapine, which is not influenced by the O+B co-treatment. Therefore, betahistine co-treatment would be an effective combination therapy to reduce olanzapine-induced weight gain side-effects without affecting olanzapine's actions on 5-HT2AR transmissions.
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.PNPBP.2008.10.001
Abstract: Perinatal phencyclidine (PCP) treatment has been used to model brain pathological processes that may be present in schizophrenia such as increased apoptosis during early brain development, and long-term alterations in expression of parvalbumin-containing interneurons and glutamatergic N-methyl-D-aspartate (NMDA) receptors. We report that this treatment also affects receptor expression of another excitatory neurotransmitter receptor, the muscarinic receptor. Female rat pups received injections of the NMDA receptor antagonist PCP (10 mg/kg, s.c.) or saline on postnatal days (PN)7, 9 and 11. [3H]Pirenzepine binding to M1/4 receptors was examined at four time-points (PN12, 18, 32 and 96) following treatment cessation. Significant effects of treatment on [3H]pirenzepine binding were evident immediately after treatment cessation with a decrease in PCP-treated rats at PN12 in the prefrontal cortex (-24%, p<0.05) and hippoc us (-19%, p<0.05). After this initial decrease, binding subsequently increased to 47% above control levels in the prefrontal cortex of adolescent animals, which remained elevated in adulthood (+10%, p<0.05), while in the hippoc us there was a trend towards increased binding in adolescent animals and no change thereafter. This work adds to findings demonstrating that perinatal PCP exposure leads to long-term imbalance of excitatory and inhibitory neurotransmitter systems, supporting its relevance as a developmental model of schizophrenia pathology. Alterations in muscarinic receptor expression may contribute specifically to the cognitive impairments reported to occur after perinatal NMDA receptor antagonist treatment.
Publisher: Wiley
Date: 29-04-2015
Abstract: Oxidative stress is involved in chronic stress-induced depression and the disruption of neurotransmission and neuroplasticity. Recently, orientin, a phenolic compound abundant in some fruits, millet, and herbs, has been shown to have antioxidant properties. This study investigated the potential antidepressant effects of orientin against chronic stress and its underlying mechanisms. The chronic unpredictable mild stress (CUMS) model was used to investigate the effects of orientin on behavior and biochemical alterations in mice. After 2 weeks of the CUMS protocol, the mice were treated with orientin (20 mg/kg and 40 mg/kg, oral gavage) for 3 weeks. Administration of orientin significantly alleviated the CUMS-induced depression-like behavior, including sucrose preference reduction, locomotor activity decline, and hypomotility. Orientin treatment attenuated the oxidative stress markers and increased the concentrations of serotonin and norepinephrine in the hippoc us and prefrontal cortex of CUMS mice. Orientin treatment also increased the brain-derived neurotrophic factor and synapse-associated proteins (synaptophysin and postsynaptic density protein 95) of CUMS mice. Orientin exerts antidepressant-like effects on CUMS mice, specifically by improving central oxidative stress, neurotransmission, and neuroplasticity. Therefore, supplementation with orientin-enriched food or fruit could be beneficial as a preventive strategy for chronic stress-induced depression.
Publisher: Cambridge University Press (CUP)
Date: 24-11-2010
DOI: 10.1017/S0007114509992856
Abstract: Epidemiological evidence shows an inverse relationship between dietary fibre intake and body weight gain. Oat β-glucan, a soluble fibre alters appetite hormones and subjective satiety in acute meal test studies, but its effects have not been demonstrated with chronic consumption. The present study aimed to test the effects in women of two different doses of oat β-glucan on weight loss and hormones associated with appetite regulation. In a 3-month parallel trial, sixty-six overweight females were randomised into one of three 2 MJ energy-deficit diets: a control and two interventions including 5–6 g or 8–9 g β-glucan. Anthropometric and metabolic variables (blood glucose level, insulin, total cholesterol (TC), LDL, HDL, TAG and leptin), together with markers of appetite regulation (cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), ghrelin, peptide YY (PYY) and PYY 3-36 ) were measured at baseline and at 3 months. After 3 months, all groups lost weight ( P 0·001) and showed a reduced waist circumference ( P 0·001). The study s le also showed reductions in TC, LDL, HDL, leptin, PYY, GLP-1 values (all P 0·001) and an increase in CCK levels ( P 0·001). No significant differences were noted between the groups for all outcome values except PYY levels ( P = 0·018). In broad terms, the addition of oat β-glucan did not enhance the effect of energy restriction on weight loss in mildly overweight women, although wide variations in observed results suggests that in idual responsiveness may be an issue.
Publisher: Elsevier BV
Date: 07-2000
DOI: 10.1016/S0361-9230(00)00228-8
Abstract: Some C57Bl/6 mice become obese, whereas others remain lean when raised on a high-fat diet. The mechanisms underlying this interin idual susceptibility to diet-induced obesity remain unknown. Because hypothalamus plays a major role in the regulation of body weight, this study was conducted to identify the differences of hypothalamic neuronal activity between diet-induced obese and diet-resistant mice. Using c-fos as a marker, this study showed that diet-induced obese mice significantly increased c-fos-like immunoreactive neurons in the dorsal part of lateral hypothalamus (+183%) and dorsomedial hypothalamic nucleus (+87.5%) compared with diet-resistant mice. Furthermore, switching from high fat to low fat, or high n-3 polyunsaturated fatty acid diet, significantly decreased body weight gain (-35.7% and -31.0%), overall fat storage (-63.4% and -59.6%), and c-fos-like immunoreactive neurons in the dorsal part of lateral hypothalamus (-76.5% and -64.7%) and dorsomedial hypothalamic nucleus (-73.3% and -56.7%) in diet-induced obese mice, respectively. The present study also showed that the ratio of serum leptin/fat mass was threefold higher in the diet-resistant mice than in the diet-induced obese mice, which may be responsible for the less fat storage in the diet-resistant mice. The current data further confirm that the increased neuronal activity in the key autonomic regulatory centers may contribute to the excessive fat storage in diet-induced obese mice. Moreover, both high-fat diet-induced excessive fat storage and the altered hypothalamic neuronal activity may be largely corrected by reducing dietary fat content or replacing it with non-obesogenic fat.
Publisher: Springer Science and Business Media LLC
Date: 02-2007
DOI: 10.1007/S11064-006-9266-9
Abstract: Quantitative in vitro autoradiography was used to examine changes in muscarinic M1/M4 and M2/M4 receptors (targeted with [3H]pirenzepine and [3H]AF-DX384 respectively), in rats treated with the typical (haloperidol) and atypical (clozapine and olanzapine) antipsychotic medications for a period of 36 days. Rats were sacrificed at either 2 h or 48 h after the last drug administration to examine immediate effects as well as the effects at 48 h after drug withdrawal. Haloperidol significantly increased [3H]pirenzepine binding in the dentate gyrus (37%) and in the CA1 region of the hippoc us (34%) in animals sacrificed 2 h after the last drug administration compared to controls. Similarly, clozapine significantly increased [3H]pirenzepine binding in dentate gyrus (29%) in rats sacrificed 2 h after the last drug administration compared to controls. Haloperidol decreased [3H]AF-DX384 binding in the basolateral nucleus of the amygdala (20%) in the rats sacrificed 48 h after the last drug administration compared to controls. These findings suggest that muscarinic receptors and limbic brain regions such as hippoc us and amygdala might represent common targets that mediate beneficial clinical effects of antipsychotic drugs.
Publisher: Public Library of Science (PLoS)
Date: 27-03-2014
Publisher: Springer Science and Business Media LLC
Date: 28-03-2016
Publisher: Springer Science and Business Media LLC
Date: 05-11-2020
DOI: 10.1038/S41598-020-75356-3
Abstract: Olanzapine is a second-generation antipsychotic (AP) drug commonly prescribed for the treatment of schizophrenia. Recently, olanzapine has been found to cause brain tissue volume loss in rodent and primate studies however, the underlying mechanism remains unknown. Abnormal autophagy and oxidative stress have been implicated to have a role in AP-induced neurodegeneration, while N -acetylcysteine (NAC) is a potent antioxidant, shown to be beneficial in the treatment of schizophrenia. Here, we investigate the role of olanzapine and NAC on cell viability, oxidative stress, mitochondrial mass and mitophagy in hypothalamic cells. Firstly, cell viability was assessed in mHypoA-59 and mHypoA NPY/GFP cells using an MTS assay and flow cytometric analyses. Olanzapine treated mHypoA-59 cells were then assessed for mitophagy markers and oxidative stress including quantification of lysosomes, autophagosomes, LC3B-II, p62, superoxide anion (O 2 – ) and mitochondrial mass. NAC (10 mM) was used to reverse the effects of olanzapine (100 µM) on O 2 − , mitochondrial mass and LC3B-II. We found that olanzapine significantly impacted cell viability in mHypoA-59 hypothalamic cells in a dose and time-dependent manner. Olanzapine inhibited mitophagy, instigated oxidative stress and prompted mitochondrial abnormalities. NAC was able to mitigate olanzapine-induced effects. These findings suggest that high doses of olanzapine may cause neurotoxicity of hypothalamic neurons via increased production of reactive oxygen species (ROS), mitochondrial damage and mitophagy inhibition. This could in part explain data suggesting that APs may reduce brain volume.
Publisher: Wiley
Date: 29-07-2000
DOI: 10.1111/J.1463-1326.2005.00506.X
Abstract: This study aims to establish a model that will allow the comparison of the phenotypic variations between a fat-preferring strain and a macronutrient non-preferring strain of mouse. Five strains (AKR, A/J, ARC, C57Bl/6 and BALB/c) were fed a two-choice diet (high-fat/low-carbohydrate and low-fat/high-carbohydrate) for 30 days. Following completion of the 30-day feeding period, the brains of the fat-preferring and macronutrient non-preferring mice were removed for the analysis of the expression of the genes - agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC). Upon completion of the experiment, it was found that the C57Bl/6 strain was the strongest fat preferrer consuming 72% of their calories from the high-fat diet, whereas the BALB/c was found to have no macronutrient preference. Using in situ hybridization techniques, no significant differences in the expression of POMC were found between the two strains. It was, however, showed that the BALB/c mice had a 33.7% higher expression level of AgRP than the C57Bl/6 mice. The lower expression level of AgRP in the C57Bl/6 mice may be suggestive of a defensive response to their chronic preferential consumption of the high-fat diet. However, the wide variety of neuroregulatory signals involved in macronutrient preference along with the possibility of the occurrence of post-transcriptional effects suggests further biological analyses need to be performed using this model.
Publisher: Springer Science and Business Media LLC
Date: 03-05-2013
DOI: 10.1007/S40263-013-0062-1
Abstract: Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA-induced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK-carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity.
Publisher: Springer Science and Business Media LLC
Date: 21-02-2023
DOI: 10.1186/S40168-023-01471-8
Abstract: Gut homeostasis, including intestinal immunity and microbiome, is essential for cognitive function via the gut-brain axis. This axis is altered in high-fat diet (HFD)-induced cognitive impairment and is closely associated with neurodegenerative diseases. Dimethyl itaconate (DI) is an itaconate derivative and has recently attracted extensive interest due to its anti-inflammatory effect. This study investigated whether intraperitoneal administration of DI improves the gut-brain axis and prevents cognitive deficits in HF diet-fed mice. DI effectively attenuated HFD-induced cognitive decline in behavioral tests of object location, novel object recognition, and nesting building, concurrent with the improvement of hippoc al RNA transcription profiles of genes associated with cognition and synaptic plasticity. In agreement, DI reduced the damage of synaptic ultrastructure and deficit of proteins (BDNF, SYN, and PSD95), the microglial activation, and neuroinflammation in the HFD-fed mice. In the colon, DI significantly lowered macrophage infiltration and the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in mice on the HF diet, while upregulating the expression of immune homeostasis-related cytokines (IL-22, IL-23) and antimicrobial peptide Reg3γ. Moreover, DI alleviated HFD-induced gut barrier impairments, including elevation of colonic mucus thickness and expression of tight junction proteins (zonula occludens-1, occludin). Notably, HFD-induced microbiome alteration was improved by DI supplementation, characterized by the increase of propionate- and butyrate-producing bacteria. Correspondingly, DI increased the levels of propionate and butyrate in the serum of HFD mice. Intriguingly, fecal microbiome transplantation from DI-treated HF mice facilitated cognitive variables compared with HF mice, including higher cognitive indexes in behavior tests and optimization of hippoc al synaptic ultrastructure. These results highlight the gut microbiota is necessary for the effects of DI in improving cognitive impairment. The present study provides the first evidence that DI improves cognition and brain function with significant beneficial effects via the gut-brain axis, suggesting that DI may serve as a novel drug for treating obesity-associated neurodegenerative diseases.
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/184845
Abstract: Endocrine disrupting chemicals (EDCs) are chemicals that have the capacity to interfere with normal endocrine systems. Two EDCs, bisphenol A (BPA) and triclosan (TCS), are mass-produced and widespread. They both have estrogenic properties and similar chemical structures and pharmacokinetic features and have been detected in human fluids and tissues. Clinical evidence has suggested a positive association between BPA exposure and implantation failure in IVF patients. Studies in mouse models have suggested that preimplantation exposure to BPA and TCS can lead to implantation failure. This paper reviews the relationship between preimplantation exposure to BPA and TCS and implantation failure and discusses the remaining problems and possible solutions.
Publisher: The Endocrine Society
Date: 10-2007
DOI: 10.1210/EN.2007-0107
Abstract: It is well known that the peripheral peptide YY (PYY)-central neuropeptide Y (NPY) Y2 receptor axis plays an important role in promoting negative energy balance regulation. Both the hypothalamus and medulla oblongata express a high level of Y2 receptors however, the functional role of this receptor in chronic high-fat diet-induced obesity has not been fully examined. Using quantitative autoradiography, this study measured binding densities of total [(125)I]PYY and Y2 receptors in the hypothalamus and medulla of chronic high-fat diet-induced obese (DIO), obese-resistant, and low-fat-fed mice. Plasma PYY was also measured using RIA after 22 wk of dietary intervention. The results revealed that body weight gain was significantly higher in the obese mice, compared with the lean mice. Furthermore, PYY and NPY Y2 receptor binding densities in the medulla of the obese mice were significantly higher, compared with the lean mice, whereas the level of plasma PYY was significantly lower in the DIO mice than the low-fat-fed mice. In conclusion, this study showed that the DIO mice had low plasma PYY, which may have caused a compensatory up-regulation of PYY and Y2 receptor densities in the medulla. A low-level response of PYY-medullary regulation to positive energy balance may have contributed to the development of high-fat diet-induced obesity in DIO mice conversely, a normal response of this regulatory axis in the obese-resistant mice may have contributed to the maintenance of body weight while on a high-fat diet.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.SCHRES.2011.01.008
Abstract: Metabotropic glutamate receptors 2 and 3 (mGluR2/3) have been shown as efficient targets for antipsychotic intervention. We therefore investigated the receptor density of mGluR2/3 in the dorsolateral prefrontal cortex (dlPFC Brodman area 46) of schizophrenia/schizoaffective patients (n=37) and matched controls (n=37) using receptor autoradiography. No difference in mGluR2/3 density was identified in relation to schizophrenia diagnosis. Overall and in in idual groups, a negative correlation of mGluR2/3 density and age at death has been found. These and previous results suggest that density of mGluR2/3 in the dlPFC is less likely to impact on the efficiency of the mGluR2/3 agonist in treating schizophrenia symptoms.
Publisher: Elsevier BV
Date: 10-2019
Publisher: Elsevier BV
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 20-06-2013
Publisher: Springer Science and Business Media LLC
Date: 23-02-2017
DOI: 10.1038/NPP.2017.40
Publisher: Wiley
Date: 2005
DOI: 10.1002/JNR.20600
Abstract: Recent studies have indicated that muscarinic receptors are involved in the pathophysiology in schizophrenia, particularly in cognitive deficits. The superior temporal gyrus (STG) is an area that has also been strongly implicated in the pathophysiology of schizophrenia. Therefore, in this study, we investigated the binding density of two muscarinic antagonists, [(3)H]pirenzepine and [(3)H]AF-DX 384, in the STG of schizophrenia patients compared with controls. A significant decrease (44% in the superficial layers and 48% in the deep layers, P<0.01) in binding density of [(3)H]pirenzepine was observed in schizophrenia patients, which suggested a reduction of muscarinic M1 and M4 receptor densities in the STG of schizophrenia patients. A tendency toward decreased [(3)H]AF-DX 384 binding density (34%, P=0.09) was also observed in schizophrenia patients compared with controls. Because of the positive correlation between [(3)H]pirenzepine and [(3)H]AF-DX 384 binding, and, insofar as both ligands have high affinities for the M4 receptor, the involvement of M4 receptor alteration is also suggested in the STG in schizophrenia. These results suggest that changes of the muscarinic receptors M1 and M4 might contribute to the STG pathology in schizophrenia.
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.AJP.2012.05.005
Abstract: Weight gain as a result of atypical anti-psychotic treatment is a common issue with different atypical anti-psychotic treatments causing differing magnitudes of weight gain. Although differing amounts of weight gain result from different atypical agents little is known about the temporal course of weight gain in anti-psychotic treatment. Specifically is the time course of weight gain comparable across different agents. Therefore this article reviews the temporal course of weight gain for three common atypical anti-psychotics namely clozapine, olanzapine and risperidone. It is evident that all three of these agents exhibit similar although at distinct magnitudes temporal courses of weight gain. That is an initial rapid increase from baseline to 3 months (stage 1), a steady increase from 3 months to 18 months (stage 2) and a plateau after this point (stage 3) with continued anti-psychotic treatment. It is postulated that each of these stages of weight gain result from distinct neural mechanisms. The hypothesized neural correlates for each stage of weight gain are reviewed and discussed. The article concludes with recommendations for future research.
Publisher: Elsevier BV
Date: 08-2004
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.JNUTBIO.2016.07.008
Abstract: High-fat (HF) diet modulates gut microbiota and increases plasma concentration of lipopolysaccharide (LPS) which is associated with obesity and its related low-grade inflammation and cognitive decline. Rhein is the main ingredient of the rhubarb plant which has been used as an anti-inflammatory agent for several millennia. However, the potential effects of rhein against HF diet-induced obesity and its associated alteration of gut microbiota, inflammation and cognitive decline have not been studied. In this study, C57BL/6J male mice were fed an HF diet for 8 weeks to induce obesity, and then treated with oral rhein (120 mg/kg body weight/day in HF diet) for a further 6 weeks. Chronic rhein treatment prevented the HF diet-induced recognition memory impairment assessed by the novel object recognition test, neuroinflammation and brain-derived neurotrophic factor (BDNF) deficits in the perirhinal cortex. Furthermore, rhein inhibited the HF diet-induced increased plasma LPS level and the proinflammatory macrophage accumulation in the colon and alteration of microbiota, including decreasing Bacteroides-Prevotella spp. and Desulfovibrios spp. DNA and increasing Bifidobacterium spp. and Lactobacillus spp. DNA. Moreover, rhein also reduced body weight and improved glucose tolerance in HF diet-induced obese mice. In conclusion, rhein improved recognition memory and prevented obesity in mice on a chronic HF diet. These beneficial effects occur via the modulation of microbiota, hypoendotoxinemia, inhibition of macrophage accumulation, anti-neuroinflammation and the improvement of BDNF expression. Therefore, supplementation with rhein-enriched food or herbal medicine could be beneficial as a preventive strategy for chronic HF diet-induced cognitive decline, microbiota alteration and neuroinflammation.
Publisher: Wiley
Date: 2008
DOI: 10.1002/JNR.21491
Abstract: Alterations in muscarinic M1 receptor protein and mRNA expression have been revealed in post-mortem brains of schizophrenia patients. Most patients had been treated with antipsychotics, so medication effects cannot be excluded as a possible explanation for these results. With in situ hybridization, this study investigated M1 receptor mRNA expression in rats treated with the typical antipsychotic haloperidol (0.3 mg/kg/day) and the atypical antipsychotics olanzapine (1.5 mg/kg/day) and aripiprazole (2.25 mg/kg/day) for 1 or 12 weeks. Compared with the control group, haloperidol significantly increased (approximately 13-21%, P < 0.05) M1 mRNA expression in the CA1, CA2, and CA3 regions of the hippoc us after both 1 and 12 weeks of treatment, and it also increased (approximately 17%, P < 0.01) M1 mRNA expression in the substantia nigra compacta after 1 week of treatment. Olanzapine significantly increased (14-22%, P < 0.05) M1 mRNA expression in the hippoc us (CA1, CA2, and CA3) and substantia nigra compacta after 12 weeks of treatment, but not after 1 week. Aripiprazole significantly increased (17%, P < 0.01) M1 mRNA expression in the hippoc us (CA1) after both 1 and 12 week treatments and increased (12%, P < 0.05) M1 mRNA expression in the nucleus accumbens after 1 week of treatment. Despite their different affinities for muscarinic M1 receptors, all three antipsychotic medications induced a similar trend of change in M1 mRNA expression in selected brain regions. These data suggest that the decreased M1 receptor protein and mRNA expression observed in schizophrenia patients is unlikely to be a consequence of drug treatments and implicates muscarinic M1 receptors in the pharmacotherapy of the disease.
Publisher: Oxford University Press (OUP)
Date: 02-2013
DOI: 10.1017/S1461145711001854
Abstract: Heavy cannabis abuse increases the risk of developing schizophrenia. Adolescents appear particularly vulnerable to the development of psychosis-like symptoms after cannabis use. To test whether the schizophrenia candidate gene neuregulin 1 (NRG1) modulates the effects of cannabinoids in adolescence, we tested male adolescent heterozygous transmembrane domain Nrg1 mutant (Nrg1 TM HET) mice and wild type-like littermates (WT) for their neurobehavioural response to repeated Δ9-tetrahydrocannabinol (THC, 10 mg/kg i.p. for 21 d starting on post-natal day 31). During treatment and 48 h after treatment withdrawal, we assessed several behavioural parameters relevant to schizophrenia. After behavioural testing we measured autoradiographic CB1, 5-HT2A and NMDA receptor binding. The hyperlocomotor phenotype typical of Nrg1 mutants emerged after drug withdrawal and was more pronounced in vehicle than THC-treated Nrg1 TM HET mice. All mice were equally sensitive to THC-induced suppression of locomotion. However, mutant mice appeared protected against inhibiting effects of repeated THC on investigative social behaviours. Neither THC nor Nrg1 genotype altered prepulse inhibition. Repeated adolescent THC promoted differential effects on CB1 and 5-HT2A receptor binding in the substantia nigra and insular cortex respectively, decreasing binding in WT while increasing it in Nrg1 TM HET mice. THC also selectively affected 5-HT2A receptor binding in several other regions in WT mice, whereas NMDA receptor binding was only affected in mutant mice. Overall, Nrg1 mutation does not appear to increase the induction of psychotomimetic symptoms by repeated adolescent THC exposure but may attenuate some of its actions on social behaviour and schizophrenia-relevant neurotransmitter receptor profiles.
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.JNUTBIO.2012.11.002
Abstract: Low levels of docosahexaenoic acid (DHA) have been linked to a number of mental illnesses such as memory loss, depression and schizophrenia. While supplementation of DHA is beneficial in improving memory and cognition, the influence of dietary fats on the neurotransmitters and receptors involved in cognitive function is still not known. The aim of this study was to investigate serotonin receptor (5-HT(1A) and 5-HT2A), cannabinoid receptor (CB1) and gamma-aminobutyric acid type A (GABA(A)) receptor binding densities in the brain of male rats fed a high-saturated-fat (HF) diet, as well as the effect of DHA supplementation on HF diet. Alterations of these receptors in the post-mortem rat brain were detected by [(3)H]-WAY-100635, [(3)H]-ketanserin, [(3)H]-CP-55,940 and [(3)H]-muscimol binding autoradiography, respectively. In the hippoc us, the 5-HT(1A), CB1 and GABA(A) receptor binding densities significantly increased in response to an HF diet, while in the hypothalamus, 5-HT(1A) and CB1 binding densities significantly increased in HF-fed rats. Importantly, DHA supplementation prevented the HF-induced increase of receptors binding density in the hippoc us and hypothalamus. Furthermore, DHA supplementation attenuated 5-HT2A receptor binding density in the caudate putamen, anterior cingulate cortex and medial mammillary nucleus, which was also increased in HF group. This study showed that an HF diet increased 5-HT(1A), 5-HT2A, CB1 and GABA(A) receptor binding densities in the brain regions involved in cognitive function and that dietary DHA can attenuate such alterations. These findings provide insight into the mechanism by which DHA supplementation ameliorates reduced cognitive function associated with an HF diet.
Publisher: Springer Science and Business Media LLC
Date: 04-03-2020
DOI: 10.1186/S12974-020-01760-1
Abstract: Western pattern diets induce neuroinflammation and impair cognitive behavior in humans and animals. Neuroinflammation and cognitive impairment have been associated with microbiota dysbiosis, through the gut-brain axis. Furthermore, microbiota-accessible carbohydrates (MACs) found in dietary fiber are important in shaping the microbial ecosystem and have the potential to improve the gut-brain-axis. However, the effects of MACs on neuroinflammation and cognition in an obese condition have not yet been investigated. The present study aimed to evaluate the effect of MACs on the microbiota-gut-brain axis and cognitive function in obese mice induced by a high-fat and fiber deficient (HF-FD) diet. C57Bl/6 J male mice were fed with either a control HF-FD or a HF-MAC diet for 15 weeks. Moreover, an additional group was fed with the HF-MAC diet in combination with an antibiotic cocktail (HF-MAC + AB). Following the 15-week treatment, cognitive behavior was investigated blood, cecum content, colon, and brain s les were collected to determine metabolic parameters, endotoxin, gut microbiota, colon, and brain pathology. We report MACs supplementation prevented HF-FD-induced cognitive impairment in nesting building and temporal order memory tests. MACs prevented gut microbiota dysbiosis, including increasing richness, α- ersity and composition shift, especially in Bacteroidetes and its lower taxa. Furthermore, MACs increased colonic mucus thickness, tight junction protein expression, reduced endotoxemia, and decreased colonic and systemic inflammation. In the hippoc us, MACs suppressed HF-FD-induced neuroglia activation and inflammation, improved insulin IRS-pAKT-pGSK3β-pTau synapse signaling, in addition to the synaptic ultrastructure and associated proteins. Furthermore, MACs’ effects on improving colon–cognitive parameters were eliminated by wide spectrum antibiotic microbiota ablation. These results suggest that MACs improve cognitive impairments via the gut microbiota-brain axis induced by the consumption of an HF-FD. Supplemental MACs to combat obesity-related gut and brain dysfunction offer a promising approach to prevent neurodegenerative diseases associated with Westernized dietary patterns and obesity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2015
Publisher: Elsevier BV
Date: 03-2004
DOI: 10.1016/J.PNPBP.2003.11.005
Abstract: Previous studies suggest that long-term cannabis use causes cognitive impairment, including lack of motivation and impaired attention, conditions that also resemble core negative symptoms of schizophrenia. The anterior cingulate cortex (ACC) plays an important role in normal cognition, particularly in relation to motivation and attention. This could suggest that changes in the cannabinoid (CB) system might be present in the ACC of patients suffering schizophrenia. The present study examined the distribution and density of CB1 cannabinoid receptors in the left ACC taken postmortem from patients with schizophrenia (n=10) and matched control subjects (n=9). Radioligand binding of [3H]SR141716A, an antagonist that specifically targets CB1 receptors of the endogenous cannabinoid system, was examined on ACC sections using quantitative autoradiography. CB1 receptors had a homogeneous distribution among the layers of ACC. A significant 64% increase in [3H]SR141716A specific binding to CB1 receptors was found in the schizophrenia group as compared to the control group (mean+/-S.E.M.: 46.15+/-6.22 versus 28.02+/-4.20 fmol/mg estimated tissue equivalents p=0.03). The present results support the suggestion that changes in the endogenous cannabinoid system in the ACC may be involved in the pathology of schizophrenia particularly in relation to negative symptoms.
Publisher: Elsevier BV
Date: 04-1995
Publisher: Springer Science and Business Media LLC
Date: 03-11-2009
Publisher: Wiley
Date: 04-05-2009
DOI: 10.1002/JCB.22187
Publisher: MDPI AG
Date: 18-04-2017
DOI: 10.3390/S17040884
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.BBR.2010.10.039
Abstract: Second generation antipsychotics are commonly prescribed for the treatment of schizophrenia, however some can induce metabolic dysfunction side-effects such as weight gain, obesity and diabetes. Clinical reports suggest olanzapine alters satiety signals, although findings appear conflicting. Previous animal model studies have utilised a range of olanzapine dosages, however the dosage that better mimics the human scenario of olanzapine-induced weight gain is unclear. Female Sprague-Dawley rats were treated orally, three times daily with olanzapine (0.25mg/kg, 0.5mg/kg, 1.0mg/kg, 2.0mg/kg), self-administered in a sweet cookie dough pellet at eight-hourly intervals) or vehicle (n=12/group) for 14-days. Olanzapine orally self-administered in multiple doses (eight-hourly intervals) may circumvent a drop in plasma drug concentration and ensure the maintenance of a consistently high olanzapine level in the rat. Olanzapine increased body weight (0.5mg/kg, 1.0mg/kg, 2.0mg/kg), food intake (2.0mg/kg) and feeding efficiency (0.5-2.0mg/kg), with no effect on water intake. Subcutaneous inguinal (1.0mg/kg, 2.0mg/kg) and intra-abdominal perirenal fat were increased (2.0mg/kg), but not interscapula brown adipose tissue. Olanzapine increased circulating ghrelin and cholecystokinin, but had no effect on peptide YY((3-36)). Olanzapine decreased insulin (0.25-2.0mg/kg) and locomotor activity in the open field arena (0.5-2.0mg/kg). A low dosage of 0.25mg/kg olanzapine had no effect on most parameters measured. Olanzapine-induced weight gain is associated with hyperphagia, enhanced feeding efficiency and adiposity, decreased locomotor activity and altered satiety signaling. The animal model used in the present study of self-administered oral olanzapine treatment (t.i.d.) at a dosage range of 0.5-2.0mg/kg (but not 0.25mg/kg) mimics aspects of the clinic.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2016
DOI: 10.1038/SREP19581
Abstract: Accumulating evidence suggests that reducing neurite outgrowth and synaptic plasticity plays a critical role in the pathology of cognitive deficits in schizophrenia. The N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) can induce symptoms of schizophrenia as well as reduce dendritic spine density and neurite growth. The antipsychotic drug olanzapine may improve these deficits. This study aimed to investigate: (1) if olanzapine prevents PCP-induced suppression of neurite outgrowth and synaptic protein expression (2) if olanzapine affects the Akt-GSK3 signaling pathway and (3) the role of neuregulin 1 (NRG1) in this process. Immunofluorescence revealed that PCP treatment for 24 hours reduces both neurite length (28.5%) and the number of neurite branches (35.6%) in primary prefrontal cortical neuron cultures. PCP reduced protein and mRNA expressions of synaptophysin (24.9% and 23.2%, respectively) and PSD95 (31.5% and 21.4%, respectively) and the protein expression of p-Akt (26.7%) and p-GSK3β (35.2%). Olanzapine co-treatment prevented these PCP-induced effects in normal neurons but not in neurons from NRG1-knockout mice. These results indicate that NRG1 mediates the preventive effects of olanzapine on the PCP-induced impairment of neurite outgrowth and synaptic protein expression. This study provides potential targets for interventions on improving the efficacy of olanzapine on preventing cognitive deficits in schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 16-12-2006
DOI: 10.1007/S00221-005-0290-9
Abstract: The superior temporal gyrus (STG) is strongly implicated in the pathophysiology of schizophrenia, particularly with regards to auditory hallucinations. In a previous study we reported a decrease in the density of M1 and M2/M4 muscarinic receptors in the STG in schizophrenia. In this study, we investigated the density of GABA(A) receptors in the left STG of schizophrenia patients compared to control subjects. We used quantitative autoradiography to investigate the binding of the agonist [(3)H] muscimol to GABA(A )receptors in the STG. A significantly higher density of [(3)H] muscimol binding was observed in the upper three quarters of the STG grey matter (corresponding to layers I-IV) than in the lower one-quarter (layers V-VI) in both groups. A significant increase (about 30%, P<0.05) in binding of [(3)H] muscimol was clearly observed in schizophrenia patients compared to control subjects. There were no significant correlations between [(3)H] muscimol binding density and age, post-mortem interval, brain pH or final recorded antipsychotic drug use. These results suggest an increase of GABA(A) receptor densities in the STG of schizophrenia patients.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.BBI.2019.07.018
Abstract: Cognitive impairment is a major source of disability in schizophrenia and current antipsychotic drugs (APDs) have minimal efficacy for this symptom domain. Cannabidiol (CBD), the major non-intoxicating component of Cannabis sativa L., exhibits antipsychotic and neuroprotective properties. We recently reported the effects of CBD on cognition in male offspring of a maternal immune activation (polyinosinic-polycytidilic acid (poly I:C)) model relevant to the aetiology of schizophrenia however, the effects of CBD treatment in females are unknown. Sex differences are observed in the onset of schizophrenia symptoms and response to APD treatment. Furthermore, the endogenous cannabinoid system, a direct target of CBD, is sexually dimorphic in humans and rodents. Therefore, the present work aimed to assess the therapeutic impact of CBD treatment on behaviour and neurochemical signalling markers in female poly I:C offspring. Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg i.v.) or saline (control) on gestational day 15. From postnatal day 56, female offspring received CBD (10 mg/kg, i.p.) or vehicle treatment for approximately 3 weeks. Following 2 weeks of CBD treatment, offspring underwent behavioural testing, including the novel object recognition, rewarded alternation T-maze and social interaction tests to assess recognition memory, working memory and sociability, respectively. After 3 weeks of CBD treatment, the prefrontal cortex (PFC) and hippoc us (HPC) were collected to assess effects on endocannabinoid, glutamatergic and gamma-aminobutyric acid (GABA) signalling markers. CBD attenuated poly I:C-induced deficits in recognition memory, social interaction and glutamatergic N-methyl-d-aspartate receptor (NMDAR) binding in the PFC of poly I:C offspring. Working memory performance was similar between treatment groups. CBD also increased glutamate decarboxylase 67, the rate-limiting enzyme that converts glutamate to GABA, and parvalbumin protein levels in the HPC. In contrast to the CBD treatment effects observed in poly I:C offspring, CBD administration to control rats reduced social interaction, cannabinoid CB1 receptor and NMDAR binding density in the PFC, suggesting that CBD administration to healthy rats may have negative consequences on social behaviour and brain maturation in adulthood. Overall, the findings of this study support the therapeutic benefits of CBD on recognition memory and sociability in female poly I:C offspring, and provide insight into the neurochemical changes that may underlie the therapeutic benefits of CBD in the poly I:C model.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.NEUROSCIENCE.2009.09.041
Abstract: Increasing evidence suggests that 5-HT1A receptors are involved in the pathophysiology and treatment of schizophrenia. This paper investigated 5-HT1A receptor mRNA expression and binding density in female rats treated with aripiprazole (2.25 mg/kg/day), olanzapine (1.5 mg/kg/day), haloperidol (0.3 mg/kg/day) or vehicle (control) orally three times/day for 1 or 12 weeks. Animals were sacrificed 48 h after the last administration. Aripiprazole significantly increased 5-HT1A receptor binding density by 33% in the CA1 region of the hippoc us and by 21% in the medial posterodorsal nuclei of posterior amygdala (MeP) compared to the control group after 1 week of treatment. Olanzapine significantly decreased 5-HT1A receptor binding density by 17-22% in Layers I-IV of the cingulate cortex after 1 week of treatment. Neither of these antipsychotic drugs affected 5-HT1A receptor binding density after 12 weeks drug treatment. As expected, haloperidol treatment did not have any significant effect on 5-HT1A binding density after 1 or 12 weeks of treatment. 5-HT1A receptor mRNA expression was not altered by antipsychotic treatment in any brain region. The results indicate that aripiprazole and olanzapine have differential effects on 5-HT1A receptor expression, which may contribute to their distinct profiles in improving negative symptoms and cognitive deficits in schizophrenia. Aripiprazole and olanzapine may produce adaptation and desensitization of 5-HT1A receptor expression after long term treatment.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.SCHRES.2015.05.001
Abstract: Metabotropic glutamate receptor 5 (mGluR5) is involved in hippoc al-dependent learning and memory, which are processes disrupted in schizophrenia. Recent evidence from human genetic and animal studies suggests that the regulation of mGluR5, including its interaction with trafficking molecules, may be altered in the disorder. However there have been no investigations of hippoc al mGluR5 or mGluR5 trafficking molecules in the postmortem schizophrenia brain to confirm this. In the present study, we investigated whether protein expression of mGluR5, as well as Norbin and Tamalin (modulators of mGluR5 signalling and trafficking), might be altered in the schizophrenia brain, using postmortem s les from the hippoc al CA1 region of schizophrenia subjects and matched controls (n=20/group). Protein levels of mGluR5 (total: 42%, p<0.001 monomer: 25%, p=0.011 dimer: 52%, p<0.001) and mGluR5 trafficking molecules (Norbin: 47%, p<0.001 Tamalin: 34%, p=0.009) were significantly higher in schizophrenia subjects compared to controls. To determine any influence of antipsychotic drug treatment, all proteins were also correlated with lifetime chlorpromazine equivalents in patients, and separately measured in the hippoc us of rats exposed to haloperidol or olanzapine treatment. mGluR5 was negatively correlated with lifetime antipsychotic drug exposure in schizophrenia patients, suggesting antipsychotic drugs could reduce mGluR5 protein in schizophrenia subjects. In contrast, mGluR5 and mGluR5 trafficking molecules were not altered in the hippoc us of antipsychotic drug treated rats. This investigation provides strong support for the hypothesis that mGluR5 is involved in the pathology of schizophrenia, and that alterations to mGluR5 trafficking might contribute to the hippoc al-dependent cognitive dysfunctions associated with this disorder.
Publisher: Springer Science and Business Media LLC
Date: 11-2002
Publisher: Elsevier BV
Date: 05-2005
DOI: 10.1016/J.BRAINRESBULL.2005.02.007
Abstract: We have previously shown a decrease in [(3)H]pirenzepine binding to M1/M4 muscarinic receptors in the anterior cingulate cortex in schizophrenia but not in major depression or bipolar disorder. The present study aimed to extend these findings by examining the binding of [(3)H]AF-DX 384 to M2/M4 receptors in the same cohort of subjects. Using quantitative autoradiography we measured [(3)H]AF-DX 384 binding in the anterior cingulate cortex of 15 schizophrenia, 15 bipolar, 15 major depression and 15 control cases. Post-mortem tissue was obtained from the Stanley Foundation Brain Bank. [(3)H]AF-DX 384 binding had a homogenous distribution amongst the layers of the anterior cingulate cortex, was higher in males than in females and declined with prolonged storage of tissue. An inverse correlation between [(3)H]AF-DX384 binding and age of onset of the disease was observed in the schizophrenia group suggesting that the earlier the age at onset the higher the binding was. In the depression group, there was a significant effect of gender on [(3)H]AF-DX 384 binding with females having lower binding in comparison to males. In the bipolar group, there was a significant inverse correlation between antipsychotic medication and [(3)H]AF-DX 384 binding, suggesting that the higher the dose of medication the lower the binding was. No differences in [(3)H]AF-DX 384 binding were seen between the four groups. The present results provide no evidence of M2/M4 receptor alterations in the anterior cingulate cortex in schizophrenia and affective disorders and extend the body of evidence implicating cortical M1 but not M2 involvement in the pathology and pharmacotherapy of schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2009
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.PNPBP.2018.12.007
Abstract: Dopamine D2 receptor (D2R) hyperactivity causes altered brain development and later produces onset of symptoms mimicking schizophrenia. It is known that D2R interacts with disrupted in schizophrenia 1 (DISC1) however, the effect of D2R-DISC1 interaction in intracellular signalling and neurite growth has not been studied. This study investigated the effect of D2R over-activation on Akt-GSK3β signalling and neurite morphology in cortical neurons. Over-activation of D2Rs caused neurite lesions, which were associated with decreased protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3β) phosphorylation in cortical neurons. The antipsychotic drug aripiprazole was more effective in the prevention of neurite lesions than haloperidol. Unlike haloperidol, aripiprazole prevented downregulation of phospho (p) Akt-pGSK3β induced by D2R hyperactivity, indicating involvement of different pathways. D2Rs were hyperactive in cortical neurons of mice with DISC1 mutation, which caused more severe neurite lesions in cortical neurons treated with quinpirole. Immunofluorescent staining for Ca
Publisher: Wiley
Date: 15-12-2002
DOI: 10.1111/J.1463-1326.2004.00312.X
Abstract: Dietary fatty acid profile, independent of caloric percent of fat, is a major regulator of body adiposity. This study examined the effects of dietary fat amount and types on fat storage and hypothalamic gene expression in the mouse model of chronic diet-induced obesity. The dietary interventions were in twofold: (1) the obesity was induced by a 13-week obesogenic fat diet compared with a low-fat (LF) diet, and (2) the reversibility was tested by using high n-3 polyunsaturated fat (PUFA) and LF diets. Fifty-four C57Bl/6 mice were fed a high-fat (59% in kcal) diet for 13 weeks and then classified as diet-induced obese (DIO) or diet-resistant (DR) mice according to upper and lower tertiles of body weight gain. The DIO mice were then sub ided into three groups for a 6-week secondary dietary intervention. Two of the groups were switched to either a high n-3 PUFA (DIO-n3) or a low-fat (10% in kcal, DIO-LF) diet, whereas the third (controls) and DR mice continued on the initial high-fat diet. Food efficiency was calculated as weekly body weight gain per gram of food intake. After switching the DIO mice to the n-3 PUFA or LF diet, their body weights were reduced to the level of the DR and LF mice. The food efficiencies were, from the highest to lowest, in the order: DIO>LF>DR>DIO-LF>DIO-n3. Using quantitative in situ hybridization, we found that the DIO mice had higher levels of leptin receptor (LR, +290%, p<0.005) and neuropeptide Y (NPY, +25%, p<0.05) mRNA expression in the hypothalamic arcuate nucleus (Arc) than the DR mice, whereas the level of pro-opiomelanocortin (POMC) mRNA expression was significantly reduced (-45%, p<0.01). All effects that were essentially returned to DR levels by the change to the n-3 PUFA diet and, with the exception of a failure to normalize Arc NPY mRNA levels, by the change to LF diet. Taken together, the present results show that both change in level and quality of dietary fat can potently alter hypothalamic neuropeptide expression and result in effective amelioration of diet-induced obesity. Interestingly, the n-3 PUFA diet when fed to already obese mice produced a pattern of hypothalamic gene expression similar to that in obesity resistant (DR) mice. It remains to be determined if the effects of n-3 fatty acids on brain neuropeptide gene expression are direct or indirect.
Publisher: Informa UK Limited
Date: 25-01-2016
DOI: 10.3109/13880209.2015.1093510
Abstract: Oxidative stress and inflammation are implicated in the aging process and its related hepatic and renal function decline. Chlorogenic acid (CGA) is one of the most abundant polyphenol compounds in the human diet. Recently, CGA has shown in vivo and in vitro antioxidant properties. The current study investigates the effects of protective effects of chlorogenic acid (CGA) on D-galactose-induced liver and kidney injury. Hepatic and renal injuries were induced in a mouse model by subcutaneously injection of D-galactose (D-gal 100 mg/kg) once a day for 8 consecutive weeks and orally administered simultaneously with CGA included in the food (200 mg/kg of diet). The liver and renal functions were examined. Histological analyses of liver and kidney were done by haematoxylin and eosin staining. The oxidative stress markers and pro-inflammatory cytokines in the liver and the kidney were measured. Results CGA significantly reduced the serum aminotransferase, serum creatinine (SCr) and blood urea nitrogen (BUN) levels in D-gal mice (p <0.05). CGA also restored superoxide dismutase, catalase, and malondialdehyde levels and decreased glutathione content in the liver and kidney in D-gal mice (p <0.05). Improvements in liver and kidney were also noted in histopathological studies. CGA reduced tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) protein levels in the liver and kidney in D-gal mice (p <0.05). These findings suggest that CGA attenuates D-gal-induced chronic liver and kidney injury and that this protection may be due to its antioxidative and anti-inflammatory activities.
Publisher: Public Library of Science (PLoS)
Date: 03-04-2012
Publisher: Elsevier BV
Date: 11-2009
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.SCHRES.2014.12.037
Abstract: Immune deregulation has been postulated to be one of the mechanisms underlying the pathogenesis of tar e dyskinesia (TD). We hypothesized that interleukins would have a link with TD in schizophrenia patients. In this study, the serum IL-2, IL-6 and IL-8 levels were examined by enzyme-linked immunosorbent assay (ELISA) in schizophrenia patients with TD (n=48) and without TD (n=45), and healthy controls (n=44). The psychopathological symptoms of schizophrenia were assessed by the Positive and Negative Syndrome Scale (PANSS). The severity of TD was evaluated using Abnormal Involuntary Movement Scale (AIMS). The results showed that serum IL-2, IL-6 and IL-8 levels were significantly different among schizophrenia patients with TD and without TD and normal controls. Moreover, IL-2 level was significantly correlated with PANSS positive subscale and general subscale in patients with TD and without TD. In addition, IL-2 level was positively correlated with AIMS score in TD patients. The results supported that immune disturbance is related to the schizophrenia patients, especially to the patients with TD and ILs might play an important role in the pathophysiology of schizophrenia patients with TD.
Publisher: Springer Science and Business Media LLC
Date: 08-02-2008
DOI: 10.1007/S11064-007-9571-Y
Abstract: This study examined how perinatal phencyclidine (PCP) treatment would affect dopamine D2 receptor and dopamine transporter (DAT) binding at different stages after treatment cessation. Female rat pups received injections of PCP (10 mg/kg, s.c.) or saline on postnatal day (PN)7, 9 and 11. D2 receptor and transporter binding was examined at four time-points (PN12, 18, 32 and 96) following injections. PCP treatment altered D2 receptor binding throughout development, with a final end-point of 22-33% decreased binding at adulthood in the nucleus accumbens and caudate putamen (P < 0.01), accompanied by a small but significant increase in DAT binding in the caudate putamen. Tyrosine hydroxylase mRNA expression was also significantly increased by 25% (P < 0.05) in the ventral tegmental area of adult rats, suggesting that this model may produce a long-term increase in dopamine output. This study demonstrates that early insult to the brain from NMDA receptor hypofunction alters the dopaminergic system at different stages of development.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.JNUTBIO.2018.08.016
Abstract: Obesity is underpinned by both genetic and environmental factors, including a high-saturated-fat diet. Some mice develop diet-induced obesity (DIO), but others remain diet resistant (DR) despite intake of the same high-saturated-fat diet, a phenomenon that mimics characteristics of the human obese phenotype. Microbiota-colon-brain axis regulation is important for energy metabolism and cognition. Using DIO and DR mouse models, this study aimed to examine gut microbiota, colonic inflammation and cognitive function to elucidate the role of microbiota-gut-brain regulation in DIO. C57Bl6/J mice fed a chronic saturated-palmitic-acid diet for 22 weeks showed significant body weight gain differences, with the top one third gaining 48% heavier body weight than the lower one third. There was significant reduction in gut microbiota richness and ersity in DIO mice but not in DR mice. At the phylum level, DIO mice had increased abundance of Firmicutes and Antinobacteria, and decreased abundance of Bacterioides and Proteobacteria in gut microbiota. DIO mice exhibited reduced tight junction proteins, increased plasma endotoxin lipopolysaccharide (LPS) and increased inflammation in the colon and liver. Recognition memory and spatial memory were impaired in DIO mice, associated with decreased Bacteroidetes. Further examination showed that hippoc al brain-derived neurotrophic factor was significantly decreased in DIO mice (vs. DR). Conversely, DR mice showed no changes in the above parameters measured. Therefore, gut microbiota, colon inflammation and circulating LPS may play a major role in the development of the obese phenotype and cognitive decline associated with a chronic high-saturated-palmitic-acid diet.
Publisher: Springer Science and Business Media LLC
Date: 09-02-2011
DOI: 10.1007/S00213-011-2188-5
Abstract: The rate-corrected electrocardiographic QT (QTc) interval may significantly increase in patients with schizophrenia taking antipsychotics. The objective of this naturalistic study was to assess the prevalence of prolonged QTc interval in a large population of inpatients with chronic schizophrenia and to explore QTc relationship with demographic variables and prescribed treatments. Electrocardiograms were obtained from age- and sex-matched 456 controls and 1,006 inpatients with schizophrenia (male/female = 689/317) taking antipsychotics. QTc prolongation was defined as a mean value of two standard deviations above the controls. The adjusted relative risk was calculated using logistic regression analysis. QTc prolongation was present in 45 (4.5%) of 1,006 patients overall. Fewer men (3.2%, 22 of 689) than women (7.3%, 23 of 317) displayed QTc prolongation (p < 0.004). Moreover, QTc intervals were shorter in male (391 ± 31 ms) than female subjects (400 ± 37 ms) (p < 0.001). Clozapine was found to produce a longer QTc intervals compared to risperidone and typical antipsychotics. Furthermore, multiple regression analysis showed that significant predictors for QTc prolongation were comorbid cardiovascular disease, antipsychotic types, sex, and age (all p < 0.01). Our present findings suggest that there are sex differences in the prevalence of QTc prolongation and QTc lengthening in schizophrenia. Antipsychotic types are risk factors for QTc prolongation, and risks are substantially higher for clozapine.
Publisher: Public Library of Science (PLoS)
Date: 28-07-2014
Publisher: Springer Science and Business Media LLC
Date: 07-02-2013
DOI: 10.1007/S00213-013-3003-2
Abstract: Identifying the signalling pathways underlying the pathophysiology of schizophrenia is an essential step in the rational development of new antipsychotic drugs for this devastating disease. Evidence from genetic, transgenic and post-mortem studies have strongly supported neuregulin-1 (NRG1)-ErbB4 signalling as a schizophrenia susceptibility pathway. NRG1-ErbB4 signalling plays crucial roles in regulating neurodevelopment and neurotransmission, with implications for the pathophysiology of schizophrenia. Post-mortem studies have demonstrated altered NRG1-ErbB4 signalling in the brain of schizophrenia patients. Antipsychotic drugs have different effects on NRG1-ErbB4 signalling depending on treatment duration. Abnormal behaviours relevant to certain features of schizophrenia are displayed in NRG1/ErbB4 knockout mice or those with NRG1/ErbB4 over-expression, some of these abnormalities can be improved by antipsychotic treatment. NRG1-ErbB4 signalling has extensive interactions with the GABAergic, glutamatergic and dopaminergic neurotransmission systems that are involved in the pathophysiology of schizophrenia. These interactions provide a number of targets for the development of new antipsychotic drugs. Furthermore, the key interaction points between NRG1-ErbB4 signalling and other schizophrenia susceptibility genes may also potentially provide specific targets for new antipsychotic drugs. In general, identification of these targets in NRG1-ErbB4 signalling and interacting pathways will provide unique opportunities for the development of new generation antipsychotics with specific efficacy and fewer side effects.
Publisher: Elsevier BV
Date: 03-2009
DOI: 10.1016/J.EXPNEUROL.2008.11.016
Abstract: Statins are widely being used for the treatment of a variety of conditions beyond their original indication for lowering cholesterol. We have previously reported that simvastatin affected the dopaminergic system in the rat brain. This study aims to investigate locomotor and anxiety effects along with the regional changes of N-methyl-d-aspartate (NMDA) receptors in the rat brain after 4-week administration of simvastatin. Hyperlocomotive and anxiolytic-like activities in the rat were observed after chronic administration of high dose simvastatin (10 mg/kg/day). Distributions and alterations of NMDA receptors in the post-mortem rat brain were detected by [(3)H] MK-801 binding autoradiography. Simvastatin increased [(3)H] MK-801 binding, predominantly in the prefrontal cortex (20%, p=0.003), primary motor cortex (20%, p<0.001), cingulate cortex (28%, p<0.001), hippoc us (41%, p<0.001), caudate putamen (30%, p=0.029), nucleus accumbens (27%, p=0.035) and amygdala (45%, p<0.001) compared to controls. Significant positive correlations were identified between hyperlocomotive as well as anxiolytic-like activities and the upregulation of NMDA receptors in different brain regions. Our results also provide strong evidence that chronic high dose simvastatin administration is to exhibit NMDA antagonist-like effects, which would partially explain the anxiolytic and hyperlocomotor activities. These findings contribute to a better understanding of the critical roles of simvastatin in modulating psycho-neurodegenerative disorders, via NMDA receptors.
Publisher: Wiley
Date: 04-04-2021
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6BM00212A
Abstract: Schizophrenia (SCZ) is a debilitating mental disorder which results in high healthcare and loss of productivity costs to society.
Publisher: Elsevier BV
Date: 10-1999
DOI: 10.1016/S0006-8993(99)01927-7
Abstract: The hypothalamus is a brain region of major importance in regulation of energy balance via autonomic nervous control of both intake and expenditure. There is substantial evidence that diets high in saturated fats lead to obesity while diets equally high in polyunsaturated fats (PUFAs) do not. Using c-Fos as a marker, this study aimed to investigate hypothalamic neuronal response in mice fed high fat diets (58% of calories as fat) emphasising saturated, n-3 or n-6 polyunsaturated fatty acids, or a low fat (10% of calories) diet over periods of 1 and 7 weeks. In addition, a 4-week "reversal" intervention with n-3 polyunsaturated or low fat diet was undertaken in saturated fat-fed mice. Food intake and body weight were measured over the feeding periods. At 1, 7 and 11 weeks mice were killed, epididymal fat pad were weighed and brains were removed for quantitation of hypothalamic c-Fos-like immunoreactive (FLI) neurons. Weight gain, and epididymal fat pad weight, were highest on the saturated fat diet and lowest on the n-3 diet despite similar food intakes (epididymal fat weight at week 7: saturated fat, 622+/-48 mg n-6 fat 423+/-69 low fat 387+/-10, n-3 fat 225+/-26). Compared to a low fat diet, FLI neurons in the dorsal part of lateral hypothalamic (dLH) area was dramatically increased by saturated fat feeding (+367% at 1 week) while ventromedial hypothalamic (VMH) activity was decreased. In contrast with n-6 and n-3 feeding dLH FLI neuronal activity was unchanged but actually increased in the VMH. Paraventricular nucleus (PVN) FLI neurons increased in the high saturated group only at 7 and 11 weeks, after substantial fat accumulation. Substitution of saturated fat diet with the n-3 diet partially reversed (48%) the increase in FLI neurons in PVN of saturated fat-fed mice, while it significantly increase FLI neurons in arcuate nucleus (+400%). In summary, this study demonstrates that dietary saturated fat modulates hypothalamic neuronal activity in a pattern (high lateral, reduced ventromedial activity) consistent with its obesogenic effects. In contrast, diets equally high in PUFA (particularly of the n-3 class) neither increase adiposity nor derange the lateral/medial neuronal activity balance.
Publisher: Springer Science and Business Media LLC
Date: 17-12-2003
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.MCE.2015.04.025
Abstract: Epidemiological evidence suggests that the consumption of a diet high in n-6 polyunsaturated fatty acids (PUFA) is associated with the development of leptin resistance and obesity. We aim to examine the central effect of n-6 PUFA, arachidonic acid (ARA) on leptin sensitivity and leptin-regulated hepatic glucose and lipid metabolism. We found that intracerebroventricular injection of ARA (25 nmol/day) for 2.5 days reversed the effect of central leptin on hypothalamic JAK2, pSTAT3, pAkt, and pFOXO1 protein levels, which was concomitant with a pro-inflammatory response in the hypothalamus. ARA also attenuated the effect of central leptin on hepatic glucose and lipid metabolism by reversing the mRNA expression of the genes involved in gluconeogenesis (G6Pase, PEPCK), glucose transportation (GLUT2), lipogenesis (FAS, SCD1), and cholesterol synthesis (HMG-CoA reductase). These results indicate that an increased exposure to central n-6 PUFA induces central cellular leptin resistance with concomitant defective JAK2-STAT3 and PI3K-Akt signaling.
Publisher: American Society for Clinical Investigation
Date: 15-02-2023
DOI: 10.1172/JCI154612
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-1997
DOI: 10.1097/00001756-199703030-00043
Abstract: Leptin receptor gene expression in the brains of lean (+/+) and obese (ob/ob) C57Bl/6 mice was examined using a non-radioactive in situ hybridization detection method. Significant increases in leptin receptor mRNA expression were found in the ventromedial and arcuate hypothalamic nuclei, piriform and olfactory cortices and medial habenular nucleus. There were very minor changes in the amount of leptin receptor mRNA expression in hippoc us proper (CA1-3). Results indicated that leptin receptor is upregulated when there is a lack of functional leptin, as in hereditary obese (ob/ob) mice. It is also suggested that leptin receptor may be an autoreceptor.
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.1016/J.JPSYCHIRES.2021.12.039
Abstract: Evidence, largely obtained from peripheral studies, suggests that alterations in the kynurenine pathway contribute to the aetiology of depression and disorders involving psychosis. Stimulation of the kynurenine pathway leads to the formation of neuroactive metabolites, including kynurenic acid (predominantly in astrocytes) and quinolinic acid (predominantly in microglia), which are antagonists and agonists of the glutamate NMDA receptor, respectively. In this study, we measured gene expression via qRT-PCR of the main kynurenine pathway enzymes in the anterior cingulate cortex (ACC) in people with major depressive disorder and matched controls. In parallel, we tested for diagnostic differences in gene expression of relevant glial markers. We used total RNA isolated from the ACC from depression subjects with psychosis (n = 12) and without psychosis (n = 12), and non-psychiatric controls (n = 12) provided by the Stanley Medical Research Institute. In the ACC, KYAT1 (KAT I), AADAT (KAT II), and the astrocytic SLC1A2 (EAAT2) mRNAs, were significantly increased in depression, when combining those with and without psychosis. The increased KYAT1 and AADAT mRNA indicates that depression is associated with increased activation of the kynurenic acid arm of the kynurenine pathway in the ACC, suggesting an astrocyte response in depression. Considering EAAT2 and KATs increase astrocytic glutamate uptake and production of the NMDA receptor antagonist kynurenic acid, the observed increases of these markers may relate to changes in glutamatergic signalling in depression. These results suggest dysfunction of the kynurenine pathway in the brain in depression and point to the kynurenine pathway as a possible driver of glutamate dysfunction in depression.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Springer Science and Business Media LLC
Date: 04-2009
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.PSYNEUEN.2015.09.005
Abstract: Accumulating evidence shows abnormal glucose metabolism in schizophrenia, even at the onset of psychosis. This study aims to examine the glucose and lipid metabolism in first-episode and drug naïve (FEDN) patients with schizophrenia and to explore their relationships with psychopathology, which have been under-investigated. Fasting glucose and lipid profiles, as well as homeostasis model of assessment-insulin resistance (HOMA-IR) index were determined in 120 never-medicated first-episode and 31 healthy control subjects matched for gender and age. The schizophrenia symptomatology was assessed by the positive and negative syndrome scale (PANSS). Our results showed that schizophrenia patients had a significantly higher level of fasting plasma glucose (p<0.0001) and insulin (p=0.038). HOMA, an indicator of insulin resistance was higher in the patients than in the healthy controls (p=0.008). No differences were found between the patients and healthy subjects in the levels of plasma triglycerides, high-density lipoprotein, and low-density lipoprotein, except that the cholesterol level was higher in the patients than health subjects (p=0.016). A significant negative association between plasma glucose levels and the PANSS positive symptom subscores was observed (p=0.013). Stepwise multiple regression analysis identified insulin resistance, insulin and the PANSS positive symptom subscore as significant predictor factors for glucose level. These results suggest that abnormal glucose metabolism may be associated with the pathogenesis and psychopathology of schizophrenia in the early phases of the disease process.
Publisher: Wiley
Date: 08-04-1992
Abstract: In order to verify the existence of the ventral and posterodorsal tegmental nuclei and to extend previous findings regarding the dorsal tegmental nucleus in the human brainstem, studies were conducted using cyto- and chemoarchitectonics, and computer reconstruction techniques. Serial sections of five brainstems from adults with no known neurological disorders were stained for Nissl substance, acetylcholinesterase, and substance P. The topography, cytoarchitecture, and acetylcholinesterase reactivity of the tegmental nuclei were presented in a mini-atlas depicting sections cut in transverse and sagittal planes. The dorsal and posterodorsal tegmental nuclei were identified fully within the central grey matter while the ventral tegmental nucleus extended across the medial longitudinal fasciculus into the pontine reticular formation. The dorsal tegmental nucleus featured a cell-poor pericentral part, strongly positive for acetylcholinesterase, and a central part comprised of densely packed small neurons that displayed moderate acetylcholinesterase reactivity and strong substance P-like immunoreactivity. The posterodorsal tegmental nucleus, located in the same transverse plane as the rostral part of the motor nucleus of the trigeminal nerve, was composed of diffusely arranged small to medium neurons with its neuropil displaying moderate acetylcholinesterase reactivity and strong substance P-like immunoreactivity. The ventral tegmental nucleus, identified as a prominent structure in the pontine tegmentum immediately rostral to the genu of the facial nerve, contained predominantly large neurons and displayed intensive acetylcholinesterase reactivity and substance P-like immunoreactivity. These studies showed that the tegmental nuclei, which displayed distinctive cyto- and chemoarchitectonic features, were fully present in adult human brainstem.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.PNPBP.2015.06.003
Abstract: Postnatal administration of phencyclidine (PCP) in rodents causes major disturbances to neurological processes resulting in severe modifications to normal behavioral traits into adulthood. It is routinely used to model psychiatric disorders such as schizophrenia, producing many of the dysfunctional processes in the brain that are present in this devastating disorder, including elevated levels of apoptosis during neurodevelopment and disruptions to myelin and plasticity processes. Lingo-1 (or Leucine-rich repeat and immunoglobulin domain-containing protein) is responsible for negatively regulating neurite outgrowth and the myelination of axons. Recent findings using a postmortem human brain cohort showed that Lingo-1 signaling partners in the Nogo receptor (NgR) 75/TNF receptor orphan Y (TROY) signaling complex, and downstream signaling partners With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1), play a significant part in schizophrenia pathophysiology. Here we have examined the implication of Lingo-1 and its signaling partners in a neurodevelopmental model of schizophrenia using PCP to determine if these pathways are altered in the hippoc us throughout different stages of neurodevelopment. Male Sprague-Dawley rats were injected subcutaneously with PCP (10mg/kg) or saline solution on postnatal days (PN) 7, 9, and 11. Rats (n=6/group) were sacrificed at PN12, 5weeks, or 14weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippoc us of the treated rats. p75 and Myt1 were decreased (0.001≤p≤0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5weeks (p>0.05). At 14weeks, p75, TROY, and Myt1 were increased in the PCP treated rats (0.014≤p≤0.022). This is the first report of an alteration in Lingo-1 signaling proteins in the rat hippoc us, both directly after PCP treatment in early development and in adulthood. Based on our results, we propose that components of the Lingo-1 signaling pathways may be involved in the acute neurotoxicity induced by perinatal administration of PCP in rats early in development and suggest that this may have implications for the hippoc al deficits seen in schizophrenia.
Publisher: Wiley
Date: 18-09-2009
DOI: 10.1002/IJC.24663
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.EXPNEUROL.2007.09.029
Abstract: This study examined regional changes of peptide YY (PYY) binding densities in the rat brain after chronic administration of olanzapine (1.2 mg/kg/day) and haloperidol (2.0 mg/kg/day) for 36 days. PYY binding densities and distributions were detected by [(125)I] binding autoradiography after rats were sacrificed either 2 h or 48 h after the last drug administration to examine both immediate and delayed effects following the drug withdrawal. Following 2 h of drug administration, it showed that olanzapine administration significantly decreased PYY binding densities, predominantly in the posterodorsal part of medial amygdaloid nucleus (52%, p<0.05), dorsal part of medial geniculate nucleus (56%, p<0.05), superficial gray layer of the superior colliculus (53%, p<0.05), parabrachial pigmented nucleus (54%, p<0.05) and periaqueductal gray (50%, p<0.05) compared to controls, while rebound increases of PYY binding densities were observed in most of examined regions 48 h later with only medial geniculate nucleus dorsal showing significant increase compared to controls (118%, p<0.01). In contrast, no change in PYY binding densities was found in the haloperidol-treated groups 2 h after drug administration, while only a significant rebound increase was observed in the dorsal part of medial geniculate nucleus (94%, p<0.01) 48 h after the haloperidol withdrawal. Alterations in PYY binding densities in brain regions such as the dorsal part of medial geniculate nucleus, superficial gray layer of superior colliculus, periaqueductal gray and parabrachial pigmented nucleus may represent the specific regions that mediate the clinical effects of antipsychotics via neuropeptide Y system. Our study also implicates NPY receptors as a novel therapeutic target in the treatment of psychotic disorders.
Publisher: Springer Science and Business Media LLC
Date: 22-10-2014
DOI: 10.1007/S00702-014-1327-7
Abstract: Overactivity of dopaminergic neurotransmission is a putative mechanism of tar e dyskinesia (TD). Previous studies have found dysfunction in plasma dopamine beta-hydoxylase (DBH) in schizophrenia with TD. Moreover, DBH, whose activity and levels are strongly controlled by the DBH gene, is a key enzyme in the conversion of dopamine (DA) to norepinephrine (NE) associated with excited behavior. This study examined whether the DBH5'-insertion/deletion (Ins/Del) polymorphism was associated with excited behavior in schizophrenia with TD. The presence of the DBH5'-Ins/Del polymorphism was determined in 741 schizophrenia with TD (n = 345) and without TD (n = 396). The Abnormal Involuntary Movement Scale and Positive and Negative Syndrome Scale were used to assess the severity of TD and psychopathology of schizophrenia. There was no significant difference in the allelic and genotypic frequencies of the DBH5'-Ins/Del polymorphism between schizophrenia with and without TD (both p > 0.05). However, the excited symptoms score was significantly different to the DBH5'-Ins/Del genotypic groups in schizophrenia with TD (p 0.05). The excited symptoms score was higher in TD patients with the Del/Del genotype than those with Ins alleles (p = 0.015). Our findings suggest that the DBH5'-Ins/Del polymorphism may not contribute directly to the development of TD in schizophrenia, but it may be involved in the excited behavior of TD patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2011
Publisher: Wiley
Date: 27-12-2019
DOI: 10.1111/CNS.13281
Publisher: Wiley
Date: 22-03-1994
Abstract: In this study we examined the distribution of calcitonin (CT) binding sites in the human medulla oblongata by in vitro autoradiography. In competition studies, the rank order of potency for calcitonins competing for 125I-salmon CT binding was salmon CT > porcine CT > human CT, which is consistent with physiologically relevant CT receptors in other systems. For the determination of CT binding in the human medulla, 20-micron cryostat sections were incubated with 125I-salmon CT in the presence or absence of 10(-6) M unlabelled salmon CT to map specific CT binding sites. Punctate binding was observed over discrete nuclei of the medulla. High binding densities were seen over subnuclei of the dorsal motor nucleus of the vagus, the nucleus of the solitary tract, the intermediate reticular zone, the gigantocellular and dorsal paragigantocellular nuclei, and the raphe obscurus nucleus. Moderate levels of binding were observed over the lateral paragigantocellular nucleus and the rostral extent of the epiolivary nucleus. The cuneate and gracile nuclei and the fiber tracts did not contain detectable binding, while the inferior olivary nucleus had moderate levels of nonspecific binding. The localization of calcitonin binding sites in the human presents similarities but also important differences to the distribution in rat and cat. The most notable difference is the extreme binding densities in the intermediate reticular zone of the human. The location of binding sites suggests involvement of calcitonin in regulation of autonomic function.
Publisher: Oxford University Press (OUP)
Date: 25-12-2014
DOI: 10.1093/IJNP/PYU114
Abstract: Substantial evidence from human post-mortem and genetic studies has linked the neurotrophic factor neuregulin 1 (NRG1) to the pathophysiology of schizophrenia. Genetic animal models and in vitro experiments have suggested that altered NRG1 signaling, rather than protein changes, contributes to the symptomatology of schizophrenia. However, little is known about the effect of NRG1 on schizophrenia-relevant behavior and neurotransmission (particularly GABAergic and glutamatergic) in adult animals. To address this question, we treated adult mice with the extracellular signaling domain of NRG1 and assessed spontaneous locomotor activity and acoustic startle response, as well as extracellular GABA, glutamate, and glycine levels in the prefrontal cortex and hippoc us via microdialysis. Furthermore, we asked whether the effect of NRG1 would differ under schizophrenia-relevant impairments in mice and therefore co-treated mice with NRG1 and phencyclidine (PCP) (3 mg/kg). Acute intraventricularly- or systemically-injected NRG1 did not affect spontaneous behavior, but prevented PCP induced hyperlocomotion and deficits of prepulse inhibition. NRG1 retrodialysis (10 nM) reduced extracellular glutamate and glycine levels in the prefrontal cortex and hippoc us, and prevented PCP-induced increase in extracellular GABA levels in the hippoc us. With these results, we provide the first compelling in vivo evidence for the involvement of NRG1 signaling in schizophrenia-relevant behavior and neurotransmission in the adult nervous system, which highlight its treatment potential. Furthermore, the ability of NRG1 treatment to alter GABA, glutamate, and glycine levels in the presence of PCP also suggests that NRG1 signaling has the potential to alter disrupted neurotransmission in patients with schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 17-10-2007
DOI: 10.1007/S11064-007-9483-X
Abstract: This experiment examined dopamine D2 receptor and its transporter (DAT) density in mice fed a high-fat or low-fat diet for twenty days as well as fed twenty days of high-fat diet then changed to low-fat diet for one and seven days. Quantitative autoradiography revealed that twenty days of high-fat diet consumption significantly increased D2 receptor and decreased DAT density in the dorsal and ventral parts of the caudal caudate putamen (D2: 32% and 35% respectively, DAT: 33.3% and 28.8% respectively) compared with low-fat diet. High-fat feeding also increased D2 binding in the nucleus accumbens shell (36%). D2 receptor and DAT density remained unchanged following reversal of the diets from high-fat to low-fat diet. The high-fat diet induced increase of D2 receptor and decrease of DAT binding may have occurred due to defensive control over dopaminergic activity in response to a positive energy balance.
Publisher: Frontiers Media SA
Date: 31-10-2019
Publisher: Mary Ann Liebert Inc
Date: 30-08-2023
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.COMPPSYCH.2015.07.003
Abstract: This study investigated gender differences in cognition in schizophrenia with and without diabetes. Cognition was assessed in 263 in iduals with schizophrenia with age range (40-68): 67 males and 34 females with schizophrenia with diabetes and 125 males and 37 females with schizophrenia without diabetes according to the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Fasting glucose, hemoglobin A1c (HbA1c) and lipid levels were measured. Results showed that male in iduals performed worse on most cognitive tasks, especially attention, in schizophrenia with than without diabetes. This result was not observed in female in iduals. Also, in iduals of both genders showed higher fasting glucose and HbA1c in schizophrenia with than without diabetes. In schizophrenia with diabetes, males had significantly worse cognition than females in all cognitive domains. Higher HbA1c, lower high-density lipoprotein, and an earlier age of onset of schizophrenia were found in males compared with female in iduals. HbA1c was negatively associated with attention and the RBANS total score for males but not for females. In schizophrenia without diabetes, males showed worse performance in immediate and delayed memory than females. This study support cognition was worse for males with schizophrenia irrespective of whether they have diabetes. However, diabetes exemplified the gender differences, especially in attention.
Publisher: Wiley
Date: 20-06-2011
Publisher: American Chemical Society (ACS)
Date: 03-06-2019
DOI: 10.1021/ACSCHEMNEURO.9B00120
Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by progressive loss of memory and cognitive function, and is associated with the deficiency of synaptic acetylcholine, as well as chronic neuroinflmmation. Tacrine, a potent acetylcholinesterase (AChE) inhibitor, was previously a prescribed clinical therapeutic agent for AD, but it was recently withdrawn because it caused widespread hepatotoxicity. Hydrogen sulfide (H
Publisher: Springer Science and Business Media LLC
Date: 10-10-2016
DOI: 10.1038/SREP34391
Abstract: Group 1 metabotropic glutamate receptors (mGluR1/mGluR5) play an integral role in neurodevelopment and are implicated in psychiatric disorders, such as schizophrenia. mGluR1 and mGluR5 are expressed as homodimers, which is important for their functionality and pharmacology. We examined the protein expression of dimeric and monomeric mGluR1α and mGluR5 in the prefrontal cortex (PFC) and hippoc us throughout development (juvenile/adolescence/adulthood) and in the perinatal phencyclidine (PCP) model of schizophrenia. Under control conditions, mGluR1α dimer expression increased between juvenile and adolescence (209–328%), while monomeric levels remained consistent. Dimeric mGluR5 was steadily expressed across all time points monomeric mGluR5 was present in juveniles, dramatically declining at adolescence and adulthood (−97–99%). The mGluR regulators, Homer 1b/c and Norbin, significantly increased with age in the PFC and hippoc us. Perinatal PCP treatment significantly increased juvenile dimeric mGluR5 levels in the PFC and hippoc us (37–50%) but decreased hippoc al mGluR1α (−50–56%). Perinatal PCP treatment also reduced mGluR1α dimer levels in the PFC at adulthood (−31%). These results suggest that Group 1 mGluRs have distinct dimeric and monomeric neurodevelopmental patterns, which may impact their pharmacological profiles at specific ages. Perinatal PCP treatment disrupted the early expression of Group 1 mGluRs which may underlie neurodevelopmental alterations observed in this model.
Publisher: Springer Science and Business Media LLC
Date: 11-11-2021
DOI: 10.1186/S40168-021-01172-0
Abstract: Cognitive impairment, an increasing mental health issue, is a core feature of the aging brain and neurodegenerative diseases. Industrialized nations especially, have experienced a marked decrease in dietary fiber intake, but the potential mechanism linking low fiber intake and cognitive impairment is poorly understood. Emerging research reported that the ersity of gut microbiota in Western populations is significantly reduced. However, it is unknown whether a fiber-deficient diet (which alters gut microbiota) could impair cognition and brain functional elements through the gut-brain axis. In this study, a mouse model of long-term (15 weeks) dietary fiber deficiency (FD) was used to mimic a sustained low fiber intake in humans. We found that FD mice showed impaired cognition, including deficits in object location memory, temporal order memory, and the ability to perform daily living activities. The hippoc al synaptic ultrastructure was damaged in FD mice, characterized by widened synaptic clefts and thinned postsynaptic densities. A hippoc al proteomic analysis further identified a deficit of CaMKIId and its associated synaptic proteins (including GAP43 and SV2C) in the FD mice, along with neuroinflammation and microglial engulfment of synapses. The FD mice also exhibited gut microbiota dysbiosis (decreased Bacteroidetes and increased Proteobacteria), which was significantly associated with the cognitive deficits. Of note, a rapid differentiating microbiota change was observed in the mice with a short-term FD diet (7 days) before cognitive impairment, highlighting a possible causal impact of the gut microbiota profile on cognitive outcomes. Moreover, the FD diet compromised the intestinal barrier and reduced short-chain fatty acid (SCFA) production. We exploit these findings for SCFA receptor knockout mice and oral SCFA supplementation that verified SCFA playing a critical role linking the altered gut microbiota and cognitive impairment. This study, for the first time, reports that a fiber-deprived diet leads to cognitive impairment through altering the gut microbiota-hippoc al axis, which is pathologically distinct from normal brain aging. These findings alert the adverse impact of dietary fiber deficiency on brain function, and highlight an increase in fiber intake as a nutritional strategy to reduce the risk of developing diet-associated cognitive decline and neurodegenerative diseases.
Publisher: Public Library of Science (PLoS)
Date: 20-06-2013
Publisher: Elsevier BV
Date: 07-2013
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.PNPBP.2014.08.006
Abstract: Olanzapine is widely prescribed for treating schizophrenia and other mental disorders, although it leads to severe body weight gain/obesity. Chronic co-treatment with betahistine has been found to significantly decrease olanzapine-induced weight gain however, it is not clear whether this co-treatment affects the therapeutic effects of olanzapine. This study investigated the effects of chronic treatment of olanzapine and/or betahistine on the binding density of the serotonergic 5-HT2A (5-HT2AR) and 5-HT2C (5-HT2CR) receptors, 5-HT transporter (5-HTT), and dopaminergic D₂ receptors (D₂R) in the brain regions involved in antipsychotic efficacy, including the prefrontal cortex (PFC), cingulate cortex (Cg), nucleus accumbens (NAc), and caudate putamen (CPu). Rats were treated with olanzapine (1 mg/kg, t.i.d.) or vehicle for 3.5 weeks, and then olanzapine treatment was withdrawn for 19 days. From week 6, the two groups were ided into 4 groups (n=6) for 5 weeks' treatment: (1) olanzapine-only (1 mg/kg, t.i.d.), (2) betahistine-only (9.6 mg/kg, t.i.d.), (3) olanzapine and betahistine co-treatment (O+B), and (4) vehicle. Compared to the control, the olanzapine-only treatment significantly decreased the bindings of 5-HT2AR, 5-HT2CR, and 5-HTT in the PFC, Cg, and NAc. Similar changes were observed in the rats receiving the O+B co-treatment. The olanzapine-only treatment significantly increased the D₂R binding in the Cg, NAc, and CPu, while the betahistine-only treatment reduced D₂R binding. The co-treatment of betahistine reversed the D₂R bindings in the NAc and CPu that were increased by olanzapine. Therefore, chronic O+B co-treatment has similar effects on serotonin transmission as the olanzapine-only treatment, but reverses the D₂R that is up-regulated by chronic olanzapine treatment. The co-treatment maintains the therapeutic effects of olanzapine but decreases revents the excess weight gain.
Publisher: Informa UK Limited
Date: 15-07-2009
Abstract: Colon cancer is the third most common cancer and third most common cause of cancer-related death in the USA according to 2008 American Cancer Society statistics. The carcinogenesis of colon cancer has been associated with both genetics and environmental factors. It has been found that several signal pathways, including K-ras, Src/PI3K/Akt, beta-catenin, TGFbeta and p53 play critical roles in its pathogenesis. The 5 y survival rate of metastatic colon cancer is below 10%. Thus, it is necessary to further understand its biology and search for effective therapy. Azoxymethane (AOM) is a common model for colon cancer. It can specifically induce colon cancer similar to the pathogenesis of human sporadic colon cancer. Thus, it has been extensively used in the study of the molecular biology, prevention and treatment of colon cancer. After administration, AOM is metabolised into methylazoxymethanol by CYP2E1, which causes DNA mutations. Mutation of K-ras activates this pathway and its downstream PI3K/Akt pathway and MAPK pathway. Mutation of beta-catenin also prevents it from being degraded by GSK-3 and accumulation of beta-catenin leads to cell proliferation. TGFbeta, a pro-apoptotic protein, is inhibited. All of these changes form the basis of AOM carcinogenesis. This model has been used in the study of the genetic deficiencies of colon cancer and in the prevention and treatment of the disease. For ex le, TGF-betaR2 and adiponectin knockout mice are more susceptible to AOM, while high amylose cornstarch, green tea and artemisia have protective effects.
Publisher: Wiley
Date: 15-12-2011
DOI: 10.1111/J.1471-4159.2011.07590.X
Abstract: Antipsychotic drugs have various neuropharmacological properties as a result of their structural ersity. Despite their therapeutic benefits, most of the prescribed atypical antipsychotics can induce severe side effects, including weight gain, type II diabetes mellitus, and cardiovascular diseases. Among the developed atypical antipsychotic agents, tetracyclic dibenzodiazepine and thienobenzodiazepine compounds, particularly clozapine and olanzapine, are associated with the greatest weight gain and metabolic disturbances. However, the unique chemical structure of these compounds causes the low risk of side effects reported for typical antipsychotics (e.g. extrapyramidal symptoms and tar e dyskinesia). This report reviews the recent discovery of the potential role of the chemical structure of antipsychotics in their therapeutic properties and metabolic disturbances. By developing structure-activity relationship studies for atypical antipsychotics, we will improve our understanding of the structural modifications of these chemical classes that lead to reduced weight gain, which will be an invaluable step toward the discovery of the next generation of atypical antipsychotics. In this review, we suggest that a novel dibenzodiazepine or thienobenzodiazepine antipsychotic drug with lower affinity for H(1) receptors may significantly advance schizophrenia therapy.
Publisher: Frontiers Media SA
Date: 23-06-2020
Publisher: AIP Publishing
Date: 05-2016
DOI: 10.1063/1.4949770
Abstract: While neurons and glial cells both play significant roles in the development and therapy of schizophrenia, their specific contributions are difficult to differentiate because the methods used to separate neurons and glial cells are ineffective and inefficient. In this study, we reported a high-throughput microfluidic platform based on the inertial microfluidic technique to rapidly and continuously separate neurons and glial cells from dissected brain tissues. The optimal working condition for an inertial biochip was investigated and evaluated by measuring its separation under different flow rates. Purified and enriched neurons in a primary neuron culture were verified by confocal immunofluorescence imaging, and neurons performed neurite growth after separation, indicating the feasibility and biocompatibility of an inertial separation. Phencyclidine disturbed the neuroplasticity and neuron metabolism in the separated and the unseparated neurons, with no significant difference. Apart from isolating the neurons, purified and enriched viable glial cells were collected simultaneously. This work demonstrates that an inertial microchip can provide a label-free, high throughput, and harmless tool to separate neurological primary cells.
Publisher: Wiley
Date: 06-2010
DOI: 10.1002/SYN.20751
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.NEUROSCIENCE.2013.06.037
Abstract: The neuregulin 1 gene has repeatedly been identified as a susceptibility gene for schizophrenia, thus mice with genetic mutations in this gene offer a valuable tool for studying the role of neuregulin 1 in schizophrenia-related neurotransmission. In this study, slide-based receptor autoradiography was used to quantify glutamatergic N-methyl-d-aspartate (NMDA), dopaminergic D2, cannabinoid CB1 and acetylcholine M1/4 receptor levels in the brains of male heterozygous transmembrane domain neuregulin 1 mutant (Nrg1(+/-)) mice at two ages. Mutant mice expressed small but significant increases in NMDA receptor levels in the cingulate cortex (7%, p=0.044), sensory cortex (8%, p=0.024), and motor cortex (8%, p=0.047), effects that were independent of age. In the nucleus accumbens and thalamus Nrg1(+/-) mice exhibited age-dependent alterations in NMDA receptors. Nrg1(+/-) mice showed a statistically significant increase in NMDA receptor levels in the nucleus accumbens of 14-week-old Nrg1(+/-) mice compared to control littermates of the same age (12%, p=0.026), an effect that was not seen in 20-week-old mice. In contrast, NMDA receptor levels in the thalamus, while initially unchanged in 14-week-old mice, were then decreased in the 20-week-old Nrg1(+/-) mice compared to control littermates of the same age (14%, p=0.011). Nrg1(+/-) mutant mice expressed a significant reduction in D2 receptor levels (13-16%) in the striatum compared to controls, independent of age. While there was a borderline significant increase (6%, p=0.058) in cannabinoid CB1 receptor levels in the substantia nigra of Nrg1(+/-) mice compared to controls, CB1 as well as acetylcholine M1/4 receptors showed no change in Nrg1(+/-) mice in any other brain region examined. These data indicate that a Nrg1 transmembrane mutation produces selective imbalances in glutamatergic and dopaminergic neurotransmission, which are two key systems believed to contribute to schizophrenia pathogenesis. While the effects on these systems are subtle, they may underlie the susceptibility of these mutants to further impacts.
Publisher: Bentham Science Publishers Ltd.
Date: 06-2011
DOI: 10.2174/157016311795563820
Abstract: Obesity has been associated with both the carcinogenesis and poor prognosis of colon cancer, one of the leading causes of cancer-related death. Increased blood levels of insulin in obese subjects have been demonstrated to play a key role in carcinogenesis. It is also possible that insulin affects treatment efficacy, leading to poor prognosis. In this study, we demonstrated that insulin can increase HT29 colon cancer cell line resistance to cycloheximide and 5-fluorouracil induced cytotoxicity. This effect can be inhibited by the PI3K/Akt inhibitor Ly294002, indicating the important role of this pathway in the insulin-induced inefficacy of chemotherapy. The insulin-induced resistance to cycloheximide and 5-fluorouracil can be used in drug screening to overcome the inefficacy of chemotherapy in obesity-associated colon cancer.
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.BRAINRESREV.2006.09.001
Abstract: Disruption to brain development at an early stage can potentially alter chemically coded neural networks and can affect behavior in later life. During early brain development antagonism of glutamate NMDA receptors, which play an important role in neuronal outgrowth and survival, leads to neuronal damage in several brain regions and causes behavioral alterations in rodents that mimic schizophrenia symptoms and endophenotypes. There are several lines of evidence implicating involvement of a dysfunctional glutamate system in schizophrenia. In normal subjects, NMDA receptor antagonists produce behavioral and neurochemical changes that mimic schizophrenia symptoms better than any other psychotomimetic drug. Moreover, these drugs worsen symptoms in schizophrenia patients and can trigger a recrudescence of the acute psychotic state in patients with stable chronic schizophrenia. In addition, genes consistently reported as being altered in schizophrenia play roles in development, neuroplasticity and glutamate/GABAergic neurotransmission. Perinatal NMDA receptor antagonist treatment is a useful model for studying the neurodevelopmental and NMDA receptor hypofunction hypotheses of schizophrenia because neurochemical and behavioral changes, reminiscent of those seen in schizophrenia, are present long after cessation of drug administration, which suggests that a permanent change in brain structure and organization has occurred during brain development.
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.EURONEURO.2011.09.003
Abstract: The second generation antipsychotic drug (SGA) olanzapine has an efficacy to treat schizophrenia, but can cause obesity and type II diabetes mellitus. Cholinergic muscarinic M3 receptors (M3R) are expressed on pancreatic β-cells and in the brain where they influence insulin secretion and may regulate other metabolic hormones via vagal innervation of the gastrointestinal tract. Olanzapine's M3R antagonism is an important risk factor for its diabetogenic liability. However, the effects of olanzapine on central M3Rs are unknown. Rats were treated with 0.25, 0.5, 1.0 or 2.0 mg olanzapine/kg or vehicle (3×/day, 14-days). M3R binding densities in the hypothalamic arcuate (Arc) and ventromedial nuclei (VMH), and dorsal vagal complex (DVC) of the brainstem were investigated using [3H]4-DAMP plus pirenzepine and AF-DX116. M3R binding correlations to body weight, food intake, insulin, ghrelin and cholecystokinin (CCK) were analyzed. Olanzapine increased M3R binding density in the Arc, VMH and DVC, body weight, food intake, circulating plasma ghrelin and CCK levels, and decreased plasma insulin and glucose. M3R negatively correlated to insulin, and positively correlated to ghrelin, CCK, food intake and body weight. Increased M3R density is a compensatory up-regulation in response to olanzapine's M3R antagonism. Olanzapine acts on M3R in regions of the brain that control food intake and insulin secretion. Olanzapine's M3R blockade in the brain may inhibit the acetylcholine pathway for insulin secretion. These findings support a role for M3Rs in the modulation of insulin, ghrelin and CCK via the vagus nerve and provide a mechanism for olanzapine's diabetogenic and weight gain liability.
Publisher: Springer Science and Business Media LLC
Date: 20-04-2022
DOI: 10.1007/S11357-022-00559-7
Abstract: Autophagy is a catabolic process to eliminate defective cellular molecules via lysosome-mediated degradation. Dysfunctional autophagy is associated with accelerated aging, whereas stimulation of autophagy could have potent anti-aging effects. We report that cannabidiol (CBD), a natural compound from Cannabis sativa , extends lifespan and rescues age-associated physiological declines in C. elegans . CBD promoted autophagic flux in nerve-ring neurons visualized by a tandem-tagged LGG-1 reporter during aging in C. elegans . Similarly, CBD activated autophagic flux in hippoc al and SH-SY5Y neurons. Furthermore, CBD-mediated lifespan extension was dependent on autophagy genes ( bec-1 , vps-34 , and sqst-1 ) confirmed by RNAi knockdown experiments. C. elegans neurons have previously been shown to accumulate aberrant morphologies, such as beading and blebbing, with increasing age. Interestingly, CBD treatment slowed the development of these features in anterior and posterior touch receptor neurons (TRN) during aging. RNAi knockdown experiments indicated that CBD-mediated age-associated morphological changes in TRNs require bec-1 and sqst-1 , not vps-34 . Further investigation demonstrated that CBD-induced lifespan extension and increased neuronal health require sir-2.1 /SIRT1. These findings collectively indicate the anti-aging benefits of CBD treatment, in both in vitro and in vivo models, and its potential to improve neuronal health and longevity.
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.EURONEURO.2011.09.002
Abstract: Schizophrenia is a complex and devastating mental disorder of unknown etiology. Hypofunction of N-methyl-D-aspartate (NMDA) receptors are implicated in the disorder, since phencyclidine (PCP) and other NMDA receptor antagonists mimic schizophrenia-like symptoms in humans and animals so well. Moreover, genetic linkage and post mortem studies strongly suggest a role for altered neuregulin 1 (Nrg1)/erbB4 signaling in schizophrenia pathology. This study investigated the relationship between the NMDA receptor and Nrg1 signaling pathways using the perinatal PCP animal model. Rats (n=5/group) were treated with PCP (10 mg/kg) or saline on postnatal days (PN) 7, 9 and 11 and were sacrificed on PN12, 5 weeks and 20 weeks for biochemical analyses. Western blotting was used to determine total and phosphorylated levels of proteins involved in NMDA receptor/Nrg1 signaling in the prefrontal cortex and hippoc us. In the cortex, PCP treatment altered Nrg1/erbB4 expression levels throughout development, including decreased Nrg1 and erbB4 at PN12 (-25-30% p<0.05) increased erbB4 and p-erbB4 (+18-27% p<0.01) at 5 weeks and decreased erbB4 and p-erbB4 (-16-18% p<0.05) along with increased Nrg1 (+33% p<0.01) at 20 weeks. In the hippoc us, levels of Nrg1/erbB4 were largely unaffected apart from a significant decrease in p-erbB4 at 20 weeks (-13% p<0.001) however NMDA receptor subunits and PSD-95 showed increases at PN12 and 5 weeks (+20-32% p<0.05), and decreases at 20 weeks (-22-29% p<0.05). This study shows that NMDA receptor antagonism early in development can have long term effects on Nrg1/erbB4 expression which could be important in understanding pathological processes which might be involved in schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2012
DOI: 10.1038/MP.2012.137
Publisher: Elsevier BV
Date: 06-2005
DOI: 10.1016/J.JCHEMNEU.2005.03.005
Abstract: The aim of this study was to examine the influence of different fat diets on muscarinic acetylcholine receptor binding. Nineteen male Sprague-Dawley rats were ided into four groups and fed a diet of either high saturated fat, n-6 polyunsaturated fatty acid (PUFA), n-3 PUFA or low fat (control) for 8 weeks. Using quantitative autoradiography, [(3)H]pirenzepine binding to muscarinic M1/M4 receptors and [(3)H]AF-DX384 binding to M2/M4 receptors were measured throughout the brain in all four groups. The main findings were that compared to the low fat control group, M2/M4 receptor binding was significantly reduced in the dorsolateral, dorsomedial and ventromedial parts of the caudate putamen (61-64%, p < 0.05), anterior cingulate cortex (59%, p < 0.01), dentate gyrus and CA1-3 fields of the hippoc us (32-43%, p < 0.01) of rats on a high n-6 PUFA diet however, no differences in M1/M4 receptor binding densities between the four groups were observed. These results suggest that a diet high in n-6 PUFA, but not of n-3 PUFAs or saturated fat, may selectively alter M2/M4 receptor-mediated signal transduction in the rat brain.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.BBRC.2019.02.152
Abstract: Schizophrenia is a severe mental disorder with unknown etiology. Many mechanisms, including dysregulation of neurotransmitters, immune disturbance, and abnormal neurodevelopment, are proposed for the pathogenesis of schizophrenia. The significance of communication between intestinal flora and the central nervous system through the gut-brain axis is increasingly being recognized. The intestinal microbiota plays an important role in regulating neurotransmission, immune homeostasis, and brain development. We hypothesize that an imbalance in intestinal flora causes immune activation and dysfunction in the gut-brain axis, contributing to schizophrenia. In this review, we examine recent studies that explore the intestinal flora and immune-mediated neurodevelopment of schizophrenia. We conclude that an imbalance in intestinal flora may reduce protectants and increase neurotoxin and inflammatory mediators, causing neuronal and synaptic damage, which induces schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2018
DOI: 10.1038/S41398-018-0303-7
Abstract: Antipsychotic pharmacotherapy is strongly obesogenic and is associated with increased oxidative stress in patients with schizophrenia. However, whether these changes reflect psychopathology, antipsychotic efficacy, or some other factor is not known. Our study aims to investigate the degree of oxidative stress in different BMI categories and to identify clinical symptomatology that may be paired with increased oxidative stress in a schizophrenia population. To this end, we performed a cross-sectional study and recruited 89 long-term inpatients with schizophrenia and collected the following variables: plasma malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), routine biochemical analysis, and psychopathology through the Positive and Negative Syndrome Scale (PANSS). The results indicate that the levels of the lipid peroxidation product, MDA, were significantly higher in the high BMI group than the low (normal) BMI group. As expected, high BMI was associated with an atherogenic lipid profile however, it was also associated with fewer psychopathological symptoms. Multiple regression analysis found that MDA levels, the PANSS general psychopathology subscore, and triglyceride levels (all p 0.05) were independent contributors to the BMI in patients. These results suggested that oxidative stress may play an important role in antipsychotic-induced weight gain. Further investigations using the longitudinal design in first-episode schizophrenia patients are needed to explore the beneficial effect of antioxidants on the abnormal lipid metabolism mediated by antipsychotic treatment.
Publisher: SAGE Publications
Date: 02-1997
DOI: 10.3109/00048679709073794
Abstract: Objective:To highlight the potential role of molecular biological studies in examining the expression of genes of interest in brain tissue to elucidate the pathophysiological basis of the major psychoses. Method:To review the principles underlying the available techniques for expression studies. Results:Detection of messenger RNA by in situ hybridisation and quantitation by Northern analysis are powerful tools to detect abnormalities in gene expression in brain tissue. Conclusion:The availability of simple techniques to examine the expression of RNA and protein products of in idual genes, including examination at the level of in idual cells, offers a clear opportunity to define the molecular basis of the major psychoses.
Publisher: SAGE Publications
Date: 02-1997
DOI: 10.3109/00048679709073795
Abstract: Objective:There is increasing acceptance that schizophrenia is associated with a generalised disorder in cortical neurodevelopment. The aim of this paper is to review the evidence that this disorder may be accounted for by abnormalities in mechanisms mediated by the main family of excitatory neuroreceptors in cortical brain systems, the N-methyl-D-aspartate (NMDA) glutamatergic receptors. Method:The neurobiological evidence is presented for an abnormality in cortical development related to synaptic pathology in schizophrenia. The unique functions of the NMDA receptor in information processing are described, especially its role in learning and memory, and in neural plasticity and brain development. It is argued that the cellular and molecular mechanisms which underlie learning and memory also govern normal brain development. Studies examining abnormalities in glutamatergic transmission in schizophrenia are reviewed. Results:There is a substantial literature in support of the possibility that NMDA receptor abnormalities may be involved in the neurodevelopmental predisposition to schizophrenia, as well as in symptom production. Conclusions:Research to determine the role of the NMDA receptor in the pathophysiology of schizophrenia is warranted and now feasible. To be successful, this research will require the application of molecular biology techniques to postmortem brain tissue studies, in addition to traditional histochemical approaches.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.NEUROSCIENCE.2014.02.031
Abstract: It is believed that muscarinic M1/4 receptors are closely correlated to the dopaminergic system and are strongly involved in the pathogenesis of Parkinson's disease (PD). In addition to regulating lipid metabolism and protection from stroke, statins have been used to regulate the declined cognition. We aimed to explore the regional changes in M1/4 receptors in the 6-hydroxydopamine (6-OHDA)-lesioned rat brain. PD rat model was set up by injecting 6-OHDA into the unilateral medial forebrain bundle while simvastatin (10mg/kg/day) or saline was orally administrated for 3weeks, respectively. Long-term memory was measured using the Morris water maze. [(3)H]pirenzepine binding autoradiography was applied to investigate the alterations of M1/4 receptors in the PD rat brains. 6-OHDA induced long-term memory deficits along with downregulation of M1/4 receptors in the hippoc us, the medial amygdala, the posteromedial cortical and the piriform cortex simvastatin administration significantly ameliorated the impaired memory and reversed the downregulation of M1/4 receptors in the examined brain regions. Profound positive correlations were verified between the decline in long-term memory activity and the restoration of M1/4 receptors in different brain regions after simvastatin treatment. Our results provide strong evidence that M1/4 receptor modulation after simvastatin administration did, at least partially, contribute to the improvement in the long-term memory in 6-OHDA-induced PD rats. These results provide a possible mechanism for simvastatin treatment in psycho-neurological diseases such as PD via M1/4 receptors.
Publisher: Elsevier BV
Date: 12-2021
Publisher: Springer Science and Business Media LLC
Date: 10-02-2016
DOI: 10.1007/S00213-016-4230-0
Abstract: An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored. We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-D-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia. Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions. In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippoc us, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine. We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2010
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.PNPBP.2017.03.009
Abstract: Risperidone is known to increase prolactin secretion in treating mental illness patients. This side-effect is thought to be mediated via central signaling pathway. However, the exact pathway involved between risperidone and hyperprolactinemia are still unknown. Therefore, we have treated mice with risperidone and investigated the central mechanisms. The present study showed that in risperidone treated group, the level of the serum prolactin significantly increased, which was consistent with increased positive prolactin staining in pituitary gland. Elevated c-fos expression was observed in the arcuate hypothalamic nucleus (Arc) where we found 65% c-fos positive neurons co-localised with neuropeptide Y (NPY) in mice treated with risperidone. In addition, the results from in situ hybridization showed that the NPY mRNA in the Arc was significantly increased, whereas the tyrosine hydroxylase (TH) mRNA dramatically decreased compared with control group in the paraventricular hypothalamic nucleus (PVN). These findings revealed that risperidone may mediate the transcriptional regulation of Arc NPY and TH in the PVN. Furthermore, risperidone induced a decreased dopamine synthesis in the PVN and thus reduced the dopamine-induced inhibition of prolactin release, ultimately lead to hyperprolactinemia. Therefore, insights into these neuronal mechanisms open up potential new ways to treat schizophrenia patients in order to ameliorate hyperprolactinemia.
Publisher: Elsevier BV
Date: 07-2003
DOI: 10.1016/S0169-328X(03)00174-8
Abstract: Some mice become obese whereas others remain lean when raised on a high-energy diet. This study examined the levels of neuropeptide Y (NPY), and of Y1, Y2, Y5 and leptin receptor mRNA expression in the hypothalamic arcuate nucleus (Arc) of chronic high-energy diet-induced obese (DIO) and resistant (DR) mice. Forty mice were ided into two groups and fed either a high-fat (HF: 40% of calories from fat, 20% of calories from saturated fat n=34) or low-fat (LF: 10% of calories from fat, 1% from saturated fat n=6) diet. After 22 weeks of feeding, visceral fat accumulation was 69% higher in DIO mice compared with DR mice, and the former showed a moderate level of glucose intolerance. In DIO mice, the levels of NPY and leptin receptor mRNA expressions were significantly higher than in LF mice (+32 and +14%, P<0.001 and 0.05 respectively), indicating central leptin resistance, whereas the DR and LF groups did not differ. The level of Y2 receptor mRNA expression was similar between the DIO and LF groups but, importantly, was reduced approximately 20% in DR mice (P<0.005). The level of Y5 receptor mRNA was 36% lower in DR mice than DIO mice (P<0.05). The differences between DIO and DR mice identified by this study may assist in a better understanding of genetic predisposition to an increased fat deposition induced by a chronic high-fat diet. A low level of Y2 and Y5 receptor mRNA expression may contribute to the prevention of chronic high-energy diet-induced obesity in DR mice.
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.PNPBP.2006.07.004
Abstract: The posterior cingulate cortex (PCC), a key component of the limbic system, has been implicated in the pathology of schizophrenia because of its sensitivity to NMDA receptor antagonists. Recent studies have shown that the PCC is dysfunctional in schizophrenia, and it is now suspected to be critically involved in the pathogenesis of schizophrenia. Studies also suggest that there are abnormalities in muscarinic and GABAergic neurotransmission in schizophrenia. Therefore, in the present study we used quantitative autoradiography to investigate the binding of [(3)H]pirenzepine, [(3)H]AF-DX 384 and [(3)H]muscimol, which respectively label M1/4 and M2/4 muscarinic and GABA(A) receptors, in the PCC of schizophrenia and control subjects matched for age and post-mortem interval. The present study found that [(3)H]pirenzepine binding was significantly decreased in the superficial (-24%, p=0.002) and deep (-35%, p<0.001) layers of the PCC in the schizophrenia group as compared with the control group. In contrast, a dramatic increase in [(3)H]muscimol binding was observed in the superficial (+112%, p=0.001) and deep layers (+100%, p=0.017) of the PCC in the schizophrenia group. No difference was observed for [(3)H]AF-DX 384 binding between the schizophrenia and control groups. The authors found a significant inverse correlation between [(3)H]pirenzepine binding in the deep cortical layers and [(3)H]muscimol binding in the superficial layers (rho=-0.732, p=0.003). In addition, negative correlations were also found between age and [(3)H]pirenzepine binding in both superficial and deep cortical layers (rho=-0.669 p=0.049 and rho=-0.778, p=0.014), and between age of schizophrenia onset and [(3)H]AF-DX 384 binding (rho=-0.798, p=0.018). These results for the first time demonstrated the status of M1/M4, M2/M4 and GABA(A) receptors in the PCC in schizophrenia. Whilst the exact mechanism causing these alterations is not yet known, a possible increased acetylcholine and down regulated GABA stimulation in the PCC of schizophrenia is suggested.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2016
DOI: 10.1007/S12031-016-0730-Y
Abstract: The GABAA receptor is implicated in the pathophysiology of schizophrenia and regulated by PKA signalling. Current antipsychotics bind with D2-like receptors, but not the GABAA receptor. The cAMP-responsive element-binding protein 1 (CREB1) is also associated with PKA signalling and may be related to the positive symptoms of schizophrenia. This study investigated the effects of antipsychotics in modulating D2-mediated PKA signalling and its downstream GABAA receptors and CREB1. Rats were treated orally with aripiprazole (0.75 mg/kg, ter in die (t.i.d.)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for 1 week. The levels of PKA-Cα and p-PKA in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) were detected by Western blots. The mRNA levels of Gabrb1, Gabrb2, Gabrb3 and Creb1, and their protein expression were measured by qRT-PCR and Western blots, respectively. Aripiprazole elevated the levels of p-PKA and the ratio of p-PKA/PKA in the NAc, but not the PFC and CPu. Correlated with this elevated PKA signalling, aripiprazole elevated the mRNA and protein expression of the GABAA (β-1) receptor and CREB1 in the NAc. While haloperidol elevated the levels of p-PKA and the ratio of p-PKA/PKA in both NAc and CPu, it only tended to increase the expression of the GABAA (β-1) receptor and CREB1 in the NAc, but not the CPu. Bifeprunox had no effects on PKA signalling in these brain regions. These results suggest that aripiprazole has selective effects on upregulating the GABAA (β-1) receptor and CREB1 in the NAc, probably via activating PKA signalling.
Publisher: The Endocrine Society
Date: 12-2014
DOI: 10.1210/EN.2014-1326
Abstract: Weight gain and its related metabolic disorders are major side effects associated with second generation antipsychotic drug treatment. The dorsal vagal complex (DVC) and AMP-activated protein kinase (AMPK) are implicated in the regulation of food intake and body weight. Blocking the histamine H1 receptor contributes to antipsychotic-induced weight gain. The present study investigated the time-dependent effect of olanzapine treatment (8, 16, and 36 d) on DVC AMPK signaling in olanzapine-induced weight gain and whether these changes are associated with olanzapine-induced H1 receptor antagonism. During the 8-day olanzapine treatment, the rats were hyperphagic and rapidly gained weight. The phosphorylation of AMPK (pAMPK) (activated AMPK) as well as its directly downstream phospho-acetyl-coenzyme A carboxylase was significantly increased. The pAMPK/AMPK ratio, an indicator of AMPK activity, was significantly positively correlated with feeding efficiency and weight gain. As treatment was prolonged (16 and 36 d of olanzapine treatment), the rats were no longer hyperphagic, and there were no longer any changes in DVC AMPK signaling. Although the DVC H1 receptor protein expression was not significantly altered by olanzapine, the pAMPK expression was significantly positively correlated with the H1 receptor level after the 8-, 16-, and 36-day olanzapine treatments. Moreover, we showed that an H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine, significantly inhibited the olanzapine-induced hyperphagia and DVC AMPK activation in a dose-dependent manner. These results suggest a time-dependent role of DVC AMPK in olanzapine-induced obesity. Thus, olanzapine-induced DVC AMPK activation may be at least partially related to olanzapine’s antagonistic effect on the H1 receptor.
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.NEURES.2007.08.001
Abstract: This study examined regional changes of 5-HT(2A and 2C) receptor mRNA expression in the rat brain after chronic administration of clozapine (1.5 mg/kg/day) and haloperidol (2.0 mg/kg/day) for 36 days. 5-HT(2A and 2C) receptor mRNA expression and distributions were detected by in situ hybridization after rats were sacrificed either 2 or 48 h after the last drug administration to examine both immediate and delayed effects following drug withdrawal. Following 2 h of drug withdrawal, it showed that clozapine administration significantly decreased 5-HT(2A) receptor mRNA, predominantly in the nucleus accumbens (65%), hippoc us (80%), lasteral septal nucleus (61%) and striatum (68%) compared to controls, whilst rebound increases were observed in most of these regions 48 h later. In contrast, no change in 5-HT(2A) receptor mRNA expression was found in the haloperidol treated groups either 2 h or 48 h after drug withdrawal. Clozapine also decreased 5-HT(2C) receptor mRNA expression in the posteromedial cortical amygdala (32%) and substantia nigra (35%) 2 h after the last drug administration, while rebound effects were also observed 48 h later. 5-HT(2C) receptor mRNA was only decreased in the substantia nigra at both 2 h (42%) and 48 h (54%) after the last haloperidol administration. Alterations in serotonin receptor expression in limbic system region such as the nucleus accumbens, hippoc us and lateral septal nucleus as well as the striatum may represent the specific regional targets that mediate the clinical effects of antipsychotics via the serotonin system.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.PHRS.2016.02.011
Abstract: Second generation antipsychotic drugs (SGAs) cause substantial body weight gain/obesity and other metabolic side-effects such as dyslipidaemia. Their antagonistic affinity to the histaminergic H1 receptor (H1R) has been identified as one of the main contributors to weight gain/obesity side-effects. The effects and mechanisms of betahistine (a histaminergic H1R agonist and H3 receptor antagonist) have been investigated for ameliorating SGA-induced weight gain/obesity in both animal models and clinical trials. It has been demonstrated that co-treatment with betahistine is effective in reducing weight gain, associated with olanzapine in drug-naïve patients with schizophrenia, as well as in the animal models of both drug-naïve rats and rats with chronic, repeated exposure to olanzapine. Betahistine co-treatment can reduce food intake and increase the effect of thermogenesis in brown adipose tissue by modulating hypothalamic H1R-NPY-AMPKα (NPY: neuropeptide Y AMPKα: AMP-activated protein kinase α) pathways, and ameliorate olanzapine-induced dyslipidaemia through modulation of AMPKα-SREBP-1-PPARα-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1 PPARα: Peroxisome proliferator-activated receptor-α) in the liver. Although reduced locomotor activity was observed from antipsychotic treatment in rats, betahistine did not affect locomotor activity. Importantly, betahistine co-treatment did not influence the effects of antipsychotics on serotonergic receptors in the key brain regions for antipsychotic therapeutic efficacy. However, betahistine co-treatment reverses the upregulated dopamine D2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D2 supersensitivity often observed in chronic antipsychotic treatment. Therefore, these results provide solid evidence supporting further clinical trials in treating antipsychotics-induced weight gain using betahistine in patients with schizophrenia and other mental disorders.
Publisher: MDPI AG
Date: 09-03-2018
DOI: 10.3390/IJMS17040459
Publisher: Elsevier BV
Date: 08-2004
Publisher: Informa UK Limited
Date: 07-02-2019
DOI: 10.1080/10408444.2019.1579780
Abstract: Nanotechnology has the potential to bring about revolutionary changes in manufacturing products, including sunscreens. However, a knowledge gap between benefits and detriments of engineered nano-materials used in sunscreens exists, which gives rise to safety concerns. This article is concerned with the protection of consumers without impairing the embellishment of this promising technology. It is widely argued that the harm associated with nano-sunscreens may only occur under certain conditions related mainly to users skin vulnerability, which can be avoided by informed and careful use of such a product. We thus recognize the need for fostering the growth of nanotech simultaneously with preventing potential harm. We revisit the Australian sunscreens regulatory policies, which embrace a "wait and see" approach, through the lens of regulatory policies in the European Union (EU) that are influenced by a "precautionary principle." We highlight the importance of informing consumers about the sunscreen they are using and recommend that product labels should disclose the presence of nano-ingredients in line with the EU disclosure requirements. This will allow users to carefully apply the product in order to avoid any potential harm and to protect manufacturers from possible costly litigation in future. This can be achieved through a combined collaborative effort of regulators, supply chain entities, and end users.
Publisher: Springer Science and Business Media LLC
Date: 11-2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-1996
DOI: 10.1097/00001756-199611040-00045
Abstract: The distribution of the leptin receptor in the brain of C57 mice was investigated using a non-radioactive in situ hybridization method. Leptin receptor mRNA expression was highest in the arcuate nucleus and median eminence of the hypothalamus, but it was also abundant in hippoc us, primarily in the dentate gyrus and CA1, and was detected at low levels in piriform cortex and the medial margin of the medial habenular nucleus. The localization of leptin receptor-containing neurones in the present study indicates the possibility that the leptin receptor is expressed on neuropeptide Y-containing neurones.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.JPSYCHIRES.2017.01.009
Abstract: Gene expression analyses in post-mortem schizophrenia brains suggest that a number of ubiquitin proteasome system (UPS) genes are associated with schizophrenia however the status of UPS proteins in the schizophrenia brain is largely unknown. Ubiquitin related proteins are inherently involved in memory, neuronal survival and morphology, which are processes implicated in neurodevelopmental disorders such as schizophrenia. We examined levels of five UPS proteins (Protein Inhibitor of Activated STAT2 [PIAS2], F-Box and Leucine rich repeat protein 21 [FBXL21], Mouse Double Minute 2 homolog [MDM2], Ubiquitin Carboxyl-Terminal Hydrolase-L1 [UCHL1] and Ubiquitin Conjugating Enzyme E2D1 [UBE2D1]) involved in these neuronal processes, within the dorsolateral prefrontal cortex of post-mortem schizophrenia subjects and matched controls (n = 30/group), in addition to across neurodevelopmental time-points (juvenile, adolescent and adult stages of life), utilizing a well-established neurodevelopmental phencyclidine (PCP) animal model of schizophrenia. We observed significant reductions in PIAS2, FBXL21 and MDM2 in schizophrenia subjects compared to controls (p-values ranging from 0.002 to 0.004). In our developmental PCP model, MDM2 protein was significantly reduced in adult PCP-treated rats compared to controls (p = 0.034). Additionally, FBXL21 (p = 0.022) and UCHL1 (p = 0.022) were significantly decreased, whilst UBE2D1 was increased (p = 0.022), in juvenile phencyclidine-treated rats compared to controls. This is the first study reporting alterations of UPS proteins in post-mortem human schizophrenia subjects and in a neurodevelopmental model of schizophrenia. The findings from this study provide strong support for a role of these UPS proteins in the pathology and development of schizophrenia.
Publisher: Public Library of Science (PLoS)
Date: 19-05-2015
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.APPET.2008.11.011
Abstract: This study aimed to characterise meal patterns and satiety effects of diets that are high in protein but differ in protein source. Using a computerised automatic recording system, meal pattern behaviour was recorded continuously for 7 days in mice fed single (whey, soy or gluten) or different combined protein diets. Overall, average energy intake was significantly lower in mice fed a whey protein diet than those fed soy, gluten and lab chow diets. Among these four diets, the inter-meal interval of mice fed a whey protein diet was the longest and their meal number was the lowest. Combination of whey and gluten caused a lower energy intake, longer inter-meal interval and lower meal number compared to the other paired combinations. A significant interaction effect between whey and gluten was found for the reduction of energy intake and meal number. In conclusion, this study showed that the whey protein diet had the most potent satiety effect (inter-meal), but no difference in satiation effect (intra-meal) compared with the other dietary proteins tested. Combination of whey and gluten in a high protein diet may be a better formula than other combinations to provide a satiety effect and suppress energy intake for antiobesity purposes.
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.NEUINT.2008.03.003
Abstract: Cocaine- and hetamine-regulated transcript (CART) peptide is widely expressed in the hypothalamus and is involved in the central regulation of energy balance. Using in situ hybridization, this study examined the roles of CART peptide in the hypothalamus of diet-induced obese (DIO) or diet-resistant (DR) mice under different dietary interventions including high-fat (HF), low-fat (LF) and pair-feeding (PF) diet for 6 weeks. Pair feeding the energy intake of the DIO and DR mice was used to determine whether there is an inherent difference in baseline CART expression that may cause the DIO and DR phenotypes. The results demonstrated that CART mRNA expression in the hypothalamus of the DIO mice responded differently on the high-fat diet compared to DR mice. The arcuate nucleus and paraventricular nucleus showed a significant reduction in CART mRNA expression in DIO mice compared to DR mice on the HF diet (-19.6%, p=0.019 -26.1%, p=0.003) whilst a profound increase in CART mRNA expression was observed in the dorsomedial nucleus and lateral hypothalamic area (+44.5%, p=0.007 +37.4%, p=0.033). Our study suggests that the decrease of CART mRNA expression in Arc and PVN regions of DIO mice may contribute to the development of high-fat diet-induced obesity. In addition, CART in the dorsomedial nucleus (DM) of hypothalamus and lateral hypothalamus (LH) may be involved in the activation of an orexigenic effect. Since pair feeding of the high-fat diet eliminated both the body weight and CART mRNA differences between the DIO and DR mice, it is likely that their alterations in gene expression were a consequence of their dissimilar body weight levels.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.CMET.2013.01.006
Abstract: Neuropepetide Y (NPY) is best known for its powerful stimulation of food intake and its effects on reducing energy expenditure. However, the pathways involved and the regulatory mechanisms behind this are not well understood. Here we demonstrate that NPY derived from the arcuate nucleus (Arc) is critical for the control of sympathetic outflow and brown adipose tissue (BAT) function. Mechanistically, a key change induced by Arc NPY signaling is a marked Y1 receptor-mediated reduction in tyrosine hydroxylase (TH) expression in the hypothalamic paraventricular nucleus (PVN), which is also associated with a reduction in TH expression in the locus coeruleus (LC) and other regions in the brainstem. Consistent with this, Arc NPY signaling decreased sympathetically innervated BAT thermogenesis, involving the downregulation of uncoupling protein 1 (UCP1) expression in BAT. Taken together, these data reveal a powerful Arc-NPY-regulated neuronal circuit that controls BAT thermogenesis and sympathetic output via TH neurons.
Publisher: MDPI AG
Date: 09-06-2015
DOI: 10.3390/NU7064705
Publisher: The Endocrine Society
Date: 10-06-2013
DOI: 10.1210/EN.2013-1218
Abstract: Chronic inflammation is involved in the pathogenesis of obesity and type 2 diabetes. Recently teasaponin, an extract from tea, has been shown to have antiinflammatory effects. We examined the effect of teasaponin on obesity, inflammation, glucose metabolism, and central leptin sensitivity in obese mice fed a high-fat (HF) diet for 16 weeks. Intraperitoneal injections of teasaponin (10 mg/kg, daily) for 21 days significantly decreased the food intake and body weight of HF diet-induced obese mice. Teasaponin treatment also reduced the protein levels of proinflammatory cytokines (TNF-α, IL-6, and/or IL-1β) and nuclear factor-κB signaling (phosphorylated inhibitory-κB kinase and phosphorylated inhibitory-κBα) in adipose tissue and the liver. The antiinflammatory effects of teasaponin were associated with improved glycemic status in the treated animals, evidenced by improved glucose tolerance, homeostasis model assessment, and fasting plasma insulin. In the hypothalamus, teasaponin decreased both proinflammatory cytokines and inflammatory signaling in the mediobasal hypothalamus. Teasaponin treatment also enhanced the anorexigenic effect of central leptin administration, restored leptin phosphorylated signal transducer and activator of transcription-3 (p-STAT3) signaling in the arcuate nucleus, and increased hypothalamic expression of the anorexigenic peptide proopiomelanocortin. These results identify a potential novel application for teasaponin as an antiobesity and antiinflammatory agent.
Publisher: SAGE Publications
Date: 26-02-2016
Abstract: Obesity induces chronic, low-grade inflammation, which increases the risk of colon cancer. We investigated the preventive effects of Bardoxolone methyl (BARD) on high-fat diet (HFD)-induced inflammation in a mouse colon. Male C57BL/6J mice ( n=7) were fed a HFD (HFD group), HFD plus BARD (10 mg/kg) in drinking water (HFD/BARD group), or normal laboratory chow diet (LFD group) for 21 weeks. In HFD mice, BARD reduced colon thickness and decreased colon weight per length. This was associated with an increase in colon crypt depth and the number of goblet cells per crypt. BARD reduced the expression of F4/80 and CD11c but increased CD206 and IL-10, indicating an anti-inflammatory effect. BARD prevented an increase of the intracellular pro-inflammatory biomarkers (NF-қB, p NF-қB, IL-6, TNF-α) and cell proliferation markers (Cox2 and Ki67). BARD prevented fat deposition in the colon wall and prevented microbial population changes. Overall, we report the preventive effects of BARD on colon inflammation in HFD-fed mice through its regulation of macrophages, NF-қB, cytokines, Cox2 and Ki67, fat deposition and microflora.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2016
DOI: 10.1038/SREP20766
Abstract: Protein Tyrosine Phosphatase 1B (PTP1B) has been recognized as a promising therapeutic target for treating obesity, diabetes, and certain cancers for over a decade. Previous drug design has focused on inhibitors targeting the active site of PTP1B. However, this has not been successful because the active site is positively charged and conserved among the protein tyrosine phosphatases. Therefore, it is important to develop PTP1B inhibitors with alternative inhibitory strategies. Using computational studies including molecular docking, molecular dynamics simulations, and binding free energy calculations, we found that lupane triterpenes selectively inhibited PTP1B by targeting its more hydrophobic and less conserved allosteric site. These findings were verified using two enzymatic assays. Furthermore, the cell culture studies showed that lupeol and betulinic acid inhibited the PTP1B activity stimulated by TNFα in neurons. Our study indicates that lupane triterpenes are selective PTP1B allosteric inhibitors with significant potential for treating those diseases with elevated PTP1B activity.
Publisher: Oxford University Press (OUP)
Date: 27-01-2014
Publisher: Oxford University Press (OUP)
Date: 12-08-2010
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.PNPBP.2009.04.010
Abstract: The superior temporal gyrus (STG) is strongly implicated in the pathophysiology of schizophrenia, particularly with regards to auditory hallucinations. In this study, using in situ quantitative autoradiography in postmortem tissue, we investigated the binding of the [3H]ketanserin to 5-HT(2A) receptors and [3H]mesulergine to 5-HT(2C) receptors in the left STG of 8 male schizophrenic patients compared to 8 control subjects. A strong [3H]ketanserin binding was observed in the STG, however there was a very weak [3H]mesulergine binding in the STG. A significant decrease in binding of [(3)H]ketanserin was clearly observed in schizophrenia patients in comparison with control subjects. There were no significant correlations between 5-HT(2A) binding density and age, postmortem intervals, or brain pH. These results suggest that the alterations of the 5-HT(2A) receptors contribute to the pathophysiology of the STG in schizophrenia. Furthermore, there is a clear tendency for a positive correlation between 5-HT(2A) and muscarinic M1 receptor bindings, and for negative correlations between 5-HT(2A) and GABA(A) receptor bindings and between muscarinic M1 and GABA(A) receptor bindings. This provides a possible mechanism of auditory hallucinations through interactions between 5-HT(2A), acetylcholine muscarinic and GABA transmissions in the STG in schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 21-03-2008
DOI: 10.1007/S11064-008-9661-5
Abstract: This study examined changes in neuropeptide Y (NPY) Y2 receptor binding in the brains of C57BL/6 mice in response to different levels of high-fat diets via three dietary intervention methods: high-fat diet, switching from high- to low-fat diet and finally, energy restricted high-fat diet. Forty-five C57Bl/6 male mice were fed a high-fat diet for 8 weeks and then classified as diet-induced obese (DIO) or diet-resistant (DR) mice according to the highest and lowest body weight gainers, respectively. The DIO and DR mice were then randomly ided into three groups each and either continued on their high-fat diet ad libitum (DIO-H and DR-H), changed to a low-fat diet (DIO-L and DR-L) or pair-fed via energy restricted high-fat diet (DIO-P and DR-P) for a further 6 weeks. During the course of this study, body weight, energy intake and plasma peptide YY (PYY) were measured. The study revealed that the replacement of a high-fat diet with a low-fat diet was associated with a significant lowering of ventromedial hypothalamic (VMH) Y2 receptor binding in both the DIO-L and DR-L mice (-37%, -36%), and also a lowered plasma PYY level in the DIO-L mice (-25%). Despite a continued consumption of the high-fat diet, energy restricted pair feeding caused a lower VMH Y2 receptor binding in the obese mice (DIO-P) following weight loss compared to the DR-P mice (-14%). In conclusion, this study showed that changing diets from high- to low-fat can significantly lower the VMH Y2 receptor binding irrespective to the obesity phenotype. Energy restriction, even while on high-fat feeding, can cause a lower VMH Y2 receptor binding compared to DR mice even after body weight loss to similar levels. This suggests either a possible intrinsic nature of the DIO mice or a body weight set-point re-establishment to drive body weight regain.
Publisher: Wiley
Date: 03-2010
DOI: 10.1002/SYN.20722
Abstract: The serotonergic system has close interactions with the dopaminergic system and is strongly implicated in the pathophysiological mechanisms and therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate regional changes in 5-hydroxytryptamine (5-HT) 2A receptors in the rat brain 3 weeks after unilateral medial forebrain bundle lesion by 6-hydroxydopamine (6-OHDA). 5-HT 2A receptor distributions and alterations in the postmortem rat brain were detected by [(3)H]ketanserin-binding autoradiography. In the 6-OHDA-induced Parkinson's rat model, nigrostriatal dopaminergic neuron loss significantly mediated the decreased [(3)H]ketanserin binding, predominantly in the agranular insular cortex (17.3%, P = 0.03), cingulate cortex (18.2%, P < 0.001), prefrontal cortex (8%, P = 0.043), primary somatosensory cortex (17.7%, P = 0.002), and caudate putamen (14.5%, P = 0.02) compared to controls while a profound reduction of tyrosine hydroxylase (TH) immunostaining in the striatum was also observed. Alterations in [(3)H]ketanserin binding in the examined brain areas may represent the specific regions that mediate cognitive dysfunctions via the serotonin system. The downregulation of 5-HT(2A) receptor binding in this study also provides indirect evidence for plasticity in the serotonergic system in the rat brains. This study contributes to a better understanding of the critical roles of 5-HT(2A) receptors in treating neurodegenerative disorders and implicates 5-HT(2A) receptors as a novel therapeutic target in the treatment of PD.
Publisher: CMA Joule Inc.
Date: 11-2014
DOI: 10.1503/JPN.130242
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.PNPBP.2011.02.017
Abstract: Schizophrenia is a debilitating neurodevelopmental psychiatric disorder. Both the N-methyl-D-aspartate receptor (NMDAR) and neuregulin1 (NRG1) are key molecules involved in normal brain development that have been linked to schizophrenia pathology and aetiology. The NR2 proteins are critical structural and functional subunits of the NMDAR and are developmentally and spatially regulated. Altered NR2 gene and protein expression has been found in human post-mortem schizophrenia brain tissue together with changes in NRG1 and its receptor ErbB4. The NR2 subunits and ErbB4 share a common anchoring domain on the postsynaptic density and therefore a disruption to either of these molecules may influence the functioning of the other. It has been shown that NRG1 signalling can affect NMDAR levels and function, particularly phosphorylation of the NR2 subunits. However little is known about the possible effects of NMDAR dysfunction on NRG1 signalling, which is important with regards to schizophrenia aetiology as numerous risk factors for the disorder can alter NMDAR functioning during early brain development. This review focuses on the role of the NMDA receptor subunits and NRG1 signalling in schizophrenia and proposes a mechanism by which a disruption to the NMDAR, particularly via altering the balance of NR2 subunits during early development, could influence NRG1 signalling.
Publisher: Oxford University Press (OUP)
Date: 29-09-2010
Publisher: Wiley
Date: 18-05-2009
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.JACL.2009.04.054
Abstract: Dietary beta-glucans lower the blood concentrations of cholesterol in animals and humans. Recent studies have uncovered mechanisms by which dietary beta-glucans may regulate cholesterol homeostasis. There is evidence that beta-glucans sequester bile acids in the intestine, reducing their reabsorption and return to the liver. Reducing hepatic bile acid concentrations activates the enzyme CYP7A1, which converts cholesterol into bile acids. This action leads to a reduction of hepatic cell cholesterol content, which up-regulates low-density lipoprotein (LDL) receptor synthesis and thereby accelerates the transportation of LDL-cholesterol from the blood into hepatocytes. Reduced intracellular cholesterol also up-regulates the hepatic synthesis of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase and could therefore provide an additive effect in suppressing hepatocyte cholesterol to that produced by enhancing its depletion with beta-glucans. Through this combination of agents, one would expect a greater clearance of LDL from the plasma with lower steady state levels of LDL-cholesterol.
Publisher: Wiley
Date: 21-09-2015
Abstract: Obesity impairs cognition, and the leptin-induced increase of brain-derived neurotrophic factor (BDNF) and neurogenesis. Tea consumption improves cognition and increases brain activation in the prefrontal cortex. This study examined whether teasaponin, an active ingredient in tea, could improve memory and central leptin effects on neurogenesis in the prefrontal cortex of obese mice, and in vitro in cultured prefrontal cortical neurons. Teasaponin (10 mg/kg, intraperitoneal) for 21 days improved downstream leptin signaling (JAK2 and STAT3), and leptin's effect on BDNF, in the prefrontal cortex of high-fat diet (HFD) fed mice. Prefrontal cortical neurons were cultured with teasaponin and palmitic acid (the most abundant dietary saturated fatty acid) to examine their effects on neurogenesis and BDNF expression in response to leptin. Palmitic acid decreased leptin's effect on neurite outgrowth, postsynaptic density protein 95, and BDNF expression in cultured cortical neurons, which was reversed by teasaponin. Teasaponin improved the leptin sensitivity of prefrontal cortical neurons in obese mice or when treated by palmitic acid. This in turn increased BDNF expression and neurite growth. Therefore, teasaponin supplementation may be used to prevent obesity-associated neurodegeneration and improve cognitive function.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-08-2005
DOI: 10.1097/01.WNR.0000174056.11403.71
Abstract: Using quantitative autoradiography, the present study examined ionotropic glutamatergic receptor binding sites using [3H]dizocilpine, [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate, and [3H]kainate in the posterior cingulate cortex of schizophrenia patients and matched controls. We found a significant increase in [3H]dizocilpine binding in the superficial layers (41%, p<0.001) and deep layers (30%, p=0.004) of the posterior cingulate cortex in the schizophrenia group compared with controls. No significant differences were observed in [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate and [3H]kainate binding. In summary, the present study has for the first time demonstrated that the glutamatergic system is affected in the posterior cingulate cortex in schizophrenia patients. The fact that only the N-methyl-D-aspartate receptor densities are significantly altered suggests that this is unlikely to be caused by a simple decrease in glutamatergic transmission.
Publisher: SAGE Publications
Date: 13-06-2012
Abstract: Olanzapine is effective at treating multiple domains of schizophrenia symptoms. However, it induces serious metabolic side effects. Antipsychotic drug’s antagonistic affinity to histamine H 1 receptors has been identified as a main contributor for weight gain/obesity side effects. This study therefore investigated whether a combined treatment of betahistine (a H 1 receptor agonist and H 3 receptor antagonist) could reduce the body weight/obesity induced by olanzapine. Female Sprague Dawley rats were treated orally with olanzapine (1 mg/kg, t.i.d.) and/or betahistine (2.67 mg/kg, t.i.d.), or vehicle for two weeks. Rats treated with olanzapine exhibited significant body weight gain and increased food intake. Co-treatment of olanzapine with betahistine significantly prevented (-45%) weight gain and reduced feeding efficiency compared to sole olanzapine treatment. Betahistine treatment alone had no effect on weight gain and food intake. Olanzapine reduced locomotor activity, but not betahistine. These findings demonstrate that olanzapine-induced body weight gain can partially be reduced by co-treatment with betahistine. Betahistine has H 3 receptor antagonistic effects to increase histamine release, which may augment its direct agonistic effects on H 1 receptors. These findings have important implications for clinical trials using betahistine to control antipsychotic-induced obesity side effects.
Publisher: American Chemical Society (ACS)
Date: 14-12-2011
DOI: 10.1021/AM201508D
Abstract: A highly sensitive and selective dopamine sensor was fabricated with the unique 3D carbon nanotube nanoweb (CNT-N) electrode. The as-synthesised CNT-N was modified by oxygen plasma to graft functional groups in order to increase selective electroactive sites at the CNT sidewalls. This electrode was characterized physically and electrochemically using HRSEM, Raman, FT-IR, and cyclic voltammetry (CV). Our investigations indicated that the O(2)-plasma treated CNT-N electrode could serve as a highly sensitive biosensor for the selective sensing of dopamine (DA, 1 μM to 20 μM) in the presence of ascorbic acid (AA, 1000 μM).
Publisher: Springer Science and Business Media LLC
Date: 10-10-2013
DOI: 10.1007/S40263-013-0115-5
Abstract: Second generation antipsychotics (SGAs) are widely prescribed to treat various disorders, most notably schizophrenia and bipolar disorder however, SGAs can cause abnormal glucose metabolism that can lead to insulin-resistance and type 2 diabetes mellitus side-effects by largely unknown mechanisms. This review explores the potential candidature of the acetylcholine (ACh) muscarinic M3 receptor (M3R) as a prime mechanistic and possible therapeutic target of interest in SGA-induced insulin dysregulation. Studies have identified that SGA binding affinity to the M3R is a predictor of diabetes risk indeed, olanzapine and clozapine, SGAs with the highest clinical incidence of diabetes side-effects, are potent M3R antagonists. Pancreatic M3Rs regulate the glucose-stimulated cholinergic pathway of insulin secretion their activation on β-cells stimulates insulin secretion, while M3R blockade decreases insulin secretion. Genetic modification of M3Rs causes robust alterations in insulin levels and glucose tolerance in mice. Olanzapine alters M3R density in discrete nuclei of the hypothalamus and caudal brainstem, regions that regulate glucose homeostasis and insulin secretion through vagal innervation of the pancreas. Furthermore, studies have demonstrated a dynamic sensitivity of hypothalamic and brainstem M3Rs to altered glucometabolic status of the body. Therefore, the M3R is in a prime position to influence glucose homeostasis through direct effects on pancreatic β-cells and by potentially altering signalling in the hypothalamus and brainstem. SGA-induced insulin dysregulation may be partly due to blockade of central and peripheral M3Rs, causing an initial disruption to insulin secretion and glucose homeostasis that can progressively lead to insulin resistance and diabetes during chronic treatment.
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.EURONEURO.2008.12.002
Abstract: N-methyl-D-aspartate (NMDA) receptor blockade in rodents induces behavioural and neurochemical changes reminiscent of schizophrenia symptoms and pathology. To examine how NMDA receptor blockade affects glutamatergic and GABAergic pathways when administered during early brain development, [3H]MK-801 and [3H]muscimol binding to NMDA and GABA(A) receptors was examined at four time-points following injections of phencyclidine (PCP) or saline on postnatal days (PN)7, 9 and 11. [3H]MK-801 binding was significantly increased in PCP-treated rats in the thalamus from PN18 to PN96, in the prefrontal and anterior cingulate cortices at PN32, and in the hippoc us at PN96. In a similar manner, [3H]muscimol binding was increased in PCP-treated rats in the thalamus and hippoc us from PN18 to PN96, and in the prefrontal and anterior cingulate cortices at PN32. Glutamatergic and GABAergic transmission is therefore chronically altered by this treatment, which has relevance to disease processes that may be involved in schizophrenia.
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.NEULET.2007.05.035
Abstract: The quantitative sudomotor axon reflex test (QSART) measures sympathetic C fibre function when iontophoresed acetylcholine (Ach) evokes a measurable reliable sweat response. This study tests a novel, simplified method of sweat stimulation which accompanies hand dynamometry. In 34 healthy subjects we compared the standard sudomotor axon reflex test with a simplified method using static handgrip as sweat stimulus and recorded from the distal forearm, thumb and little finger tips. The standard method failed on technical grounds beyond the forearm. At the distal forearm, sweat rates were 313+/-140nl/min, representing a four-fold increase from baseline. Static handgrip induced sweat rates of 339+/-156 (thumb) and 296+/-139 (little finger)nl/min, representing a 1.7 and 1.6 fold increase from baseline. Static handgrip did not significantly alter distal forearm sweat secretion, and in females handgrip induced significantly less sweating over the thumb than in males. After dynamometry or Ach stimulation, over the three sites (thumb, little finger and forearm), the stimulated sweat secretion volumes were measured at 0.0278+/-0.021microl/cm(2)/min (thumb), 0.0204+/-0.020microl/cm(2)/min (little finger), and 0.0503+/-0.0283microl/cm(2)/min (forearm) after correction. Our study suggests the static handgrip method can be used to stimulate distal sweat production and may be of particular significance in investigating length-dependant neuropathies and assessing distal C fiber function.
Publisher: Springer Science and Business Media LLC
Date: 21-09-2023
Publisher: Springer Science and Business Media LLC
Date: 08-10-2014
Publisher: Wiley
Date: 06-2008
Publisher: Wiley
Date: 08-04-1993
Abstract: In order to investigate the topography and sub isions of the human dorsal motor nucleus of the vagus nerve (10), studies were conducted using cyto- and chemoarchitectonic (acetylcholinesterase and substance P-like immunoreactivity) and computer reconstruction techniques. The six brainstems examined were obtained within 17 hours postmortem from adults with no known neurological disorders. Serial sections cut in transverse, sagittal, and coronal planes were stained with cresyl violet, or tested for acetylcholinesterase or substance P. The neurons of the 10 (16,826 +/- 967) displayed cyto- and chemoarchitectonic heterogeneity and could be classified into six types. Types I-V consist of presumed vagal motor neurons (13,802 +/- 844), while the remaining type (Type VI) consisted of presumed interneurons (3,024 +/- 769). The 10 was sub ided into nine subnuclei grouped regionally into rostral, intermediate, and caudal isions on the basis of neuronal morphology, cell density, and differential AChE and substance P reactivities. The rostral ision contains the dorsorostral (DoR) and the ventrorostral (VeR) subnuclei the intermediate ision contains the rostrointermediate (RoI), dorsointermediate (DoI), centrointermediate (CeI), ventrointermediate (VeI), and caudointermediate (CaI) subnuclei the caudal ision (Ca) is not sub ided. Morphologically, small round or oval cells populate the VeR and VeI. Medium-sized oval cells occur in the DoR, CeI, and Ca, while medium-sized fusiform and multipolar cells are the main features of CaI. Large triangular cells appear mainly in DoI. Glial cells show the highest predilection for CeI, lowest densities in DoI and medial fringe subnucleus (MeF), and intermediate densities in the remaining six subnuclei. VeI showed the strongest AChE reactivity. Although the cell bodies of VeR and DoI are AChE positive, the neuropil (background) is weakly stained. Densely distributed fine granular substance P-like immunoreactivity occurs throughout the entire nucleus, while the intermediate and caudal isions contain substance P-like-immunoreactive neurons. Three-dimensional computer reconstructions afforded an appreciation of the distinctiveness of the intermediate ision (a ision that contains the majority of cells) and the caudal ision, which displays the lowest density of presumed vagal motoneurons. It is possible that the subnuclei identified herein form functional units innervating specific organs.
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1016/J.BBR.2006.08.034
Abstract: This study examined the density of dopamine transporter (DAT) and D2 receptors in the brains of chronic high-fat diet-induced obese (cDIO), obese-resistant (cDR) and low-fat-fed (LF) control mice. Significantly decreased DAT densities were observed in cDR mice compared to cDIO and LF mice, primarily in the nucleus accumbens, striatal and hypothalamic regions. D2 receptor density was significantly lower in the rostral part of caudate putamen in cDIO mice compared to cDR and LF mice.
Publisher: Wiley
Date: 13-10-2008
DOI: 10.1111/J.1365-2826.2008.01785.X
Abstract: The cannabinoid CB1 receptor has been implicated in the regulation of appetite and the consumption of palatable foods. This experiment aimed to explore the involvement of the CB1 receptor in the early and late stages of high fat diet-induced obesity in C57BL/6 mice. The C57Bl/6 mice were placed on a high fat (HF) or low fat/high carbohydrate (LF) diet for 3 or 20 weeks. Quantitative autoradiography revealed that binding of [3H] CP-55,940 (CB1 receptor ligand) was elevated following 3 weeks of HF feeding in areas including the medial/ventral anterior olfactory nucleus (22.1%), agranular insular cortex (24.0%) and the hypothalamus (31.5%) compared to LF controls. This increased level of binding was correlated with an increase in plasma leptin in the hypothalamus, raising the possibility that this hormone may exert inhibitory control over endocannabinoid signalling at this stage of obesity. Mice fed a HF diet for 20 weeks were obese, hyperphagic and had decreased CB1 receptor binding levels in the substantia nigra (12.8%) and ventral tegmental area (17.1%) compared to LF controls. The low [3H] CP-55,940 binding density seen in these reward-related areas in the late stage of obesity may be indicative of increased endocannabinoid release due to the chronic HF diet consumption.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Wiley
Date: 09-1993
Abstract: The aim of this study was to provide a comprehensive account of the topography, morphology, and frequencies of the substance P- and tyrosine hydroxylase-containing neurons in the human dorsal motor nucleus of the vagus nerve. The morphology of immunoreactive neurons was studied and the variations of the cell distributions were presented by three-dimensional computer reconstructions. Three types of substance P-like immunoreactive neurons were identified. They were predominantly located in the dorsointermediate, centrointermediate, caudointermediate, and caudal ision of the dorsal motor nucleus of the vagus nerve. The morphology of substance P-like immunoreactive neurons varied according to the subnuclei in which they were found. Three types of tyrosine hydroxylase-like immunoreactive neurons were identified, mainly in the periphery of the dorsal motor nucleus of the vagus nerve, including the medial fringe, ventrointermediate, and dorsointermediate subnuclei of the 10. Many cells throughout the ventrointermediate subnucleus of the dorsal motor nucleus of the vagus nerve are seen ventrally to intermingle with the tyrosine hydroxylase neurons of the intermediate reticular zone. Computer reconstructions provided a three-dimensional view of the positions of substance P- and tyrosine hydroxylase-like immunoreactive neurons within the sub isions of the dorsal motor nucleus of the vagus nerve. The uneven distribution of substance P- and tyrosine hydroxylase-like immunoreactive neurons within the sub isions suggests an involvement of these substances in some, but not all, autonomic functions of the dorsal motor nucleus of the vagus nerve.
Publisher: Springer Science and Business Media LLC
Date: 08-11-2016
DOI: 10.1038/SREP36087
Abstract: Prenatal infection and subsequent abnormal neurodevelopment of offspring is involved in the etiology of schizophrenia. Brain-derived neurotrophic factor (BDNF) and its high affinity receptor, tropomyosin receptor kinase B (TrkB) signaling plays a key role in the neurodevelopment. Pregnant mice exposed to polyriboinosinic-polyribocytidylic acid [poly(I:C)] causes schizophrenia-like behavioral abnormalities in their offspring at adulthood. Here we found that the juvenile offspring of poly(I:C)-treated mice showed cognitive deficits, as well as reduced BDNF-TrkB signaling in the prefrontal cortex (PFC). Furthermore, the adult offspring of poly(I:C)-treated mice showed cognitive deficits, prepulse inhibition (PPI) deficits, reduced BDNF-TrkB signaling, immunoreactivity of parvalbumin (PV) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in the prelimbic (PrL) of medial PFC and CA1 of hippoc us. Supplementation of a TrkB agonist 7,8-dihydroxyflavone (1 mg/mL in drinking water) during juvenile and adolescent stages could prevent these behavioral abnormalities, reduced BDNF-TrkB signaling in PFC and CA1, and immunoreactivity of PV and PGC-1α in the PrL of medial PFC and CA1 in the adult offspring from poly(I:C)-treated mice. These findings suggest that early intervention by a TrkB agonist in subjects with ultra-high risk for psychosis may reduce the risk of subsequent transition to schizophrenia.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.BBR.2015.09.024
Abstract: There is increasing evidence that chronic noise stress impairs cognition and induces oxidative stress in the brain. Recently, orientin, a phenolic compound abundant in some fruits, millet, and herbs, has been shown to have antioxidant properties. This study investigated the potential effects of orientin against chronic noise-induced cognitive decline and its underlying mechanisms. A moderate-intensity noise exposure model was used to investigate the effects of orientin on behavior and biochemical alterations in mice. After 3 weeks of the noise exposure, the mice were treated with orientin (20mg/kg and 40 mg/kg, oral gavage) for 3 weeks. The chronic noise exposure impaired the learning and memory in mice in the Morris water maze and step-through tests. The noise exposure also decreased exploration and interest in a novel environment in the open field test. The administration of orientin significantly reversed noise-induced alterations in these behavior tests. Moreover, the orientin treatment significantly improved the noise-induced alteration of serum corticosterone and catecholamine levels and oxidative stress in the hippoc us and prefrontal cortex. Furthermore, the orientin treatment ameliorated the noise-induced decrease in brain-derived neurotrophic factor and synapse-associated proteins (synaptophysin and postsynaptic density protein 95) in the hippoc us and prefrontal cortex. Thus, orientin exerts protective effects on noise-induced cognitive decline in mice, specifically by improving central oxidative stress, neurotransmission, and increases synapse-associated proteins. Therefore, supplementation with orientin-enriched food or fruit could be beneficial as a preventive strategy for chronic noise-induced cognitive decline.
Publisher: Elsevier BV
Date: 09-04-2008
DOI: 10.1016/J.BBR.2007.11.017
Abstract: Perinatal phencyclidine (PCP) treatment leads to neuronal damage and causes long-term behavioural alterations in rodents. This study examined the effects of perinatal PCP treatment on behaviour of adult rats in holeboard, elevated plus maze, social interaction and forced swim tests. PCP-treated rats displayed hyperactivity in the holeboard and forced swim tests. These persistent behavioural changes are relevant to the study of psychiatric disorders such as schizophrenia.
Start Date: 06-2006
End Date: 03-2009
Amount: $225,444.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2010
End Date: 12-2010
Amount: $450,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 09-2009
End Date: 12-2009
Amount: $400,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2014
End Date: 12-2014
Amount: $370,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 01-2012
End Date: 12-2012
Amount: $300,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2019
End Date: 12-2019
Amount: $1,480,000.00
Funder: Australian Research Council
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