ORCID Profile
0000-0002-8825-734X
Current Organisation
Deakin University
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Publisher: MDPI AG
Date: 14-07-2022
DOI: 10.3390/PHARMACEUTICS14071464
Abstract: Despite advances in pharmacology and neuroscience, the path to new medications for psychiatric disorders largely remains stagnated. Drug repurposing offers a more efficient pathway compared with de novo drug discovery with lower cost and less risk. Various computational approaches have been applied to mine the vast amount of biomedical data generated over recent decades. Among these methods, network-based drug repurposing stands out as a potent tool for the comprehension of multiple domains of knowledge considering the interactions or associations of various factors. Aligned well with the poly-pharmacology paradigm shift in drug discovery, network-based approaches offer great opportunities to discover repurposing candidates for complex psychiatric disorders. In this review, we present the potential of network-based drug repurposing in psychiatry focusing on the incentives for using network-centric repurposing, major network-based repurposing strategies and data resources, applications in psychiatry and challenges of network-based drug repurposing. This review aims to provide readers with an update on network-based drug repurposing in psychiatry. We expect the repurposing approach to become a pivotal tool in the coming years to battle debilitating psychiatric disorders.
Publisher: MDPI AG
Date: 02-07-2021
DOI: 10.3390/IJMS22137164
Abstract: Recent reports suggest a link between positive regulation of the Hippo pathway with bipolar disorder (BD), and the Hippo pathway is known to interact with multiple other signaling pathways previously associated with BD and other psychiatric disorders. In this study, neuronal-like NT2 cells were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM), or vehicle control for 24 h. Genome-wide mRNA expression was quantified and analyzed using gene set enrichment analysis (GSEA), with genes belonging to Hippo, Wnt, Notch, TGF- β, and Hedgehog retrieved from the KEGG database. Five of the eight drugs downregulated the genes of the Hippo pathway and modulated several genes involved in the interacting pathways. We speculate that the regulation of these genes, especially by aripiprazole, clozapine, and quetiapine, results in a reduction of MAPK and NFκB pro-inflammatory signaling through modulation of Hippo, Wnt, and TGF-β pathways. We also employed connectivity map analysis to identify compounds that act on these pathways in a similar manner to the known psychiatric drugs. Thirty-six compounds were identified. The presence of antidepressants and antipsychotics validates our approach and reveals possible new targets for drug repurposing.
Publisher: Springer Science and Business Media LLC
Date: 03-05-2020
Publisher: EDITORA SCIENTIFIC
Date: 02-2022
Publisher: Springer Science and Business Media LLC
Date: 16-12-2010
DOI: 10.1007/S11064-010-0364-3
Abstract: The present study was aimed to evaluate the behavioral and molecular effects of maternal deprivation in adult rats. To this aim, male rats deprived and non-deprived were assessed in the forced swimming and open-field tests in adult phase. In addition adrenocorticotrophin hormone (ACTH) levels was assessed in serum and brain-derived-neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor (NGF) protein levels were assessed in prefrontal cortex, hippoc us and amygdala. We observed that maternal deprivation increased immobility time, and decreased climbing time, without affecting locomotor activity. ACTH circulating levels were increased in maternal deprived rats. Additionally, BDNF protein levels were reduced in the amygdala and NT-3 and NGF were reduced in both hippoc us and amygdala in maternal deprived rats, compared to control group. In conclusion, our results support the idea that behavioral, ACTH circulating levels and neurotrophins levels altered in maternal deprivation model could contribute to stress-related diseases, such as depression.
Publisher: Wiley
Date: 23-03-2023
DOI: 10.1111/BDI.13319
Abstract: The aim of this study was to repurpose a drug for the treatment of bipolar depression. A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal‐like (NT2‐N) cells. A compound library of 960 approved, off‐patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co‐cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive‐like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats). The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal‐like cells. Transcriptomic analysis in induced pluripotent stem cell‐derived neuron/astrocyte co‐cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive‐like behaviours, trimetazidine exhibited antidepressant‐like activity with reduced anhedonia and reduced immobility in the forced swim test. Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.
Publisher: Informa UK Limited
Date: 07-2013
DOI: 10.1586/14737175.2013.811981
Abstract: Recent studies highlight the presence of systemic toxicity as an integral dimension of bipolar disorder pathophysiology, possibly linking this mood disorder with other medical conditions and comorbidities. This review summarizes recent findings on possible peripheral biomarkers of illness activity, with a focus on neurotrophins, inflammation and oxidative stress. The possible mechanisms underlying the systemic toxicity associated with acute episodes in bipolar disorder are also discussed. Finally, the authors outline novel therapies that emerge from this new research and the assessment of multiple biomarkers as a potential approach to improving management strategies in bipolar disorder.
Publisher: SAGE Publications
Date: 08-01-2020
Abstract: The drugs commonly used to treat bipolar disorder have limited efficacy and drug discovery is h ered by the paucity of knowledge of the pathophysiology of this disease. This study aims to explore the role of microRNAs in bipolar disorder and understand the molecular mechanisms of action of commonly used bipolar disorder drugs. The transcriptional effects of bipolar disorder drug combination (lithium, valproate, lamotrigine and quetiapine) in cultured human neuronal cells were studied using next generation sequencing. Differential expression of genes ( n=20) and microRNAs ( n=6) was assessed and the differentially expressed microRNAs were confirmed with TaqMan MicroRNA Assays. The expression of the differentially expressed microRNAs were inhibited to determine bipolar disorder drug effects on their target genes ( n=8). Independent s les t-test was used for normally distributed data and Kruskal-Wallis/Mann-Whitney U test was used for data not distributed normally. Significance levels were set at p .05. We found that bipolar disorder drugs tended to increase the expression of miR-128 and miR-378 ( p .05). Putative target genes of these microRNAs targeted pathways including those identified as “neuron projection development” and “axonogenesis”. Many of the target genes are inhibitors of neurite outgrowth and neurogenesis and were downregulated following bipolar disorder drug combination treatment (all p .05). The bipolar disorder drug combination tended to decrease the expression of the target genes ( NOVA1, GRIN3A, and VIM), however this effect could be reversed by the application of microRNA inhibitors. We conclude that at a transcriptional level, bipolar disorder drugs affect several genes in concert that would increase neurite outgrowth and neurogenesis and hence neural plasticity, and that this effect is mediated (at least in part) by modulation of the expression of these two key microRNAs.
Publisher: Oxford University Press (OUP)
Date: 19-02-2018
DOI: 10.1093/IJNP/PYY014
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.JPSYCHIRES.2013.06.018
Abstract: Evidence suggests that mitochondrial dysfunction is involved in the pathophysiology of psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD). However, the exact mechanisms underlying this dysfunction are not well understood. Impaired activity of electron transport chain (ETC) complexes has been described in these disorders and may reflect changes in mitochondrial metabolism and oxidative stress markers. The objective of this study was to compare ETC complex activity and protein and lipid oxidation markers in 12 euthymic patients with BD type I, in 18 patients with stable chronic SZ, and in 30 matched healthy volunteers. Activity of complexes I, II, and III was determined by enzyme kinetics of mitochondria isolated from peripheral blood mononuclear cells (PBMCs). Protein oxidation was evaluated using the protein carbonyl content (PCC) method, and lipid peroxidation, the thiobarbituric acid reactive substances (TBARS) assay kit. A significant decrease in complex I activity was observed (p = 0.02), as well as an increase in plasma levels of TBARS (p = 0.00617) in patients with SZ when compared to matched controls. Conversely, no significant differences were found in complex I activity (p = 0.17) or in plasma TBARS levels (p = 0.26) in patients with BD vs. matched controls. Our results suggest that mitochondrial complex I dysfunction and oxidative stress play important roles in the pathophysiology of SZ and may be used in potential novel adjunctive therapy for SZ, focusing primarily on cognitive impairment and disorder progression.
Publisher: MDPI AG
Date: 06-11-2020
DOI: 10.3390/IJMS21218333
Abstract: Although neurogenesis is affected in several psychiatric diseases, the effects and mechanisms of action of psychoactive drugs on neurogenesis remain unknown and/or controversial. This study aims to evaluate the effects of psychoactive drugs on the expression of genes involved in neurogenesis. Neuronal-like cells (NT2-N) were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), or valproate (0.5 mM) for 24 h. Genome wide mRNA expression was quantified and analysed using gene set enrichment analysis, with the neurogenesis gene set retrieved from the Gene Ontology database and the Mammalian Adult Neurogenesis Gene Ontology (MANGO) database. Transcription factors that are more likely to regulate these genes were investigated to better understand the biological processes driving neurogenesis. Targeted metabolomics were performed using gas chromatography-mass spectrometry. Six of the eight drugs decreased the expression of genes involved in neurogenesis in both databases. This suggests that acute treatment with these psychoactive drugs negatively regulates the expression of genes involved in neurogenesis in vitro. SOX2 and three of its target genes (CCND1, BMP4, and DKK1) were also decreased after treatment with quetiapine. This can, at least in part, explain the mechanisms by which these drugs decrease neurogenesis at a transcriptional level in vitro. These results were supported by the finding of increased metabolite markers of mature neurons following treatment with most of the drugs tested, suggesting increased proportions of mature relative to immature neurons consistent with reduced neurogenesis.
Publisher: EDITORA SCIENTIFIC
Date: 17-10-2016
Publisher: Cambridge University Press (CUP)
Date: 16-07-2018
DOI: 10.1017/NEU.2018.13
Abstract: This study aimed to explore effects of adjunctive treatment with N -acetyl cysteine (NAC) on markers of inflammation and neurogenesis in bipolar depression. This is a secondary analysis of a placebo-controlled randomised trial. Serum s les were collected at baseline, week 8, and week 32 of the open-label and maintenance phases of the clinical trial to determine changes in interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor-α (TNF-α), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following adjunctive NAC treatment, and to explore mediation and moderator effects of the listed markers. Levels of brain-derived neurotrophic factor (BDNF), tumour necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukins (IL) -6, 8, or 10 were not significantly changed during the course of the trial or specifically in the open-label and maintenance phases. There were no mediation or moderation effects of the biological factors on the clinical parameters. The results suggest that these particular biological parameters may not be directly involved in the therapeutic mechanism of action of adjunctive NAC in bipolar depression.
Publisher: Cambridge University Press (CUP)
Date: 20-03-2017
DOI: 10.1017/NEU.2017.2
Abstract: This study aimed to explore effects of adjunctive N -acetylcysteine (NAC) treatment on inflammatory and neurogenesis markers in unipolar depression. We embarked on a 12-week clinical trial of NAC (2000 mg/day compared with placebo) as an adjunctive treatment for unipolar depression. A follow-up visit was conducted 4 weeks following the completion of treatment. We collected serum s les at baseline and the end of the treatment phase (week 12) to determine changes in interleukin-6 (IL6), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following NAC treatment. NAC treatment significantly improved depressive symptoms on the Montgomery–Asberg Depression Rating Scale (MADRS) over 16 weeks of the trial. Serum levels of IL6 were associated with reductions of MADRS scores independent of treatment response. However, we found no significant changes in IL6, CRP and BDNF levels following NAC treatment. Overall, this suggests that our results failed to support the hypothesis that IL6, CRP and BDNF are directly involved in the therapeutic mechanism of NAC in depression. IL6 may be a useful marker for future exploration of treatment response.
Publisher: MDPI AG
Date: 09-03-2023
DOI: 10.3390/IJMS24065250
Abstract: Minocycline has anti-inflammatory, antioxidant, and anti-apoptotic properties that explain the renewed interest in its use as an adjunctive treatment for psychiatric and neurological conditions. Following the completion of several new clinical trials using minocycline, we proposed an up-to-date systematic review and meta-analysis of the data available. The PICO (patient opulation, intervention, comparison and outcomes) framework was used to search 5 databases aiming to identify randomized controlled trials that used minocycline as an adjunctive treatment for psychiatric and neurological conditions. Search results, data extraction, and risk of bias were performed by two independent authors for each publication. Quantitative meta-analysis was performed using RevMan software. Literature search and review resulted in 32 studies being included in this review: 10 in schizophrenia, 3 studies in depression, and 7 in stroke, with the benefit of minocycline being used in some of the core symptoms evaluated 2 in bipolar disorder and 2 in substance use, without demonstrating a benefit for using minocycline 1 in obsessive-compulsive disorder, 2 in brain and spinal injuries, 2 in amyotrophic lateral sclerosis, 1 in Alzheimer’s disease, 1 in multiple systems atrophy, and 1 in pain, with mixes results. For most of the conditions included in this review the data is still limited and difficult to interpret, warranting more well-designed and powered studies. On the other hand, the studies available for schizophrenia seem to suggest an overall benefit favoring the use of minocycline as an adjunctive treatment.
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.NEULET.2011.04.039
Abstract: Evidence is emerging for a role for neurotrophins in the treatment of mood disorders. In this study, we evaluated the effects of chronic administration of fluoxetine, olanzapine and the combination of fluoxetine/olanzapine on the brain-derived-neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) in the rat brain. Wistar rats received daily injections of olanzapine (3 or 6 mg/kg) and/or fluoxetine (12.5 or 25mg/kg) for 28 days, and we evaluated for BDNF, NGF and NT-3 protein levels in the prefrontal cortex, hippoc us and amygdala. Our results showed that treatment with fluoxetine and olanzapine alone or in combination did not alter BDNF in the prefrontal cortex (p=0.37), hippoc us (p=0.98) and amygdala (p=0.57) or NGF protein levels in the prefrontal cortex (p=0.72), hippoc us (p=0.23) and amygdala (p=0.64), but NT-3 protein levels were increased by olanzapine 6 mg/kg/fluoxetine 25mg/kg combination in the prefrontal cortex (p=0.03), in the hippoc us (p=0.83) and amygdala (p=0.88) NT-3 protein levels did not alter. Finally, these findings further support the hypothesis that NT-3 could be involved in the effect of treatment with antipsychotic and antidepressant combination in mood disorders.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.JAD.2014.12.010
Abstract: Bipolar disorder (BD) is commonly comorbid with many medical disorders including atopy, and appears characterized by progressive social, neurobiological, and functional impairment associated with increasing number of episodes and illness duration. Early and late stages of BD may present different biological features and may therefore require different treatment strategies. Consequently, the aim of this study was to evaluate serum levels of eotaxin/CCL11, eotaxin-2/CCL24, IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFNγ, BDNF, TBARS, carbonyl, and GPx in a s le of euthymic patients with BD at early and late stages compared to controls. Early-stage BD patients, 12 late-stage patients, and 25 controls matched for sex and age were selected. 10mL of peripheral blood was drawn from all subjects by venipuncture. Serum levels of BDNF, TBARS, carbonyl content, glutathione-peroxidase activity (GPx), cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α and IFNγ), and chemokines (eotaxin/CCL11 and eotaxin-2/CCL24) were measured. There were no demographic differences between patients and controls. No significant differences were found for any of the biomarkers, except chemokine eotaxin/CCL11, whose serum levels were higher in late-stage patients with BD when compared to controls (p=0.022 Mann-Whitney U test). Small number of subjects and use of medication may have influenced in our results. The present study suggests a link between biomarkers of atopy and eosinophil function and bipolar disorder. These findings are also in line with progressive biological changes partially mediated by inflammatory imbalance, a process referred to as neuroprogression.
Publisher: Informa UK Limited
Date: 03-08-2020
DOI: 10.1080/15622975.2018.1492734
Abstract: To create a gene expression signature (GES) to represent the biological effects of a combination of known drugs for bipolar disorder (BD) on cultured human neuronal cells (NT2-N) and rat brains, which also has evidence of differential expression in in iduals with BD. To use the GES to identify new drugs for BD using Connectivity Map (CMap).
Publisher: MDPI AG
Date: 10-09-2021
DOI: 10.3390/JCM10184095
Abstract: Weight gain and consequent metabolic alterations are common side-effects of many antipsychotic drugs. Interestingly, several studies have suggested that improvement in symptoms and adverse metabolic effects are correlated. We used next generation sequencing data from NT-2 (human neuronal) cells treated with aripiprazole, amisulpride, risperidone, quetiapine, clozapine, or vehicle control, and compared with the Pillinger P-score (ranked from 0 to 1, indicating greater increase in weight gain and related metabolic parameters) to identify the genes most associated with the drugs’ propensity to cause weight gain. The top 500 genes ranked for their correlation with the drugs’ propensity to cause weight gain were subjected to pathway analysis using DAVID (NIH). We further investigated transcription factors (TFs) that are more likely to regulate the genes involved in these processes using the prediction tool of key TFs from TRRUST. The results suggest an enrichment for genes involved in lipid biosynthesis and metabolism, which are of interest for mechanisms underpinning weight-gain. The list of genes involved in the lipid pathways that correlated with weight gain was enriched for genes transcriptionally regulated by SREBF1 and SREBF2. Furthermore, quetiapine significantly increased the expression of SREBF1 and SREBF2 in NT-2 cells. Our results suggest that the effects of these antipsychotic drugs on lipid metabolism may be mediated, at least in part, via regulation of SREBF1/SREBF2 expression, with evidence of a direct effect of quetiapine on the expression of SREBF1/2. The effects of antipsychotic drugs on lipid metabolism may influence white matter structure (therapeutic effect) and the risk of weight gain, lipid disturbances, and, consequently, metabolic syndrome (adverse effects). Understanding the different molecular effects of these drugs could inform a personalized medicine approach in treating patients with schizophrenia.
Publisher: MDPI AG
Date: 06-07-2022
DOI: 10.3390/IJMS23147508
Abstract: There is little understanding of the underlying molecular mechanism(s) involved in the clinical efficacy of antipsychotics for schizophrenia. This study integrated schizophrenia-associated transcriptional perturbations with antipsychotic-induced gene expression profiles to detect potentially relevant therapeutic targets shared by multiple antipsychotics. Human neuronal-like cells (NT2-N) were treated for 24 h with one of the following antipsychotic drugs: amisulpride, aripiprazole, clozapine, risperidone, or vehicle controls. Drug-induced gene expression patterns were compared to schizophrenia-associated transcriptional data in post-mortem brain tissues. Genes regulated by each of four antipsychotic drugs in the reverse direction to schizophrenia were identified as potential therapeutic-relevant genes. A total of 886 genes were reversely expressed between at least one drug treatment (versus vehicle) and schizophrenia (versus healthy control), in which 218 genes were commonly regulated by all four antipsychotic drugs. The most enriched biological pathways include Wnt signaling and action potential regulation. The protein-protein interaction (PPI) networks found two main clusters having schizophrenia expression quantitative trait loci (eQTL) genes such as PDCD10, ANK2, and AKT3, suggesting further investigation on these genes as potential novel treatment targets.
Publisher: Mary Ann Liebert Inc
Date: 11-2017
DOI: 10.1089/SUR.2017.219
Abstract: This declaration, signed by an interdisciplinary task force of 234 experts from 83 different countries with different backgrounds, highlights the threat posed by antimicrobial resistance and the need for appropriate use of antibiotic agents and antifungal agents in hospitals worldwide especially focusing on surgical infections. As such, it is our intent to raise awareness among healthcare workers and improve antimicrobial prescribing. To facilitate its dissemination, the declaration was translated in different languages.
Publisher: Elsevier BV
Date: 02-2014
Publisher: EDITORA SCIENTIFIC
Date: 09-2017
Publisher: MDPI AG
Date: 28-06-2022
DOI: 10.3390/IJMS23137180
Abstract: Altered protein synthesis has been implicated in the pathophysiology of several neuropsychiatric disorders, particularly schizophrenia. Ribosomes are the machinery responsible for protein synthesis. However, there remains little information on whether current psychotropic drugs affect ribosomes and contribute to their therapeutic effects. We treated human neuronal-like (NT2-N) cells with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM) or vehicle control for 24 h. Transcriptomic and gene set enrichment analysis (GSEA) identified that the ribosomal pathway was altered by these drugs. We found that three of the eight drugs tested significantly decreased ribosomal gene expression, whilst one increased it. Most changes were observed in the components of cytosolic ribosomes and not mitochondrial ribosomes. Protein synthesis assays revealed that aripiprazole, clozapine and lithium all decreased protein synthesis. Several currently prescribed psychotropic drugs seem to impact ribosomal gene expression and protein synthesis. This suggests the possibility of using protein synthesis inhibitors as novel therapeutic agents for neuropsychiatric disorders.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.SCHRES.2016.04.004
Abstract: Schizophrenia (SZ) is associated with broad burden. The clinical manifestations of SZ are related to pathophysiological alterations similar to what is seen in normal aging. Our aim was to evaluate the differences in telomere length (TL), a biomarker of cellular aging, in subjects with SZ (n=36), unaffected siblings (SB, n=36) and healthy controls (HC, n=47). SZ had shorter TL compared to HC, but no difference was found in SB comparing to SZ. These findings indicate that a pathological accelerated aging profile could be present in the course of SZ and further studies are needed to confirm TL as potential endophenotype, especially in at risk populations.
Publisher: Informa UK Limited
Date: 16-10-2019
Publisher: Informa Healthcare
Date: 21-03-2014
DOI: 10.1517/14728222.2014.897329
Abstract: Neurosteroids are molecules that regulate physiological functions of the CNS. There is increasing evidence suggesting that impaired neurosteroid biosynthesis has been associated with distinct psychiatric disorders. This review summarizes data from studies that have investigated the relationship between progesterone (PROG) and psychiatric disorders as well as the mechanisms potentially involved in PROG-induced neuroprotection. The review covers the role of PROG and its metabolites in psychiatric disorders, focusing on results from preclinical and some clinical studies that support the relationship between alterations on PROG levels and pathophysiology of psychiatric illness. We also discussed the main mechanisms underlying the neuroprotective effects of PROG metabolites. Our review points out the possible relationship between PROG and its metabolites and the pathophysiology of psychiatric disorders. Furthermore, both preclinical and clinical studies show that certain treatments (antidepressants or antipsychotics) may normalize the levels of PROG, suggesting that the amelioration of psychiatric symptoms may occur due to upregulation of PROG metabolites. Therefore, these results give support to new possibilities of treatment for patients with psychiatric symptoms from anxiety- and depressive-like behaviors to aggressive behaviors.
Publisher: Oxford University Press (OUP)
Date: 22-02-2017
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.SCHRES.2012.08.002
Abstract: Omega-3 has shown efficacy to prevent schizophrenia conversion in ultra-high risk population. We evaluated the efficacy of omega-3 in preventing ketamine-induced effects in an animal model of schizophrenia and its effect on brain-derived neurotrophic factor (BDNF). Omega-3 or vehicle was administered in Wistar male rats, both groups at the 30th day of life for 15days. Each group was split in two to receive along the following 7days ketamine or saline. Locomotor and exploratory activities, memory test and social interaction between pairs were evaluated at the 52nd day of life. Prefrontal-cortex, hippoc us and striatum tissues were extracted right after behavioral tasks for mRNA BDNF expression analysis. Bloods for serum BDNF were withdrawn 24h after the end of behavioral tasks. Locomotive was increased in ketamine-treated group compared to control, omega-3 and ketamine plus omega-3 groups. Ketamine group had fewer contacts and interaction compared to other groups. Working memory and short and long-term memories were significantly impaired in ketamine group compared to others. Serum BDNF levels were significantly higher in ketamine plus omega-3 group. There was no difference between groups in prefrontal-cortex, hippoc us and striatum for mRNA BDNF expression. Administration of omega-3 in adolescent rats prevents positive, negative and cognitive symptoms in a ketamine animal model of schizophrenia. Whether these findings are consequence of BDNF increase it is unclear. However, this study gives compelling evidence for larger clinical trials to confirm the use of omega-3 to prevent schizophrenia and for studies to reinforce the beneficial role of omega-3 in brain protection.
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.NEUROSCIENCE.2013.11.049
Abstract: Supplementation with omega-3 has been identified as an adjunctive alternative for the treatment of psychiatric disorders, in order to minimize symptoms. Considering the lack of understanding concerning the pathophysiology of schizophrenia, the present study hypothesized that omega 3 prevents the onset of symptoms similar to schizophrenia in young Wistar rats submitted to ketamine treatment. Moreover, the role of oxidative stress in this model was assessed. Omega-3 (0.8g/kg) or vehicle was given by orogastric gavage once daily. Both treatments were performed during 21days, starting at the 30th day of life in young rats. After 14days of treatment with omega-3 or vehicle, a concomitant treatment with saline or ketamine (25mg/kg ip daily) was started and maintained until the last day of the experiment. We evaluated the pre-pulse inhibition of the startle reflex, activity of antioxidant systems and damage to proteins and lipids. Our results demonstrate that supplementation of omega-3 prevented: decreased inhibition of startle reflex, damage to lipids in the hippoc us and striatum and damage to proteins in the prefrontal cortex. Furthermore, these changes are associated with decreased GPx in brain tissues evaluated. Together, our results suggest the prophylactic role of omega-3 against the outcome of symptoms associated with schizophrenia.
No related grants have been discovered for Bruna Panizzutti.