ORCID Profile
0000-0002-5793-6147
Current Organisation
University of South Australia
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Publisher: Wiley
Date: 12-09-2021
DOI: 10.1002/JNR.24959
Abstract: Cancer patients may experience symptom clusters, including chemotherapy‐induced (CI) gut toxicity (CIGT) and cognitive impairment. Analgesic selection for pain associated with CIGT is difficult as opioids induce glial reactivity and unwanted side effects. This study quantified central glial reactivity and proinflammatory effects in rats with CIGT using three mechanistically different analgesics. Regional adaptations were indicative of immune‐to‐brain signaling routes. Utilizing a 5‐fluorouracil‐induced GT (5IGT) rat model and analgesic intervention (carprofen (CAR), buprenorphine (BUP), and tramadol (TRAM)), spinal and brain neuroimmune modulation was examined via microglial, astrocyte, and proinflammatory (cluster of differentiation molecule 11b CD11b, glial fibrillary associated protein GFAP, and interleukin‐1 beta IL1β) reactivity marker expression changes by western blot analysis. 5IGT significantly increased thoracic GFAP ( p 0.05) and IL‐1β ( p 0.0001) expression, CAR and BUP ameliorated these effects. BUP and TRAM with 5‐FU synergistically increased hippoc al GFAP expression. CAR administered with 5IGT significantly elevated hippoc al and thoracic CD11b expression levels ( p 0.05). The neuroimmune responses observed in this study suggest activation of peripheral‐to‐central immune signaling pathways. We speculate that the opioid‐induced hippoc al changes inferred a humorally mediated mechanism, whereas thoracic neuroimmune modifications indicated activation of an indirect neural route. Although TRAM ameliorated 5IGT‐intestinal inflammation, this opioid presents complications relating to bodyweight and regional glial dysregulation (neuroinflammation) and may not be optimal in the management of pain associated with 5IGT. The chemotherapy‐induced gut‐derived neuroimmune consequences observed suggest a potential mechanistic contribution to central components of the cancer symptom cluster experience, while the opioid‐related glial changes have implications for optimal pain management in this setting warranting further investigation.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2016
DOI: 10.1007/S11064-016-1875-3
Abstract: In this study we investigated the effects of insulin-induced hypoglycaemia on tyrosine hydroxylase (TH) protein and TH phosphorylation in the adrenal gland, C1 cell group, locus coeruleus (LC) and midbrain dopaminergic cell groups that are thought to play a role in response to hypoglycaemia and compared the effects of different concentrations of insulin in rats. Insulin (1 and 10 U/kg) treatment caused similar reductions in blood glucose concentration (from 7.5-9 to 2-3 mmol/L) however, plasma adrenaline concentration was increased 20-30 fold in response to 10 U/kg insulin and only 14 fold following 1 U/kg. Time course studies (at 10 U/kg insulin) revealed that in the adrenal gland, Ser31 phosphorylation was increased between 30 and 90 min (4-5 fold), implying that TH was activated to increase catecholamine synthesis in adrenal medulla to replenish the stores. In the brain, Ser19 phosphorylation was limited to certain dopaminergic groups in the midbrain, while Ser31 phosphorylation was increased in most catecholaminergic regions at 60 min (1.3-2 fold), suggesting that Ser31 phosphorylation may be an important mechanism to maintain catecholamine synthesis in the brain. Comparing the effects of 1 and 10 U/kg insulin revealed that Ser31 phosphorylation was increased to similar extent in the adrenal gland and C1 cell group in response to both doses whereas Ser31 and Ser19 phosphorylation were only increased in response to 1 U/kg insulin in LC and in response to 10 U/kg insulin in most midbrain regions. Thus, the adrenal gland and some catecholaminergic brain regions become activated in response to insulin administration and brain catecholamines may be important for initiation of physiological defences against insulin-induced hypoglycaemia.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.PHYSBEH.2022.113721
Abstract: Stress hormones such as cortisol play a critical role in depressive disorders. Therefore, corticosterone has been used to develop a depression model in animals. Our previous studies found that the precursor of brain-derived neurotrophic factor (proBDNF) and its receptors are upregulated in depression in human and animal models. In the present study, we aimed to examine whether proBDNF and mature BDNF (mBDNF) are altered in the corticosterone-induced depression model in mice. Male and female mice were given corticosterone dissolved in 0.3% hydroxypropyl- β-cyclodextrin (β-CD) or vehicle (β-CD) in drinking water for 33 days. We have found that corticosterone induced depressive-like behaviours as reflected by increased immobility time in the tail suspension test and decreased grooming time in the splash test. Corticosterone also induced anxiety-like behaviours as represented by decreased entries into the central zone of the open field test and the open arms of the elevated plus maze test. We found that corticosterone administration resulted in differential changes of proBDNF and mature BDNF in different brain regions and peripheral tissues. ProBDNF was increased in the hippoc us and cerebellum, but no change was found in the prefrontal cortex and hypothalamus. Both proBDNF and mBDNF were significantly increased in the pituitary gland. In contrast, proBDNF was significantly decreased in the adrenal gland. There were no significant changes in proBDNF or mBDNF in other peripheral tissues, including the liver and sex organs. We conclude that the stress hormone corticosterone causes depressive behaviours but differentially regulates the processing of proBDNF in mice. ProBDNF may participate in the development of depression behaviours in corticosterone treated animals.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.PNEUROBIO.2018.01.002
Abstract: Parkinson's disease (PD) is a common neurodegenerative disease worldwide. While the typical motor symptoms of PD are well known, the lesser known non-motor symptoms can also greatly impact the patient's quality of life. These symptoms often appear before motor impairment, therefore identifying biomarkers that may predict PD risk or pathology has been a major and challenging endeavour. Given that the loss of dopamine, and its rate-limiting enzyme tyrosine hydroxylase (TH) occurs in PD, the expression and accompanying post-translational changes in TH during PD progression could yield insight into the disruption of cellular signalling occurring in the CNS, and also in peripheral tissues wherein catecholamine function plays a role. Furthermore, changes in expression and phosphorylation of TH in the brain and periphery can potentially reveal how TH stability and function are compromised in PD. As such, these changes can reveal how catecholamine synthesis capacity is gradually compromised and how changes in cellular signalling may govern the functional status of remaining catecholaminergic neurons. This review summarises the findings of clinical PD and neurotoxin models of PD that assessed TH expression or phosphorylation in catecholaminergic pathways in the brain and relevant peripheral tissues. We propose that establishing similar changes in TH expression and function in the CNS and periphery of established neurotoxin models can be a potential reference for comparison to changes in TH in human peripheral tissues. These changes in TH expression and phosphorylation may have predictive validity to estimate risk of PD progression before motor impairment is evident.
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.CELLSIG.2006.12.006
Abstract: Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine synthesis. Its activity is controlled by PACAP, acutely by phosphorylation at Ser40 and chronically by protein synthesis. Using bovine adrenal chromaffin cells we found that PACAP, acting via the continuous activation of PACAP 1 receptors, sustained the phosphorylation of TH at Ser40 and led to TH activation for up to 24 h in the absence of TH protein synthesis. The sustained phosphorylation of TH at Ser40 was not mediated by hierarchical phosphorylation of TH at either Ser19 or Ser31. PACAP caused sustained activation of PKA, but did not sustain activation of other protein kinases including ERK, p38 kinase, PKC, MAPKAPK2 and MSK1. The PKA inhibitor H89 substantially inhibited the acute and the sustained phosphorylation of TH mediated by PACAP. PACAP also inhibited the activity of PP2A and PP2C at 24 h. PACAP therefore sustained TH phosphorylation at Ser40 for 24 h by sustaining the activation of PKA and causing inactivation of Ser40 phosphatases. The PKA activator 8-CPT-6Phe-cAMP also caused sustained phosphorylation of TH at Ser40 that was inhibited by the PKA inhibitor H89. Using cyclic AMP agonist pairs we found that sustained phosphorylation of TH was due to both the RI and the RII isotypes of PKA. The sustained activation of TH that occurred as a result of TH phosphorylation at Ser40 could maintain the synthesis of catecholamines without the need for further stimulus of the adrenal cells or increased TH protein synthesis.
Publisher: Springer Science and Business Media LLC
Date: 11-07-2018
Publisher: Elsevier BV
Date: 07-2018
Publisher: Elsevier
Date: 2023
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.EXPNEUROL.2017.10.018
Abstract: Amyloid plaque is one of the hallmarks of Alzheimer's disease (AD). The key component beta-amyloid (Aβ) is generated via proteolytic processing of amyloid precursor protein (APP). Sortilin (encoded by the gene Sort1) is a vacuolar protein sorting 10 protein domain-containing receptor, which is up-regulated in the brain of AD, colocalizes with amyloid plaques and interacts with APP. However, its role in amyloidogenesis remains unclear. In this study, we first found that the protein level of sortilin was up-regulated in the neocortex of aged (7 and 9months old) but not young (2 and 5months old) AD mice (APP/PS1). 9months old APP/PS1 transgenic mice with Sort1 gene knockout showed increased amyloid pathology in the brain and this phenotype was rescued by intrahippoc al injection of AAV-hSORT1. Moreover, the 9months old APP/PS1 mice without Sort1 also displayed a decreased number of neurons and increased astrocyte activation in the hippoc us. In addition, the present study showed that the intracellular domain of sortilin was involved in the regulation of the non-specific degradation of APP. Together, our findings indicate that sortilin is a beneficial protein for the reduction of amyloid pathology in APP/PS1 mice by promoting APP degradation.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2018
DOI: 10.1007/S11064-017-2464-9
Abstract: Treatment with mature brain-derived neurotrophic factor (mBDNF) promotes functional recovery after ischemia in animal trials but the possible role of its precursor protein proBDNF and its receptors or the factors responsible for the conversion of proBDNF to mBDNF in ischemic stroke are not known. The main aim of this study was to characterize the time-dependent expression of genes and/or proteins related to BDNF processing and signaling after ischemia as well as the sensorimotor behavioral dysfunction in a photothrombotic ischemic model in rats. Characterization of different genes and proteins related to BDNF processing and signaling was performed using qPCR, immunoblotting and enzyme-linked immunosorbent assays. We showed in this study that some sensory and motor functional deficiencies appeared in the ischemic group at day 1 and persisted until day 14. Most changes in gene expression of BDNF and its processing enzymes occurred within the first 24 h in the ipsilateral cortex, but not in the contralateral cortex. At the protein level, proBDNF expression was increased at 6 h, mBDNF expression was increased between 15 h and 1 day while p75 receptor protein expression was increased between 6 h and 3 days in the ipsilateral cortex, but not in the contralateral cortex. Therefore, cerebral ischemia in rats led to the up-regulation of genes and/or proteins of BDNF, proBDNF and their processing enzymes and receptors in a time-dependent manner. We propose that the balance between BDNF and proBDNF and their associated proteins may play an important role in the pathogenesis and recovery from ischemia.
Publisher: Springer Science and Business Media LLC
Date: 07-02-2013
DOI: 10.1007/S11064-013-0985-4
Abstract: Previous studies have shown that early life stress induced by maternal separation or non-handling can lead to behavioural deficits in rats and that these deficits can be alleviated by providing palatable cafeteria high-fat diet (HFD). In these studies we investigated the effects of maternal separation or non-handling and HFD on tyrosine hydroxylase (TH) protein and TH phosphorylation at Ser40 (pSer40TH) and the expression of angiotensin II receptor type 1 (AT1R) protein in the adrenal gland as markers of sympatho-adrenomedullary activation. After littering, Sprague-Dawley rats were assigned to short maternal separation, S15 (15 min), prolonged maternal separation, S180 (180 min) daily from postnatal days 2-14 or were non-handled (NH) until weaning. Siblings were exposed to HFD or chow from day 21 until 19 weeks when adrenals were harvested. Maternal separation and non-handling had no effects on adrenal TH protein in both sexes. We found an effect of HFD only in the females HFD significantly increased TH levels in NH rats and pSer40TH in S180 rats (relative to corresponding chow-fed groups), but had no effect on AT1R expression in any group. In contrast, in male rats HFD had no effect on TH protein levels, but significantly increased pSer40TH across all treatment groups. There was no effect of HFD on AT1R expression in male rats however, maternal separation (for 15 or 180 min) caused significant increases in AT1R expression (relative to NH group regardless of diet). This is the first study to report that early life stress and diet modulate TH protein, pSer40TH and AT1R protein levels in the adrenal gland in a sex dependent manner. These results are interpreted in respect to the potential adverse effects that these changes in the adrenal gland may have in males and females in adult life.
Publisher: MDPI AG
Date: 03-02-2022
DOI: 10.3390/IJMS23031740
Abstract: Induced neural stem cells (iNSCs) reprogrammed from somatic cells hold great potentials for drug discovery, disease modelling and the treatment of neurological diseases. Although studies have shown that human somatic cells can be converted into iNSCs by introducing transcription factors, these iNSCs are unlikely to be used for clinical application due to the safety concern of using exogenous genes and viral transduction vectors. Here, we report the successful conversion of human fibroblasts into iNSCs using a cocktail of small molecules. Furthermore, our results demonstrate that these human iNSCs (hiNSCs) have similar gene expression profiles to bona fide NSCs, can proliferate, and are capable of differentiating into glial cells and functional neurons. This study collectively describes a novel approach based on small molecules to produce hiNSCs from human fibroblasts, which may be useful for both research and therapeutic purposes.
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.NEUROSCIENCE.2011.06.087
Abstract: Tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, is regulated acutely by protein phosphorylation. No studies have systematically investigated the time course of TH phosphorylation in vivo in response to different stressors. We therefore determined the extent of TH phosphorylation at Ser19, Ser31, and Ser40 over a 40-min period in response to footshock or immobilization stress in the rat locus coeruleus and adrenal medulla. There were significant changes in TH phosphorylation in both tissues and the responses to the two stressors differed markedly. With each of the phosphorylation sites immobilization stress caused a much smaller, or less sustained, response than footshock stress. With immobilization stress there was a transient increase in Ser31 phosphorylation in the locus coeruleus and in the adrenal medulla, but there were no effects on Ser19 or Ser40 phosphorylation. With footshock stress there was a substantial decrease in Ser19 phosphorylation over time, a substantial increase in Ser31 phosphorylation over time, but there were no effects on Ser40 phosphorylation. Measuring TH phosphorylation at Ser19, Ser31, and Ser40 over time can therefore be used as a sensitive index to differentiate the effects of different stressors on catecholaminergic cells.
Publisher: OMICS Publishing Group
Date: 2017
Publisher: Springer Science and Business Media LLC
Date: 17-06-2016
DOI: 10.1038/NPP.2016.100
Publisher: Springer Science and Business Media LLC
Date: 17-03-2020
Publisher: Wiley
Date: 2018
DOI: 10.1002/J.2769-2795.2018.TB00030.X
Abstract: To investigate the clinical effectiveness of treatment with hypothermia, erythropoietin (EPO), hyperbaric oxygenation (HBO), xenon gas treatment, melatonin for neonates with hypoxic‐ischemia encephalopathy (HIE). A comprehensive searching work of related publications was carried out in the Pubmed and CNKI database. Those randomized controlled trials deemed eligible, which made comparisons between the therapies for neonates with HIE and the normal treatment. The continuous and dichotomous data were evaluated by weighted mean difference (WMD) and risk ratio (RR) or Odds Ratio (OR) with 95% confidence interval (CI), respectively. After searching for the interesting publications concerning the therapies, xenon gas and melatonin treatment were out of analysis due to the lack of enough clinical data. Hypothermia treatment made contributions to a notable reduction concerning the incidence of death in neonatal HIE compared with normothermic treatment during the follow‐up (OR = 0.66 95% CI = 0.48, 0.91 p = 0.01) EPO treatment correlated with a great reduction in the incidence of severe brain injury in neonatal HIE compared with placebo treatment. There was no significance between the EPO and placebo groups concerning incidence of death (OR = 0.84 95% CI = 0.45, 1.56 p = 0.57). Moreover, HBO shortened the time of muscular tension recovery and awareness restoration (MD = ‐1.67 95% CI = ‐2.05, ‐1.3 p .00001). Hypothermia, EPO and HBO were effective in the treatment of neonates with HIE. Whereas, there are still lack of le clinical data to guarantee the proper handle of their long‐term effects.
Publisher: Informa UK Limited
Date: 06-02-2019
Publisher: Elsevier BV
Date: 07-2021
DOI: 10.1016/J.NEURO.2021.05.015
Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disease, characterised by the loss of dopaminergic neurons in the substantia nigra. Mounting evidence indicates a crucial role of inflammation and concomitant oxidative stress in the disease progression. Therefore, the aim of this study was to investigate the ability of systemically administered lipopolysaccharide (LPS) to induce motor and non-motor symptoms of PD, inflammation, oxidative stress and major neuropathological hallmarks of the disease in regions postulated to be affected, including the olfactory bulb, hippoc us, midbrain and cerebellum. Twenty-one male C57BL/6 mice, approximately 20 weeks old, received a dose of 0.3 mg/kg/day of LPS systemically on 4 consecutive days and behavioural testing was conducted on days 14-18 post-treatment, followed by tissue collection. Systemically administered LPS increased latency time in the buried food seeking test (indicative of olfactory impairment), and decreased time spent in central zone of the open field (anxiety-like behaviour). However, there was no change in latency time in the rotarod test or the expression of tyrosine hydroxylase (TH) in the midbrain. Systemically administered LPS induced increased glial markers GFAP and Iba-1 and oxidative stress marker 3-nitrotyrosine (3-NT) in the olfactory bulb, hippoc us, midbrain and cerebellum, and there were region specific changes in the expression of NFκB, IL-1β, α-synuclein, TH and BDNF proteins. The model could be useful to further elucidate early non-motor aspects of PD and the possible mechanisms contributing to the non-motor deficits.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2012
Publisher: Mary Ann Liebert Inc
Date: 15-04-2020
Publisher: Elsevier BV
Date: 10-2020
Publisher: Wiley
Date: 19-01-2011
DOI: 10.1111/J.1471-4159.2010.07151.X
Abstract: Striatal delivery of dopamine (DA) by midbrain substantia nigra pars compacta (SNc) neurons is vital for motor control and its depletion causes the motor symptoms of Parkinson's disease. While membrane potential changes or neuronal activity regulates tyrosine hydroxylase (TH, the rate limiting enzyme in catecholamine synthesis) expression in other catecholaminergic cells, it is not known whether the same occurs in adult SNc neurons. We administered drugs known to alter neuronal activity to mouse SNc DAergic neurons in various experimental preparations and measured changes in their TH expression. In cultured midbrain neurons, blockade of action potentials with 1 μM tetrodotoxin decreased TH expression beginning around 20 h later (as measured in real time by green fluorescent protein (GFP) expression driven off TH promoter activity). By contrast, partial blockade of small-conductance, Ca(2+) -activated potassium channels with 300 nM apamin increased TH mRNA and protein between 12 and 24 h later in slices of adult midbrain. Two-week infusions of 300 nM apamin directly to the adult mouse midbrain in vivo also increased TH expression in SNc neurons, measured immunohistochemically. Paradoxically, the number of TH immunoreactive (TH+) SNc neurons decreased in these animals. Similar in vivo infusions of drugs affecting other ion-channels and receptors (L-type voltage-activated Ca(2+) channels, GABA(A) receptors, high K(+) , DA receptors) also increased or decreased cellular TH immunoreactivity but decreased or increased, respectively, the number of TH+ cells in SNc. We conclude that in adult SNc neurons: (i) TH expression is activity-dependent and begins to change ∼20 h following sustained changes in neuronal activity (ii) ion-channels and receptors mediating cell-autonomous activity or synaptic input are equally potent in altering TH expression and (iii) activity-dependent changes in TH expression are balanced by opposing changes in the number of TH+ SNc cells.
Publisher: Springer Science and Business Media LLC
Date: 15-06-2022
DOI: 10.1007/S11011-022-01029-X
Abstract: Most Alzheimer disease (AD) patients present as sporadic late onset AD, with metabolic factors playing an important role in the occurrence and development of AD. Given the link between peripheral insulin resistance and tau pathology in streptozotocin-injected and db/db mouse models of diabetes, we fed high fat diet (HFD) to pR5 mice expressing P301L mutant human tau, with the aim of developing a new model with characteristics of obesity, T2DM and AD to mimic AD patients exacerbated by obesity and T2DM, an increasing trend in modern society. In our study, pR5 and C57BL/6 (WT) mice were randomly allocated to a standard diet (STD) or HFD for 30 weeks starting at 8 weeks of age. Food intake was measured weekly, body weight and fasting glucose levels were measured fortnightly, and a comprehensive behavioral test battery was performed to assess anxiety, depression and cognitive dysfunction. Glucose and insulin tolerance tests were performed after 30 weeks of HFD. We also investigated the effect of long term HFD on tau pathology in the brains of WT and P301L mice by performing western blotting of whole brain homogenates for total tau, phosphorylated tau at Ser396 and Thr231. Our results show that pR5 mice fed with HFD are more vulnerable to diet induced obesity compared to WT, especially with increasing age. In addition, pR5 mice on HFD developed glucose intolerance and insulin resistance. It was identified that long term HFD significantly aggravates depression like behavior and impairs cognitive function in pR5 mice, and also induces anxiety like behavior in both pR5 and WT mice. Long term HFD was also shown to aggravate tau hyperphosphorylation in pR5 transgenic mice, and increase total and hyperphosphorylated tau in WT mice. These results indicate that diet induced obesity of pR5 transgenic mice expressing P301L mutant human tau generates T2DM, and aggravates tau phosphorylation, and is therefore a model useful for investigations that seek to understand the relationships between AD, T2DM and obesity, and the underlying biochemical changes and mechanisms associated with metabolic disorders and AD tauopathy.
Publisher: MDPI AG
Date: 27-09-2023
Publisher: Public Library of Science (PLoS)
Date: 29-11-2012
Publisher: Wiley
Date: 27-09-2018
DOI: 10.1111/JNC.14206
Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deposition of amyloid beta (Aβ) and dysregulation of neurotrophic signaling, causing synaptic dysfunction, loss of memory, and cell death. The expression of p75 neurotrophin receptor is elevated in the brain of AD patients, suggesting its involvement in this disease. However, the exact mechanism of its action is not yet clear. Here, we show that p75 interacts with beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), and this interaction is enhanced in the presence of Aβ. Our results suggest that the colocalization of BACE1 and amyloid precursor protein (APP) is increased in the presence of both Aβ and p75 in cortical neurons. In addition, the localization of APP and BACE1 in early endosomes is increased in the presence of Aβ and p75. An increased phosphorylation of APP-Thr668 and BACE1-Ser498 by c-Jun N-terminal kinase (JNK) in the presence of Aβ and p75 could be responsible for this localization. In conclusion, our study proposes a potential involvement in amyloidogenesis for p75, which may represent a future therapeutic target for AD. Cover Image for this Issue: doi. 10.1111/jnc.14163.
Publisher: Elsevier BV
Date: 04-2016
Publisher: MDPI AG
Date: 06-11-2021
Abstract: Neurological disorders are big public health challenges that are afflicting hundreds of millions of people around the world. Although many conventional pharmacological therapies have been tested in patients, their therapeutic efficacies to alleviate their symptoms and slow down the course of the diseases are usually limited. Cell therapy has attracted the interest of many researchers in the last several decades and has brought new hope for treating neurological disorders. Moreover, numerous studies have shown promising results. However, none of the studies has led to a promising therapy for patients with neurological disorders, despite the ongoing and completed clinical trials. There are many factors that may affect the outcome of cell therapy for neurological disorders due to the complexity of the nervous system, especially cell types for transplantation and the specific disease for treatment. This paper provides a review of the various cell types from humans that may be clinically used for neurological disorders, based on their characteristics and current progress in related studies.
Publisher: Oxford University Press (OUP)
Date: 08-10-2009
Abstract: In this study, we demonstrate that human neuroblastoma SH-SY5Y cells transfected with human tyrosine hydroxylase isoform 1 (SH + TH cells) were substantially more resistant to cell death induced by hydrogen peroxide and 6-hydroxydopamine when compared to wild-type SH-SY5Y cells (SH cells). SH + TH cells exhibit increased levels of dopamine (DA) compared to SH cells. Incubation with hydrogen peroxide or 6-hydroxydopamine (10-100microM) for 24 h caused a significant reduction in cell viability and increased apoptosis in both cell types. However, these effects were significantly reduced in the SH + TH cells when compared to the SH cells. The SH + TH cells showed an improved ability to detoxify peroxide, which correlated with an increase in glutathione peroxidase and glutathione reductase activities, while catalase activity was unchanged. Our data suggest that a preconditioning-like mechanism linked to higher DA levels increased the resistance of SH + TH cells against oxidative insults, which is at least in part related to an augmentation in the activity of glutathione-related antioxidant enzymes.
Publisher: MDPI AG
Date: 11-11-2022
DOI: 10.3390/NU14224776
Abstract: Poorer mental health is common in undergraduate students due to academic stress. An interplay between stress and diet exists, with stress influencing food choices. Nutritional interventions may be effective in preventing mental health decline due to complex bidirectional interactions between the brain, the gut and the gut microbiota. Previous studies have shown walnut consumption has a positive effect on mental health. Here, using a randomized clinical trial (Australian New Zealand Clinical Trials Registry, #ACTRN12619000972123), we aimed to investigate the effects of academic stress and daily walnut consumption in university students on mental health, biochemical markers of general health, and the gut microbiota. We found academic stress had a negative impact on self-reported mood and mental health status, while daily walnut consumption improved mental health indicators and protected against some of the negative effects of academic stress on metabolic and stress biomarkers. Academic stress was associated with lower gut microbial ersity in females, which was improved by walnut consumption. The effects of academic stress or walnut consumption in male participants could not be established due to small numbers of participants. Thus, walnut consumption may have a protective effect against some of the negative impacts of academic stress, however sex-dependent mechanisms require further study.
Publisher: Wiley
Date: 18-10-2018
DOI: 10.1002/CNE.24523
Abstract: Low blood glucose activates brainstem adrenergic and cholinergic neurons, driving adrenaline secretion from the adrenal medulla and glucagon release from the pancreas. Despite their roles in maintaining glucose homeostasis, the distributions of insulin-responsive adrenergic and cholinergic neurons in the medulla are unknown. We fasted rats overnight and gave them insulin (10 U/kg i.p.) or saline after 2 weeks of handling. Blood s les were collected before injection and before perfusion at 90 min. We immunoperoxidase-stained transverse sections of perfused medulla to show Fos plus either phenylethanolamine N-methyltransferase (PNMT) or choline acetyltransferase (ChAT). Insulin injection lowered blood glucose from 4.9 ± 0.3 mmol/L to 1.7 ± 0.2 mmol/L (mean ± SEM n = 6) saline injection had no effect. In insulin-treated rats, many PNMT-immunoreactive C1 neurons had Fos-immunoreactive nuclei, with the proportion of activated neurons being highest in the caudal part of the C1 column. In the rostral ventrolateral medulla, 33.3% ± 1.4% (n = 8) of C1 neurons were Fos-positive. Insulin also induced Fos in 47.2% ± 2.0% (n = 5) of dorsal medullary C3 neurons and in some C2 neurons. In the dorsal motor nucleus of the vagus (DMV), insulin evoked Fos in many ChAT-positive neurons. Activated neurons were concentrated in the medial and middle regions of the DMV beneath and just rostral to the area postrema. In control rats, very few C1, C2, or C3 neurons and no DMV neurons were Fos-positive. The high numbers of PNMT-immunoreactive and ChAT-immunoreactive neurons that express Fos after insulin treatment reinforce the importance of these neurons in the central response to a decrease in glucose bioavailability.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2017
Publisher: Frontiers Media SA
Date: 23-01-2019
Publisher: Bentham Science Publishers Ltd.
Date: 03-2020
DOI: 10.2174/1389200221666200502015203
Abstract: p75ECD-Fc is a recombinant human protein that has recently been developed as a novel therapy for Alzheimer’s disease. Current studies showed that it is able to alleviate Alzheimer’s disease pathologies in animal models of dementia. Thus, knowledge about the pharmacokinetic behavior and tissue distribution of this novel protein is crucial in order to better understand its pharmacodynamics and more importantly for its clinical development. The aim of this study is to characterize the pharmacokinetics of p75ECD-Fc after single intravenous and subcutaneous injection of 3mg/kg in Sprague Dawley rats. We calculated the bioavailability of the SC route and studied the distribution of that protein in different tissues, cerebrospinal fluid and urine using ELISA and immunofluorescence techniques. In-vitro stability of the drug was also assessed. Data obtained were analyzed with Non-compartmental pharmacokinetic method using R. Results showed that the bioavailability of SC route was 66.15%. Half-life time was 7.5 ± 1.7 and 6.2 ± 2.4 days for IV and SC injection, respectively. Tissue distribution of p75ECD-Fc was modest with the ability to penetrate the blood brain barrier. It showed high in vitro stability in human plasma. These acceptable pharmacokinetic properties of p75ECD-Fc present it as a potential candidate for clinical development for the treatment of Alzheimer’s disease.
Publisher: Elsevier BV
Date: 2002
Publisher: Wiley
Date: 06-1998
DOI: 10.1046/J.1471-4159.1998.70062565.X
Abstract: The aim of this study was to determine the effect of angiotensin II (AII) on tyrosine hydroxylase (TOH) activity and phosphorylation in bovine adrenal chromaffin cells (BACCs). We report here that stimulation of BACCs with AII (100 nM) produced a significant increase in both TOH activity and phosphorylation over a period of 10 min. The increase in TOH activity was receptor-mediated. Tryptic phosphopeptide analysis by HPLC revealed that AII stimulated an increase in phosphorylation of three sites on TOH, Ser19, Ser31, and Ser40, with the largest increase being observed for Ser31 phosphorylation. Pretreatment of the cells with the protein kinase C inhibitor Ro 31-8220 (10 microM, 15 min) did not affect TOH activity or phosphorylation produced by AII. The inhibitor also did not affect the TOH activity or Ser40 phosphorylation produced by forskolin (10 microM, 10 min). In contrast, Ro 31-8220 fully inhibited the TOH activation as well as Ser31 and Ser40 phosphorylation of TOH produced by phorbol 12,13-dibutyrate (500 nM, 10 min). Removal of extracellular Ca2+ from the incubation medium inhibited the AII-induced TOH activity by 50% and significantly blocked Ser19 and Ser31 phosphorylation but did not affect Ser40 phosphorylation in response to AII. These results indicate that AII activates a complex and perhaps novel signaling pathway leading to the phosphorylation and activation of TOH. The TOH activation by AII appears to be partially independent of Ser40 phosphorylation, suggesting a potentially important role for Ser31 phosphorylation.
Publisher: Springer Science and Business Media LLC
Date: 18-07-2020
Publisher: MDPI AG
Date: 11-02-2022
DOI: 10.3390/IJMS23042013
Abstract: Compelling evidence is building for the involvement of the complex, bidirectional communication axis between the gastrointestinal tract and the brain in neuropsychiatric disorders such as depression. With depression projected to be the number one health concern by 2030 and its pathophysiology yet to be fully elucidated, a comprehensive understanding of the interactions between environmental factors, such as stress and diet, with the neurobiology of depression is needed. In this review, the latest research on the effects of stress on the bidirectional connections between the brain and the gut across the most widely used animal models of stress and depression is summarised, followed by comparisons of the ersity and composition of the gut microbiota across animal models of stress and depression with possible implications for the gut–brain axis and the impact of dietary changes on these. The composition of the gut microbiota was consistently altered across the animal models investigated, although differences between each of the studies and models existed. Chronic stressors appeared to have negative effects on both brain and gut health, while supplementation with prebiotics and/or probiotics show promise in alleviating depression pathophysiology.
Publisher: Elsevier BV
Date: 03-1999
DOI: 10.1016/S0165-0270(99)00002-3
Abstract: A method for simultaneous measurement of tyrosine hydroxylase (TH) activation and phosphorylation in permeabilised and intact bovine adrenal chromaffin cells (BACCs) was established. Permeabilised cells were stimulated with cyclic AMP (1--10 microM) in the presence of [32P]ATP and L-[carboxyl-(14)C]tyrosine. Intact BACCs were preincubated with 32P(i) for 3 h and stimulated with forskolin (1--5 microM) in the presence of L-[carboxyl-(14)C]tyrosine. On stimulation each well was covered with a sealed 'chimney' fitted with a small plastic cup containing 300 microl of 1.0 M NaOH that trapped the 14CO(2) released. TH activity was determined by measuring 14C radioactivity. TH phosphorylation was measured in the same cells by separating the solubilized proteins on SDS PAGE followed by autoradiography and/or HPLC analysis. It was found that H89, a protein kinase A inhibitor, significantly blocked both TH phosphorylation and activation in response to cyclic AMP in permeabilised cells. However, in intact cells, H89 was effective only in respect to forskolin-stimulated TH activity and did not block the forskolin-stimulated TH phosphorylation of Ser-40. The reason(s) for this lack of correlation between TH activation and phosphorylation is presently not understood.
Publisher: Springer Science and Business Media LLC
Date: 02-09-2010
DOI: 10.1007/S11064-010-0255-7
Abstract: Tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, is regulated acutely by protein phosphorylation and chronically by protein synthesis. No studies have systematically investigated the phosphorylation of these sites in vivo in response to stressors. We specifically investigated the phosphorylation of TH occurring within the first 24 h in response to the social defeat stress in the rat adrenal, the locus coeruleus, substantia nigra and ventral tegmental area. Five groups were investigated home cage control (HCC), two groups that underwent social defeat (SD+) which were sacrificed either 10 min or 24 h after the end of the protocol and two groups that were put into the cage without the resident being present (SD-) which were sacrificed at time points identical to the SD+. We found at 10 min there were significant increases in serine 40 and 31 phosphorylation levels in the locus coeruleus in SD+ compared to HCC and increases in serine 40 phosphorylation levels in the substantia nigra in SD+ compared to SD-. We found at 24 h there were significant increases in serine 19 phosphorylation levels in the ventral tegmental area in SD+ compared to HCC and decreases in serine 40 phosphorylation levels in the adrenal in SD+ compared to SD-. These findings suggest that the regulation of TH phosphorylation in different catecholamine-producing cells varies considerably and is dependent on both the nature of the stressor and the time at which the response is analysed.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.AUTNEU.2013.05.001
Abstract: The principal aim of this study was to determine whether prolonged chronic footshock stress can evoke sustained changes in blood pressure in rats and to elucidate possible underlying neurochemical mechanisms as mediated by the sympathoadrenal system. Adult male Wistar rats instrumented for telemetric recording of arterial pressure, heart rate and locomotor activity were subjected to six weeks of inescapable unpredictable electrical footshocks (FS+) or were exposed to shock chambers but were not shocked (FS-). Compared to FS- animals, FS+ animals had significantly reduced body weight gain (by 30%), locomotor activity (by 25%) and social interaction time (by 30%)--symptoms commonly induced by chronic stress and depression in humans. These changes were associated with small, but significant increases in systolic blood pressure (by 7%) and pulse pressure (by 11%) in FS+ rats relative to FS- rats. We have also found neurochemical alterations in sympathoadrenal pathways (that lasted for at least one week post-stress) including about 2-3 fold increases in the levels of tyrosine hydroxylase phosphorylation in the sympathetic ganglia and adrenal gland and a 1.8-fold increase in the expression of the Angiotensin II receptor type 1 protein in the adrenal gland of FS+ rats relative to FS- rats. We conclude that uncontrollable and unpredictable footshock stress can lead to elevation in systolic blood pressure when applied for an extended period of time (six weeks) in Wistar rats, and that these changes could be mediated by stress-induced modifications in sympathoadrenal pathways.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.JCHEMNEU.2019.01.010
Abstract: Loss of dopaminergic neurons in the substantia nigra (SN) is one of the pathological hallmarks in Parkinson's disease (PD). This neuron loss is accompanied by reduced protein and activity levels of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine synthesis. Reduced nigral brain-derived neurotrophic factor (BDNF) has been postulated to contribute to the loss of nigral dopaminergic neurons in PD by causing a lack of trophic support. Prior to this nigral cell loss many patients develop non-motor symptoms such as hyposmia, constipation and orthostatic hypotension. We investigated how TH, BDNF and BDNF related receptors are altered in the SN, olfactory bulb, adrenal glands and colon (which are known to be affected in PD) using rotenone-treated rats. Rotenone was administered to Sprague-Dawley rats at a dose of 2.75 mg/kg, 5 days/week for 4 weeks, via intraperitoneal injections. Rats underwent behavioural testing, and tissues were collected for western blot and ELISA analysis. This rotenone treatment induced reduced rears and distance travelled in the rearing and open field test, respectively but caused no impairments in forced movement (rotarod test). The SN had changes consistent with a pro-apoptotic state, such as increased proBDNF but no change in TH whereas, the colon had significantly reduced TH and increased sortilin. Thus, our results indicate further investigation is warranted for this rotenone-dosing paradigm's capacity for reproducing the early stage of PD, as we observed impairments in voluntary movement and pathology in the colon without overt motor symptoms or nigral dopaminergic loss.
Publisher: Springer Science and Business Media LLC
Date: 07-07-2022
DOI: 10.1007/S00216-022-04186-1
Abstract: Low-dose methotrexate (MTX) plays a key role in treatment of rheumatoid arthritis. However, not all patients respond satisfactorily, and no therapeutic drug monitoring has been implemented in clinical practice, despite the fact that MTX therapy has now been available for decades. Analysis of in idual intracellular MTX metabolites among rheumatoid arthritis (RA) patients is h ered by the low intracellular concentrations of MTX-PGs which require a highly sensitive method to quantify. Here, we present a rapid and highly sensitive LC (HILIC) MS/MS method with LLOQ 0.1 nM, 0.8 nmol/L for each metabolite of MTX-PG 1-5 and MTX-PG 6-7 respectively. Over a linear range of 0.1–100 nM, 0.8–100 nmol/L for each metabolite of MTX-PG 1-5 and MTX-PG 6-7 , respectively, the inter- and intra- accuracy and precision were within 15% of the nominal value for all MTX metabolites. The presented assay was used to assess and compare MTX metabolite concentrations extracted from four different matrices: red blood cells, plasma, peripheral blood mononuclear cells, and whole blood that have been collected either using traditional venepuncture or volumetric absorptive micro-s ling (VAMS) s ling techniques. The presented method not only improves analyte coverage and sensitivity as compared to other published methods it also improves the greenness. Graphical abstract
Publisher: Wiley
Date: 08-2001
DOI: 10.1046/J.1471-4159.2001.00445.X
Abstract: Angiotensin II (AII, 100 nM) stimulation of bovine adrenal chromaffin cells (BACCs) produced angiotensin II receptor subtype 1 (AT1)-mediated increases in extracellular regulated protein kinase 1/2 (ERK1/2) and stress-activated p38MAPK (p38 kinase) phosphorylation over a period of 10 min. ERK1/2 and p38 kinase phosphorylation preceded Ser31 phosphorylation on tyrosine hydroxylase (TOH). The inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) activation, PD98059 (0.1-50 microM) and UO126 (0.1-10 microM), dose-dependently inhibited both ERK2 and Ser31 phosphorylation on TOH in response to AII, suggesting MEK1/2 involvement. The p38 kinase inhibitor SB203580 (20 microM, 30 min) abolished Ser31 and Ser19 phosphorylation on TOH and partially inhibited ERK2 phosphorylation produced by AII. In contrast, 1 microM SB203580 did not affect AII-stimulated TOH phosphorylation, but fully inhibited heat shock protein 27 (HSP27) phosphorylation produced by AII. Also, 1 microM SB203580 fully inhibited Ser19 phosphorylation on TOH and HSP27 phosphorylation in response to anisomycin (30 min, 10 microg/mL). The results suggest that ERKs mediate Ser31 phosphorylation on TOH in response to AII, but p38 kinase is not involved. Previous studies suggesting a role for p38 kinase in the phosphorylation of Ser31 are explained by the non-specific effects of 20 microM SB203580 in BACCs. The p38 kinase pathway is able to phosphorylate Ser19 on TOH in response to anisomycin, but does not do so in response to AII.
Publisher: Wiley
Date: 22-11-2020
DOI: 10.1111/SMS.13858
Publisher: Elsevier BV
Date: 07-2020
Publisher: Springer Science and Business Media LLC
Date: 24-05-2019
DOI: 10.1007/S12031-019-01328-6
Abstract: In this study, we aimed to establish the effects of chronic corticosterone (CORT) and ethanol administration on mood-related behaviour and the levels of mature brain-derived neurotrophic factor (mBDNF) and its precursor protein proBDNF in mice. C57BL6 male and female mice received drinking water (n = 22), 1% ethanol in drinking water (n = 16) or 100 μg/ml corticosterone in drinking water (containing 1% ethanol, n = 18) for 4.5 weeks. At the end of experimental protocol, the open field test (OFT) and elevated plus maze test were performed. Brain and adrenal tissues were collected and mBDNF and proBDNF were measured by ELISA assays. We found that the mice fed with corticosterone and ethanol developed anxiety-like behaviours as evidenced by reduced time in the central zone in the OFT compared with the control group. Both proBDNF and mBDNF were significantly decreased in the corticosterone and ethanol groups compared with the control group in the prefrontal cortex, hippoc us, hypothalamus and adrenal. The ratio of proBDNF/mBDNF in prefrontal cortex in the corticosterone group was increased compared with the ethanol group. Our data suggest that the ratio of proBDNF/mBDNF is differentially regulated in different tissues. Ethanol and corticosterone downregulate both mBDNF and proBDNF and alter the balance of proBDNF/mBDNF in some tissues. In conclusion, the ethanol and corticosterone may cause abnormal regulation of mBDNF and proBDNF which may lead to mood disorders.
Publisher: IEEE
Date: 05-2019
Publisher: Elsevier BV
Date: 2021
Publisher: MDPI AG
Date: 05-01-2021
DOI: 10.3390/IJMS22010459
Abstract: Elucidation of the biological functions of extracellular vesicles (EVs) and their potential roles in physiological and pathological processes is an expanding field of research. In this study, we characterized USC–derived EVs and studied their capacity to modulate the human immune response in vitro. We found that the USC–derived EVs are a heterogeneous population, ranging in size from that of micro–vesicles (150 nm–1 μm) down to that of exosomes (60–150 nm). Regarding their immunomodulatory functions, we found that upon isolation, the EVs (60–150 nm) induced B cell proliferation and IgM antibody secretion. Analysis of the EV contents unexpectedly revealed the presence of BAFF, APRIL, IL–6, and CD40L, all known to play a central role in B cell stimulation, differentiation, and humoral immunity. In regard to their effect on T cell functions, they resembled the function of mesenchymal stem cell (MSC)–derived EVs previously described, suppressing T cell response to activation. The finding that USC–derived EVs transport a potent bioactive cargo opens the door to a novel therapeutic avenue for boosting B cell responses in immunodeficiency or cancer.
Publisher: Wiley
Date: 02-07-2004
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.NEURO.2018.02.013
Abstract: While people are often aware of the motor symptoms in Parkinson's disease (PD), few know of the many non-motor symptoms, which patients report have a greater impact on their quality of life. Gastrointestinal (GI) dysfunction is one of the most common non-motor symptoms, which can occur at any stage of PD, even years prior to diagnosis, and can affect all sections along the GI tract causing a range of symptoms including drooling, gastroparesis and constipation. We have investigated whether a neurotoxin model of PD induced by rotenone, a mitochondrial complex I inhibitor, is capable of reproducing the GI dysfunction seen clinically. Sprague-Dawley rats were administered 2.75 mg/kg rotenone, 5 days/week for 4 weeks, via intraperitoneal injection. Rats underwent behavioural testing, including the one-hour stool and gastric emptying tests before GI contents and tissues were collected for microbiota and histological analysis. Rats exposed to rotenone had more days with evidence of diarrhoea and significantly delayed gastric emptying, reproducing the clinical symptom of gastroparesis. Microbiota analysis revealed alterations in the small intestine and colon of rotenone-treated rats, relatively consistent with changes described in PD patients. Histological analysis demonstrated mucosal thickening and goblet cell hyperplasia in the colon of rotenone rats, which may be an adaptive response to the toxin or changes in GI microbiota. Our results indicate that rotenone may be a good model for investigating the mechanisms involved with Parkinson's GI symptoms and for screening potential therapeutic options as it is capable of recapitulating some key GI changes that occur during PD progression.
Publisher: Wiley
Date: 07-2016
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.EXPNEUROL.2016.04.015
Abstract: Exposure to stressful life events plays a central role in the development of mood disorders in vulnerable in iduals. However, the mechanisms that link mood disorders to stress are poorly understood. Brain-derived neurotrophic factor (BDNF) has long been implicated in positive regulation of depression and anxiety, while its precursor (proBDNF) recently showed an opposing effect on such mental illnesses. P75(NTR) and sortilin are co-receptors of proBDNF, however, the role of these receptors in mood regulation is not established. Here, we aimed to investigate the role of sortilin in regulating mood-related behaviors and its role in the proBDNF-mediated mood abnormality in mice. We found that sortilin was up-regulated in neocortex (by 78.3%) and hippoc us (by 111%) of chronically stressed mice as assessed by western blot analysis. These changes were associated with decreased mobility in the open field test and increased depression-like behavior in the forced swimming test. We also found that sortilin deficiency in mice resulted in hyperlocomotion in the open field test and increased anxiety-like behavior in both the open field and elevated plus maze tests. No depression-like behavior in the forced swimming test and no deficit in spatial cognition in the Morris water maze test were found in the Sort1-deficient mice. Moreover, the intracellular and extracellular levels of mature BDNF and proBDNF were not changed when sortilin was absent in vivo and in vitro. Finally, we found that both WT and Sort1-deficient mice injected with proBDNF in lateral ventricle displayed increased depression-like behavior in the forced swimming test but not anxiety-like behaviors in the open field and elevated plus maze tests. The present study suggests that sortilin functions as a negative regulator of mood performance and can be a therapeutic target for the treatment of mental illness.
Publisher: Elsevier BV
Date: 06-2006
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.NEUINT.2010.05.009
Abstract: The regulation of tyrosine hydroxylase (TH, the rate limiting enzyme involved in catecholamine synthesis) is critical for the acute and sustained release of catecholamines from adrenal medullary chromaffin cells, however the mechanisms involved have only ever been investigated under in vitro/in situ conditions. Here we explored the effects on, TH phosphorylation and synthesis, and upstream signalling pathways, in the adrenal medulla evoked by the glucoprivic stimulus, 2-deoxy-d-glucose (2DG) administered intraperitoneally to conscious rats. Our results show that 2DG evoked expected increases in plasma adrenaline and glucose at 20 and 60min. We demonstrated that protein kinase A (PKA) and cyclin dependent kinases (CDK) were activated 20min following 2DG, whereas mitogen activated protein kinase (MAPK) was activated later and PKC was not significantly activated. We demonstrated that phosphorylation of Ser40TH peaked after 20min whereas phosphorylation of Ser31TH was still increasing at 60min. Serine 19 was not phosphorylated in this time frame. TH phosphorylation also occurred on newly synthesized protein 24h after 2DG. Thus 2DG increases secretion of adrenaline into the plasma and the consequent rise in glucose levels. In the adrenal medulla 2DG activates PKA, CDK and MAPK, and evokes phosphorylation of Ser40 and Ser31 in the short term and induces TH synthesis in the longer term all of which most likely contribute to increased capacity for the synthesis of adrenaline.
Publisher: Springer Science and Business Media LLC
Date: 28-01-2021
Publisher: Wiley
Date: 07-06-2004
Publisher: World Scientific Pub Co Pte Lt
Date: 2021
DOI: 10.1142/S0192415X21500312
Abstract: To investigate the therapeutic efficacy of Scutellarin (SCU) on neurite growth and neurological functional recovery in neonatal hypoxic-ischemic (HI) rats. Primary cortical neurons were cultured to detect the effect of SCU on cell viability of neurons under oxygen-glucose deprivation (OGD). Double immunofluorescence staining of Tuj1 and TUNEL then observed the neurite growth and cell apoptosis in vitro,and double immunofluorescence staining of NEUN and TUNEL was performed to examine the neuronal apoptosis and cell apoptosis in brain tissues after HI in vivo. Pharmacological efficacy of SCU was also evaluated in HI rats by neurobehavioral tests, triphenyl tetrazolium chloride staining, Hematoxylin and eosin staining and Nissl staining. Astrocytes and microglia expression in damaged brain tissues were detected by immunostaining of GFAP and Iba1. A quantitative real-time polymerase chain reaction and western blot were applied to investigate the genetic expression changes and the protein levels of autophagy-related proteins in the injured cortex and hippoc us after HI. We found that SCU administration preserved cell viability, promoted neurite outgrowth and suppressed apoptosis of neurons subjected to OGD both in vitroand in vivo. Meanwhile, 20 mg/kg SCU treatment improved neurological functions and decreased the expression of astrocytes and microglia in the cortex and hippoc us of HI rats. Additionally, SCU treatment depressed the elevated levels of autophagy-related proteins and the p75 neurotrophin receptor (p75NTR) in both cortex and hippoc us. This study demonstrated the potential therapeutic efficacy of SCU by enhancing neurogenesis and restoring long-term neurological dysfunctions, which might be associated with p75NTR depletion in HI rats.
Publisher: Wiley
Date: 30-10-2013
DOI: 10.1111/JNC.12482
Abstract: Stress activates selected neuronal systems in the brain and this leads to activation of a range of effector systems. Our aim was to investigate some of the relationships between these systems under basal conditions and over a 40-min period in response to footshock stress. Specifically, we investigated catecholaminergic neurons in the locus coeruleus (LC), ventral tegmental area and medial prefrontal cortex (mPFC) in the brain, by measuring tyrosine hydroxylase (TH) protein, TH phosphorylation and TH activation. We also measured the effector responses by measuring plasma adrenocorticotrophic hormone, corticosterone, glucose and body temperature as well as activation of adrenal medulla protein kinases, TH protein, TH phosphorylation and TH activation. The LC, ventral tegmental area and adrenal medulla all had higher basal levels of Ser19 phosphorylation and lower basal levels of Ser31 phosphorylation than the mPFC, presumably because of their cell body versus nerve terminal location, while the adrenal medulla had the highest basal levels of Ser40 phosphorylation. Ser31 phosphorylation was increased in the LC at 20 and 40 min and in the mPFC at 40 min TH activity was increased at 40 min in both tissues. There were significant increases in body temperature between 10 and 40 min, as well as increases in plasma adrenocorticotropic hormone at 20 min and corticosterone and glucose at 20 and 40 min. The adrenal medulla extracellular signal-regulated kinase 2 was increased between 10 and 40 min and Ser31 phosphorylation was increased at 20 min and 40 min. Protein kinase A and Ser40 phosphorylation were increased only at 40 min. TH activity was increased between 20 and 40 min. TH protein and Ser19 phosphorylation levels were not altered in any of the brain regions or adrenal medulla over the first 40 min. These findings indicate that acute footshock stress leads to activation of TH in the LC, pre-synaptic terminals in the mPFC and adrenal medullary chromaffin cells, as well as changes in activity of the hypothalamic-pituitary-adrenal axis.
Publisher: MDPI AG
Date: 09-07-2021
DOI: 10.3390/IJMS22147380
Abstract: Parkinson’s disease (PD) is the most common movement disorder, characterized by progressive degeneration of the nigrostriatal pathway, which consists of dopaminergic cell bodies in substantia nigra and their neuronal projections to the striatum. Moreover, PD is associated with an array of non-motor symptoms such as olfactory dysfunction, gastrointestinal dysfunction, impaired regulation of the sleep-wake cycle, anxiety, depression, and cognitive impairment. Inflammation and concomitant oxidative stress are crucial in the pathogenesis of PD. Thus, this study aimed to model PD via intrastriatal injection of the inflammagen lipopolysaccharide (LPS)to investigate if the lesion causes olfactory and motor impairments, inflammation, oxidative stress, and alteration in synaptic proteins in the olfactory bulb, striatum, and colon. Ten µg of LPS was injected unilaterally into the striatum of 27 male C57BL/6 mice, and behavioural assessment was conducted at 4 and 8 weeks post-treatment, followed by tissue collection. Intrastriatal LPS induced motor impairment in C57BL/6 mice at 8 weeks post-treatment evidenced by reduced latency time in the rotarod test. LPS also induced inflammation in the striatum characterized by increased expression of microglial marker Iba-1 and astrocytic marker GFAP, with degeneration of dopaminergic neuronal fibres (reduced tyrosine hydroxylase immunoreactivity), and reduction of synaptic proteins and DJ-1 protein. Additionally, intrastriatal LPS induced inflammation, oxidative stress and alterations in synaptic proteins within the olfactory bulb, although this did not induce a significant impairment in olfactory function. Intrastriatal LPS induced mild inflammatory changes in the distal colon, accompanied by increased protein expression of 3-nitrotyrosine-modified proteins. This model recapitulated the major features of PD such as motor impairment and degeneration of dopaminergic neuronal fibres in the striatum, as well as some pathological changes in the olfactory bulb and colon thus, this model could be suitable for understanding clinical PD and testing neuroprotective strategies.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.NEURO.2014.12.002
Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disorder that is characterized by two major neuropathological hallmarks: the degeneration of dopaminergic neurons in the substantia nigra (SN) and the presence of Lewy bodies in the surviving SN neurons, as well as other regions of the central and peripheral nervous system. Animal models have been invaluable tools for investigating the underlying mechanisms of the pathogenesis of PD and testing new potential symptomatic, neuroprotective and neurorestorative therapies. However, the usefulness of these models is dependent on how precisely they replicate the features of clinical PD with some studies now employing combined gene-environment models to replicate more of the affected pathways. The rotenone model of PD has become of great interest following the seminal paper by the Greenamyre group in 2000 (Betarbet et al., 2000). This paper reported for the first time that systemic rotenone was able to reproduce the two pathological hallmarks of PD as well as certain parkinsonian motor deficits. Since 2000, many research groups have actively used the rotenone model worldwide. This paper will review rotenone models, focusing upon their ability to reproduce the two pathological hallmarks of PD, motor deficits, extranigral pathology and non-motor symptoms. We will also summarize the recent advances in neuroprotective therapies, focusing on those that investigated non-motor symptoms and review rotenone models used in combination with PD genetic models to investigate gene-environment interactions.
Publisher: Springer Science and Business Media LLC
Date: 04-06-2018
DOI: 10.1038/S41380-018-0071-Z
Abstract: Tau pathology is characterized as a form of frontotemporal lobar degeneration (FTLD) known as FTLD-tau. The underlying pathogenic mechanisms are not known and no therapeutic interventions are currently available. Here, we report that the neurotrophin receptor p75NTR plays a critical role in the pathogenesis of FTLD-tau. The expression of p75NTR and the precursor of nerve growth factor (proNGF) were increased in the brains of FTLD-tau patients and mice (P301L transgenic). ProNGF-induced tau phosphorylation via p75NTR in vitro, which was associated with the AKT/glycogen synthase kinase (GSK)3β pathway. Genetic reduction of p75NTR in P301L mice rescued the memory deficits, alleviated tau hyperphosphorylation and restored the activity of the AKT/GSK3β pathway. Treatment of the P301L mice with the soluble p75NTR extracellular domain (p75ECD-Fc), which can antagonize neurotoxic ligands of p75NTR, effectively improved memory behavior and suppressed tau pathology. This suggests that p75NTR plays a crucial role in tau paGSKthology and represents a potential druggable target for FTLD-tau and related tauopathies.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.BBAMCR.2009.10.001
Abstract: The major human tyrosine hydroxylase isoforms (hTH1 and 2) differ in their ability to be phosphorylated in vitro. hTH1 is phosphorylated at Ser31 by extracellular signal-regulated kinase (ERK). This kinase is not capable of phosphorylating hTH2 at Ser35 (the residue that corresponds to Ser31 in hTH1). We have stably transfected SH-SY5Y cells with hTH1 or hTH2 to determine if hTH2 can be phosphorylated at Ser35 in situ. Forskolin increased the phosphorylation of Ser40 in hTH1 and Ser44 in hTH2. Muscarine increased the phosphorylation of both Ser19 and Ser40/44 in both hTH1 and hTH2. EGF increased the phosphorylation of Ser31 in hTH1. Phosphorylation of Ser35 in hTH2 was not detected under any of the conditions tested. Inhibition of ERK by UO126 decreased the phosphorylation of Ser31 and this lead to a 50% decrease in the basal level of phosphorylation of Ser40 in hTH1. The basal level of Ser44 phosphorylation in hTH2 was not altered by treatment with UO126. Therefore, phosphorylation of Ser31 contributes to the phosphorylation of Ser40 in hTH1 in situ however, this effect is absent in hTH2. This represents a major difference between the two human TH isoforms, and has implications for the regulation of catecholamine synthesis in vivo.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.BRAINRES.2017.05.013
Abstract: ProBDNF, a precursor of brain-derived neurotrophic factor (BDNF), is an important regulator of neurodegeneration, hippoc al long-term depression, and synaptic plasticity. ProBDNF and its receptors pan-neurotrophin receptor p75 (p75NTR), vps10p domain-containing receptor Sortilin and tropomyosin receptor kinase B (TrkB) are expressed in neuronal and glial cells. The role of proBDNF in regulation of neurogenesis is not fully defined. This study aims to uncover the function of proBDNF in regulating the differentiation, migration and proliferation of mouse neural stem cells (NSCs) in vitro. We have found that proBDNF and its receptors are constitutively expressed in NSCs when assessed by immunocytochemistry and western blotting. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay showed that exogenous proBDNF treatment reduced mouse NSCs viability by 38% at 10ng/mL. The migration of NSCs was also reduced by exogenous proBDNF treatment in a concentration-dependent manner (by 90% at 10ng/mL) but increased by anti-proBDNF antibody treatment (by 50%). BrdU (5-Bromo-2'-Deoxyuridine) incorporation was performed for detection of newborn cells. We have found that proBDNF significantly inhibited proliferation of NSCs and reduced the number of differentiated neurons, oligodendrocytes and astrocytes, while anti-proBDNF antibody treatment promoted proliferation and differentiation of NSCs. In conclusion, proBDNF may oppose the functions of mature BDNF by inhibiting the proliferation, differentiation and migration of NSCs during development. Conversely, anti-proBDNF antibody treatment promoted proliferation and differentiation of NSCs.
Publisher: Springer Science and Business Media LLC
Date: 21-02-2017
DOI: 10.1007/S11010-016-2923-7
Abstract: Grossamide, a representative lignanamide in hemp seed, has been reported to possess potential anti-inflammatory effects. However, the potential anti-neuroinflammatory effects and underlying mechanisms of action of grossamide are still unclear. Therefore, the present study investigated the possible effects and underlying mechanisms of grossamide against lipopolysaccharide (LPS)-induced inflammatory response in BV2 microglia cells. BV2 microglia cells were pre-treated with various concentrations of grossamide before being stimulated with LPS to induce inflammation. The levels of pro-inflammatory cytokines were determined using the enzyme-linked immunoassay (ELISA) and mRNA expression levels were measured by real-time PCR. The translocation of nuclear factor-kappa B (NF-κB) and contribution of TLR4-mediated NF-κB activation on inflammatory effects were evaluated by immunostaining and Western blot analysis. This study demonstrated that grossamide significantly inhibited the secretion of pro-inflammatory mediators such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), and decreased the level of LPS-mediated IL-6 and TNF-α mRNA. In addition, it significantly reduced the phosphorylation levels of NF-κB subunit p65 in a concentration-dependent manner and suppressed translocation of NF-κB p65 into the nucleus. Furthermore, grossamide markedly attenuated the LPS-induced expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). Taken together, these data suggest that grossamide could be a potential therapeutic candidate for inhibiting neuroinflammation in neurodegenerative diseases.
Publisher: Wiley
Date: 08-2009
DOI: 10.1111/J.1471-4159.2009.06185.X
Abstract: Manganese (Mn2+) is an essential metal involved in normal functioning of a range of physiological processes. However,occupational overexposure to Mn2+ causes neurotoxicity. The dopaminergic system is a particular target for Mn2+ neurotoxicity.Tyrosine hydroxylase (TH) is the rate limiting enzyme for dopamine synthesis and is regulated acutely by phosphorylation at Ser40 and chronically by protein synthesis. In this study we used pheochromocytoma 12 cells to investigate the effects of Mn2+ exposure on the phosphorylation and activity of TH. Mn2+ treatment for 24 h caused a sustained increase in Ser40 phosphorylation and TH activity at a concentration of 100 lM, without altering the level of TH protein orPC12 cell viability. Inhibition of protein kinase A and protein kinase C and protein kinases known to be involved in sustained phosphorylation of TH in response to other stimuli didnot block the effects of Mn2+ on Ser40 phosphorylation.A substantial increase in H2O2 production occurred in response to 100 lM Mn2+. The antioxidant Trolox completely inhibited H2O2 production but did not block TH phosphorylation at Ser40, indicating that oxidative stress was not involved. Sustained TH phosphorylation at Ser40 and the consequent activation of TH both occurred at low concentrations of Mn2+ and this provides a potential new mechanism for Mn2+-induced neuronal action that does not involve H2O2-mediated cell death.
Publisher: Elsevier
Date: 2013
Publisher: Springer Science and Business Media LLC
Date: 24-05-2018
DOI: 10.1007/S12035-018-1106-9
Abstract: The accumulation of excess intracellular or extracellular amyloid beta (Aβ) is one of the key pathological events in Alzheimer's disease (AD). Aβ is generated from the cleavage of amyloid precursor protein (APP) by beta secretase-1 (BACE1) and gamma secretase (γ-secretase) within the cells. The endocytic trafficking of APP facilitates amyloidogenesis while at the cell surface, APP is predominantly processed in a non-amyloidogenic manner. Several adaptor proteins bind to both APP and BACE1, regulating their trafficking and recycling along the secretory and endocytic pathways. The phosphorylation of APP at Thr668 and BACE1 at Ser498, also influence their trafficking. Neurotrophins and proneurotrophins also influence APP trafficking through their receptors. In this review, we describe the molecular trafficking pathways of APP and BACE1 that lead to Aβ generation, the involvement of different signaling molecules or adaptor proteins regulating APP and BACE1 subcellular localization. We have also discussed how neurotrophins could modulate amyloidogenesis through their receptors.
Publisher: Walter de Gruyter GmbH
Date: 05-01-2022
DOI: 10.1515/REVNEURO-2021-0111
Abstract: Alzheimer’s disease is a neurodegenerative condition that is potentially mediated by synaptic dysfunction before the onset of cognitive impairments. The disease mostly affects elderly people and there is currently no therapeutic which halts its progression. One therapeutic strategy for Alzheimer’s disease is to regenerate lost synapses by targeting mechanisms involved in synaptic plasticity. This strategy has led to promising drug candidates in clinical trials, but further progress needs to be made. An unresolved problem of Alzheimer’s disease is to identify the molecular mechanisms that render the aged brain susceptible to synaptic dysfunction. Understanding this susceptibility may identify drug targets which could halt, or even reverse, the disease’s progression. Brain derived neurotrophic factor is a neurotrophin expressed in the brain previously implicated in Alzheimer’s disease due to its involvement in synaptic plasticity. Low levels of the protein increase susceptibility to the disease and post-mortem studies consistently show reductions in its expression. A desirable therapeutic approach for Alzheimer’s disease is to stimulate the expression of brain derived neurotrophic factor and potentially regenerate lost synapses. However, synthesis and secretion of the protein are regulated by complex activity-dependent mechanisms within neurons, which makes this approach challenging. Moreover, the protein is synthesised as a precursor which exerts the opposite effect of its mature form through the neurotrophin receptor p75NTR. This review will evaluate current evidence on how age-related alterations in the synthesis, processing and signalling of brain derived neurotrophic factor may increase the risk of Alzheimer’s disease.
Publisher: Wiley
Date: 18-11-2004
DOI: 10.1111/J.1471-4159.2004.02797.X
Abstract: The rate-limiting enzyme in catecholamine synthesis is tyrosine hydroxylase. It is phosphorylated at serine (Ser) residues Ser8, Ser19, Ser31 and Ser40 in vitro, in situ and in vivo. A range of protein kinases and protein phosphatases are able to phosphorylate or dephosphorylate these sites in vitro. Some of these enzymes are able to regulate tyrosine hydroxylase phosphorylation in situ and in vivo but the identity of the kinases and phosphatases is incomplete, especially for physiologically relevant stimuli. The stoichiometry of tyrosine hydroxylase phosphorylation in situ and in vivo is low. The phosphorylation of tyrosine hydroxylase at Ser40 increases the enzyme's activity in vitro, in situ and in vivo. Phosphorylation at Ser31 also increases the activity but to a much lesser extent than for Ser40 phosphorylation. The phosphorylation of tyrosine hydroxylase at Ser19 or Ser8 has no direct effect on tyrosine hydroxylase activity. Hierarchical phosphorylation of tyrosine hydroxylase occurs both in vitro and in situ, whereby the phosphorylation at Ser19 increases the rate of Ser40 phosphorylation leading to an increase in enzyme activity. Hierarchical phosphorylation depends on the state of the substrate providing a novel form of control of tyrosine hydroxylase activation.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.NBD.2019.104524
Abstract: Tyrosine hydroxylase is the key enzyme controlling the synthesis of the catecholamines including dopamine. The breakdown of dopamine into toxic compounds has been suggested to have a key role in the degeneration of the dopaminergic neurons in Parkinson's disease. Humans are unique in containing four isoforms of tyrosine hydroxylase, but understanding of the role of these isoforms under normal conditions and in disease states is limited. The aim of this work was to determine the level and distribution of the four human isoforms in tissues from healthy controls and patients with Parkinson's disease. The results show that isoform 1 and isoform 2 are the major tyrosine hydroxylase isoforms in human brain, but that tyrosine hydroxylase isoform 2 is more abundant in the substantia nigra than the tyrosine hydroxylase isoform 1. The two minor isoforms, isoform 3 and isoform 4, are expressed at a proportionally higher level in the terminal field regions (caudate and putamen) compared to the substantia nigra. There was a selective loss of tyrosine hydroxylase isoform 1 in Parkinson's disease compared to age-matched controls and a corresponding increase in the proportion of tyrosine hydroxylase isoform 2. Phosphorylation of serine 40 was significantly increased in caudate, putamen and ventral tegmental area, but not in the substantia nigra, in Parkinson's disease brain. These results show a selective sparing of tyrosine hydroxylase isoform 2 in Parkinson's disease. Isoform 2 exhibits a reduced capacity for activation compared to isoform 1, which may account for the selective sparing of cells expressing isoform 2 in Parkinson's disease. Surviving neurons in Parkinson's disease brain exhibit a substantial increase in tyrosine hydroxylase phosphorylation consistent with a compensatory mechanism of increased dopamine synthesis in the terminal field regions.
Publisher: Impact Journals, LLC
Date: 03-09-2019
Publisher: Hindawi Limited
Date: 2016
DOI: 10.1155/2016/9801640
Abstract: Recurrent insulin-induced hypoglycaemia is a major limitation to insulin treatment in diabetes patients leading to a condition called hypoglycaemia-associated autonomic failure (HAAF). HAAF is characterised by reduced sympathoadrenal response to subsequent hypoglycaemia thereby predisposing the patients to severe hypoglycaemia that can lead to coma or even death. Despite several attempts being made, the mechanism of HAAF is yet to be clearly established. In order for the mechanism of HAAF to be elucidated, establishing a human/animal model of the phenomenon is the foremost requirement. Several research groups have attempted to reproduce the phenomenon in diabetic and nondiabetic humans and rodents and reported variable results. The success of the phenomenon is marked by a significant reduction in plasma adrenaline response to subsequent hypoglycaemic episode relative to that of the antecedent hypoglycaemic episode. A number of factors such as the insulin dosage, route of administration, fasting conditions, blood s ling methods and analyses, depth, duration, and number of antecedent hypoglycaemic episodes can impact the successful reproduction of the phenomenon and thus have to be carefully considered while developing the protocol. In this review, we have outlined the protocols followed by different research groups to reproduce the phenomenon in diabetic and nondiabetic humans and rodents including our own observations in rats and discussed the factors that have to be given careful consideration in reproducing the phenomenon successfully.
Publisher: OMICS Publishing Group
Date: 2018
Publisher: Medknow
Date: 2022
Publisher: Springer Science and Business Media LLC
Date: 02-04-2021
Publisher: Frontiers Media SA
Date: 09-11-2020
DOI: 10.3389/FCELL.2020.529544
Abstract: Neonatal hypoxic ischemic encephalopathy (HIE) due to birth asphyxia is common and causes severe neurological deficits, without any effective therapies currently available. Neuronal death is an important driving factors of neurological disorders after HIE, but the regulatory mechanisms are still uncertain. Long non-coding RNA (lncRNA) or ceRNA network act as a significant regulator in neuroregeneration and neuronal apoptosis, thus owning a great potential as therapeutic targets in HIE. Here, we found a new lncRNA, is the most functional in targeting the Igfbp3 gene in HIE, which enriched in the cell growth and cell apoptosis processes. In addition, luciferase reporter assay showed competitive regulatory binding sites to the target gene Igfbp3 between TCONS00044054 (Vi4) and miR-185-5p. The change in blood miR-185-5p and Igfbp3 expression is further confirmed in patients with brain ischemia. Moreover, Vi4 overexpression and miR-185-5p knock-out promote the neuron survival and neurite growth, and suppress the cell apoptosis, then further improve the motor and cognitive deficits in rats with HIE, while Igfbp3 interfering got the opposite results. Together, Vi4-miR-185-5p-Igfbp3 regulatory network plays an important role in neuron survival and cell apoptosis and further promote the neuro-functional recovery from HIE, therefore is a likely a drug target for HIE therapy.
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.PHYSBEH.2017.02.006
Abstract: Metabolic cages are a type of housing used in biomedical research. Metabolic cage housing has been demonstrated to elicit behavioural and physiological changes in rodents housed within them. The nature of this effect has been characterized as anxiogenic. However, few studies have evaluated positive affect in response to metabolic cage housing and the interaction between this, sex and traditional physiological measures of stress. Cognitive biasing, as measured through a judgment bias paradigm has proven a reliable measure of animal affective state, particularly through its ability to measure positive affect. The current study investigated differences in cognitive biasing between male and female rats when transferred from open-top, grouped housing to a metabolic cage. Rats (Rattus norvegicus) (n=60) were trained in a judgment bias paradigm previously validated for use in the rat model. Upon exposure to an intermediate, ambiguous probe rats responded with either an optimistic or pessimistic decision. The animals were also subjected to the sucrose preference test to identify the presence of anhedonia. Faecal corticosterone and changes in adrenal tyrosine hydroxylase were also measured to establish whether a stress-like state was experienced. There was a significant interaction between sex and metabolic cage housing on the number of optimistic decisions made F (1, 56)=7.461, p=0.008. Female rats that remained in control housing responded with a reduced number of days featuring an optimistic decision compared to males in control housing (p=0.036). However, both males and females responded with significantly fewer optimistic decisions in the metabolic cage compared to control (p<0.001). There was a significant negative correlation between treatment and sucrose consumption (r
Publisher: Elsevier BV
Date: 04-2020
Publisher: MDPI AG
Date: 19-06-2023
Abstract: Anxiety and depressive disorders are closely associated however, the pathophysiology of these disorders remains poorly understood. Further exploration of the mechanisms involved in anxiety and depression such as the stress response may provide new knowledge that will contribute to our understanding of these disorders. Fifty-eight 8–12-week-old C57BL6 mice were separated into experimental groups by sex as follows: male controls (n = 14), male restraint stress (n = 14), female controls (n = 15) and female restraint stress (n = 15). These mice were taken through a 4-week randomised chronic restraint stress protocol, and their behaviour, as well as tryptophan metabolism and synaptic proteins, were measured in the prefrontal cortex and hippoc us. Adrenal catecholamine regulation was also measured. The female mice showed greater anxiety-like behaviour than their male counterparts. Tryptophan metabolism was unaffected by stress, but some basal sex characteristics were noted. Synaptic proteins were reduced in the hippoc us in stressed females but increased in the prefrontal cortex of all female mice. These changes were not found in any males. Finally, the stressed female mice showed increased catecholamine biosynthesis capability, but this effect was not found in males. Future studies in animal models should consider these sex differences when evaluating mechanisms related to chronic stress and depression.
Publisher: Elsevier BV
Date: 2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2004
DOI: 10.1097/00001756-200402090-00021
Abstract: S100B is a calcium binding protein from astrocytes that regulates protein phosphorylation by binding to substrates and protein kinases. S100B might also regulate protein phosphatases and this was investigated for protein phosphatase 2B (calcineurin). The results indicate that S100B (5-10 microM) increased the activity of both purified and cytoskeletal calcineurin in a Ca-dependent manner. This effect was blocked by a specific inhibitor of calcineurin activity, but not by TRTK-12 (an inhibitor of S100B binding to other protein targets). The present results and the known co-localization of S100B and calcineurin in the astrocyte cytoskeleton suggest that S100B may play a role in the phosphorylation state of cytoskeletal proteins.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.AUTNEU.2017.12.004
Abstract: In this study, we investigated the effects of recurrent hypoglycaemia on the adrenal catecholamine synthetic enzymes in a rat model of hypoglycaemia-associated autonomic failure (HAAF). We found that plasma adrenaline was significantly reduced by about 50% in response to recurrent hypoglycaemia versus single hypoglycaemia. However, tyrosine hydroxylase (TH) protein and phosphorylation at Ser31 and Ser40 were increased in HAAF similarly, aromatic aminoacid decarboxylase protein was also increased indicating a likely increase in catecholamine synthesis in the adrenal gland. Opioid antagonists, naloxone and methylnaltrexone did not restore plasma adrenaline in HAAF however, naloxone increased TH phosphorylation at Ser31 and Ser40.
Publisher: Springer Science and Business Media LLC
Date: 02-10-2021
DOI: 10.1007/S12640-021-00405-2
Abstract: Oxidative stress is a key factor in the pathogenesis of several neurodegenerative disorders and is involved in the accumulation of amyloid beta plaques and Tau inclusions. Edaravone (EDR) is a free radical scavenger that is approved for motor neuron disease and acute ischemic stroke. EDR alleviates pathologies and cognitive impairment of AD via targeting multiple key pathways in transgenic mice. Herein, we aimed to study the effect of EDR on Tau pathology in P301L mice an animal model of frontotemporal dementia (FTD), at two age time points representing the early and late stages of the disease. A novel EDR formulation was utilized in the study and the drug was delivered orally in drinking water for 3 months. Then, behavioral tests were conducted followed by animal sacrifice and brain dissection. Treatment with EDR improved the reference memory and accuracy in the probe trial as evaluated in Morris water maze, as well as novel object recognition and significantly alleviated motor deficits in these mice. EDR also reduced the levels of 4-hydroxy-2-nonenal and 3-nitrotyrosine adducts. In addition, immunohistochemistry showed that EDR reduced tau phosphorylation and neuroinflammation and partially rescued neurons against oxidative neurotoxicity. Moreover, EDR attenuated downstream pathologies involved in Tau hyperphosphorylation. These results suggest that EDR may be a potential therapeutic agent for the treatment of FTD.
Publisher: Springer Science and Business Media LLC
Date: 27-03-2019
DOI: 10.1007/S12640-019-00022-0
Abstract: Stroke is accompanied by severe inflammation in the brain. The role of mature brain-derived neurotrophic factor (mBDNF) in ischemic stroke has received intensive attention, but the function of its precursor proBDNF is less understood. Recent studies showed that mBDNF and proBDNF in the ischemic brain are upregulated, but the significance of mBDNF and proBDNF in the lymphocytes in ischemic stroke is not known. Here, we propose that the expression levels of mBDNF and proBDNF in lymphocytes correlate with those in the brain after ischemic stroke and therefore can be surrogate markers for the ischemic brain. Using a photothrombotic model in rats and ELISA assay technique, we found that proBDNF and mBDNF in peripheral lymphocytes were upregulated but produced differential time courses after ischemia. The levels of mBDNF and proBDNF in lymphocytes at early stages of stroke (1 day), showed a strong positive correlation with those in the brain. The levels of p75, sortilin, were also increased in a time-dependent manner after ischemic stroke however, the levels of p-TrkB in the ischemic brain at 6 h, 1 and 3 days were significantly reduced in the brain. The present study suggests that the levels of proBDNF and mBDNF in the blood lymphocytes in acute ischemic stroke reflect those in the brain at early stages.
Publisher: Wiley
Date: 02-2015
DOI: 10.14814/PHY2.12270
Publisher: Wiley
Date: 2007
DOI: 10.1111/J.1471-4159.2006.04213.X
Abstract: Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine synthesis. Its activity is known to be controlled acutely (minutes) by phosphorylation and chronically (days) by protein synthesis. Using bovine adrenal chromaffin cells we found that nicotine, acting via nicotinic receptors, sustained the phosphorylation of TH at Ser40 for up to 48 h. Nicotine also induced sustained activation of TH, which for the first 24 h was completely independent of TH protein synthesis, and the phosphorylation of TH at Ser31. Imipramine did not inhibit the acute phosphorylation of TH at Ser40 or TH activation induced by nicotine, but did inhibit the sustained responses to nicotine seen at 24 h. The protein kinase(s) responsible for TH phosphorylation at Ser40 switched from being protein kinase C (PKC) independent in the acute phase to PKC dependent in the sustained phase. Sustained phosphorylation and activation of TH were also observed with histamine and angiotensin II. Sustained phosphorylation of TH at Ser40 provides a novel mechanism for increasing TH activity and this leads to increased catecholamine synthesis. Sustained phosphorylation of TH may be a selective target for drugs or pathology in neurons that contain TH and synthesize dopamine, noradrenaline or adrenaline.
Publisher: IMR Press
Date: 07-05-2022
Abstract: The major hallmark of Parkinson's disease (PD) is the degeneration of dopaminergic neurons in the substantia nigra (SN), which is responsible for the core motor symptoms of PD. Currently, there is no cure for PD, and its prevalence is increasing, prompting the search for novel neuroprotective treatments. Neuroinflammation is a core pathological process in PD, evident by increased inflammatory biomarkers in the SN and cerebrospinal fluid. Interestingly, epidemiological studies have reported a reduced risk of PD in users of non-steroidal anti-inflammatory drugs compared to non-users, suggesting the neuroprotective potential of anti-inflammatory drugs. Therefore, this study aimed to: (1) test the efficacy of novel oral formulations of edaravone (EDR) and curcumin (CUR) (which possess anti-inflammatory and anti-oxidative properties) to alleviate motor and non-motor symptoms, and associated pathology in the intrastriatal lipopolysaccharide (LPS) model of PD (2) investigate the expression of proteins linked to familial PD and markers of autophagy in the intrastriatal LPS model treated with EDR and CUR. Fifty-two C57BL/6 mice were ided into 4 groups, namely (1) control + vehicle (2) LPS + vehicle (3) LPS + EDR (made in vehicle) and (4) LPS + CUR (made in vehicle). 10 μg of LPS was administered stereotaxically into the right striatum, and EDR and CUR treatments were initiated 2-weeks after the LPS injections. Behavioural tests were carried out at 4- and 8-weeks after LPS injection followed by tissue collection at 8-weeks. Intrastriatal administration of LPS induced motor deficits and anxiety-like behaviours at 4- and 8-weeks, which were accompanied by astroglial activation, increased protein expression of α-synuclein, heat shock cognate protein of 70 kDa (HSC-70) and Rab-10, and reduced levels of tyrosine hydroxylase (TH) protein in the striatum. Additionally, LPS induced astroglial activation in the olfactory bulb, along with changes in the protein expression of HSC-70. The changes associated with EDR and CUR in the striatum and olfactory bulb were not statistically significant compared to the LPS group. Intrastriatal administration of LPS induced pathological changes of PD such as motor deficits, reduced expression of TH protein and increased α-synuclein protein, as well as some alterations in proteins linked to familial PD and autophagy in the olfactory bulb and striatum, without pronounced therapeutic effects of EDR and CUR. Our results may suggest that EDR and CUR lack therapeutic effects when administered after the disease process was already initiated. Thus, our treatment regimen or the physicochemical properties of EDR and CUR could be further refined to elevate the therapeutic effects of these formulations.
Publisher: Springer Science and Business Media LLC
Date: 06-2023
DOI: 10.1007/S12031-023-02131-0
Abstract: The early transition to Alzheimer’s disease is characterized by a period of accelerated brain atrophy that exceeds normal ageing. Identifying the molecular basis of this atrophy could facilitate the discovery of novel drug targets. The precursor of brain-derived neurotrophic factor, a well characterized neurotrophin, is increased in the hippoc us of aged rodents, while its mature isoform is relatively stable. This imbalance could increase the risk of Alzheimer’s disease by precipitating its pathological hallmarks. However, less is known about how relative levels of these isoforms change in middle-aged mice. In addition, the underlying mechanisms that might cause an imbalance are unknown. The main aim of this study was to determine how precursor brain-derived neurotrophic factor changes relative to its mature isoform with normal brain ageing in wild type mice. A secondary aim was to determine if signaling through the neurotrophin receptor, p75 influences this ratio. An increasing ratio was identified in several brain regions, except the hippoc us, suggesting a neurotrophic imbalance occurs as early as middle age. Some changes in receptors that mediate the isoforms effects were also identified, but these did not correspond with trends in the isoforms. Relative amounts of precursor brain-derived neurotrophic factor were mostly unchanged in mutant p75 mice. The lack of changes suggested that signaling through the receptor had no influence on the ratio.
Publisher: Elsevier BV
Date: 02-2022
Publisher: Springer Science and Business Media LLC
Date: 11-11-2014
DOI: 10.1038/TP.2014.121
Publisher: Wiley
Date: 07-2016
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.JCHEMNEU.2015.11.002
Abstract: Tyrosine hydroxylase (TH, the rate limiting-enzyme in catecholamine synthesis) is regulated acutely via phosphorylation of 3 serine residues--Ser19, 31 and 40, and chronically via changes in TH protein levels. In this study, we aimed to investigate how TH is regulated in the brain, gut and adrenal gland as well as changes in mature brain-derived neurotrophic factor (mBDNF) and proBDNF levels in a low-dose (2 mg/kg, 5 days/week for 4 weeks) rotenone model of Parkinson's disease (PD). Rearing behaviour decreased by week 3 in the rotenone group (p<0.01), with further decreases in rearing by week 4 (p<0.001) however, TH remained unchanged in the substantia nigra (SN) and striatum TH levels were also unaltered in other catecholaminergic cell groups of the brainstem such as A1C1 neurons or locus coeruleus. In the olfactory bulb, TH protein decreased (2.5-fold, p<0.01) while Ser31 phosphorylation increased (1.4-fold, p<0.05) in the rotenone group. In contrast, TH protein was increased in the adrenal gland (2-fold, p<0.05) and colon (5-fold, p<0.05) of rotenone rats. mBDNF levels were not changed in the SN but were significantly reduced in plasma and significantly increased in the colon (2-fold, p<0.01) of rotenone-treated rats. This is the first study to assess TH and BDNF in the brain and periphery in the rotenone model before SN/striatum degeneration is evident. Together these results suggest that low-dose rotenone may have some potential to model the early stages of PD.
No related grants have been discovered for Larisa Bobrovskaya.