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Background: The drugs commonly used to treat bipolar disorder have limited efficacy and drug discovery is hampered 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., Methods: 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 samples 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 <0.05., Results: We found that bipolar disorder drugs tended to increase the expression of miR-128 and miR-378 ( p <0.05). 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 <0.05). 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., Conclusions: 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.

Objectives: The aim of this study was to repurpose a drug for the treatment of bipolar depression. Methods: 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). Results: 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. Conclusion: Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression. [ABSTRACT FROM AUTHOR]

Novel approaches are required to find new treatments for schizophrenia and other neuropsychiatric disorders. This study utilised a combination of in vitro transcriptomics and in silico analysis with the BROAD Institute's Connectivity Map to identify drugs that can be repurposed to treat psychiatric disorders. Human neuronal (NT2-N) cells were treated with a combination of atypical antipsychotic drugs commonly used to treat psychiatric disorders (such as schizophrenia, bipolar disorder, and major depressive disorder), and differential gene expression was analysed. Biological pathways with an increased gene expression included circadian rhythm and vascular endothelial growth factor signalling, while the adherens junction and cell cycle pathways were transcriptionally downregulated. The Connectivity Map (CMap) analysis screen highlighted drugs that affect global gene expression in a similar manner to these psychiatric disorder treatments, including several other antipsychotic drugs, confirming the utility of this approach. The CMap screen specifically identified metergoline, an ergot alkaloid currently used to treat seasonal affective disorder, as a drug of interest. In mice, metergoline dose-dependently reduced MK-801- or methamphetamine-induced locomotor hyperactivity confirming the potential of metergoline to treat positive symptoms of schizophrenia in an animal model. Metergoline had no effects on prepulse inhibition deficits induced by MK-801 or methamphetamine. Taken together, metergoline appears a promising drug for further studies to be repurposed as a treatment for schizophrenia and possibly other psychiatric disorders. [ABSTRACT FROM AUTHOR]

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 individuals with BD. To use the GES to identify new drugs for BD using Connectivity Map (CMap).Methods: NT2-N (n = 20) cells and rats (n = 8) were treated with a BD drug combination (lithium, valproate, quetiapine and lamotrigine) or vehicle for 24 and 6 h, respectively. Following next-generation sequencing, the differential expression of genes was assessed using edgeR in R. The derived GES was compared to differentially expressed genes in post-mortem brains of individuals with BD. The GES was then used in CMap analysis to identify similarly acting drugs.Results: A total of 88 genes showed evidence of differential expression in response to the drug combination in both models, and therefore comprised the GES. Six of these genes showed evidence of differential expression in post-mortem brains of individuals with BD. CMap analysis identified 10 compounds (camptothecin, chlorambucil, flupenthixol, valdecoxib, rescinnamine, GW-8510, cinnarizine, lomustine, mifepristone and nimesulide) acting similarly to the BD drug combination.Conclusions: This study shows that GES and CMap can be used as tools to repurpose drugs for BD. [ABSTRACT FROM AUTHOR]

Altered metabolism in tissues such as the liver, skeletal muscle and adipose tissue is observed in metabolic diseases characterized by nutrient excess and energy imbalance, such as obesity and type 2 diabetes. These alterations in metabolism can include resistance to the hormone insulin, lipid accumulation, mitochondrial dysfunction and transcriptional remodelling of major metabolic pathways. The underlying assumption has been that these same alterations in metabolism are fundamental to the pathogenesis of metabolic diseases. An alternative view is that these alterations in metabolism occur to protect cell and tissue viability in the face of constant positive energy balance. This speculative review presents evidence that many of the metabolic adaptations that occur in metabolic diseases characterized by nutrient excess can be viewed as protective in nature, rather than pathogenic per se for disease progression. Finally, we also briefly discuss the usefulness and potential pitfalls of therapeutic approaches that attempt to correct these same metabolic defects when energy balance is not altered, and the potential links between metabolic survival responses and other chronic diseases such as cancer. [ABSTRACT FROM AUTHOR]

Background and Aims: A major impediment to establishing new treatments for non-alcoholic steatohepatitis is the lack of suitable animal models that accurately mimic the biochemical and metabolic characteristics of the disease. The aim of this study was to explore a unique polygenic animal model of metabolic disease as a model of non-alcoholic steatohepatitis by determining the effects of 2% dietary cholesterol supplementation on metabolic and liver endpoints in Psammomys obesus (Israeli sand rat). Methods: P. obesus were provided ad libitum access to either a standard rodent diet (20% kcal/fat) or a standard rodent diet supplemented with 2% cholesterol (w/w) for 4 weeks. Histological sections of liver from animals on both diets were examined for key features of non-alcoholic steatohepatitis. The expression levels of key genes involved in hepatic lipid metabolism were measured by real-time PCR. Results: P. obesus fed a cholesterol-supplemented diet exhibited profound hepatomegaly and steatosis, and higher plasma transaminase levels. Histological analysis identified extensive steatosis, inflammation, hepatocyte injury and fibrosis. Hepatic gene expression profiling revealed decreased expression of genes involved in delivery and uptake of lipids, and fatty acid and triglyceride synthesis, and increased expression of genes involved in very low density lipoprotein cholesterol synthesis, triglyceride and cholesterol export. Conclusions: P. obesus rapidly develop non-alcoholic steatohepatitis when fed a cholesterol-supplemented diet that appears to be histologically and mechanistically similar to patients. [ABSTRACT FROM AUTHOR]

Abstract: Study background: Insulin resistance plays an important role in the pathogenesis of type 2 diabetes and the metabolic syndrome. Many of the genes and pathways involved have been identified but some remain to be defined. Metallothioneins (Mts) are a family of anti-oxidant proteins and metallothionein 2a (Mt2a) polymorphims have been recently associated with type 2 diabetes and related complications. Our objective was to determine the Mt2a gene expression levels in adipose tissues from diabetic patients and the effect of Mt treatment on adipocyte insulin sensitivity. Methods: Samples of subcutaneous and visceral adipose tissues from lean, type 2 diabetic and non-diabetic obese patients were analysed using RT-qPCR for Mt2a mRNA abundance. The regulation of Mt2a expression was further studied in 3T3-L1 adipocytes treated or not with TNFα (10ng/ml, 72h) to induce insulin resistance. The effects of Mt on glucose uptake were investigated in cultured adipocytes treated with recombinant Mt protein. Results: We found that the Mt2a gene expression was significantly higher in adipose tissue of type 2 diabetic patients in comparison to that of lean (p=0.003) subjects. In 3T3-L1 adipocytes, insulin resistance induced by TNFα increased Mt2a mRNA levels (p=3×10−4) and insulin-stimulated glucose uptake was significantly inhibited by 53% (p=8×10−4) compared to vehicle, when 3T3-L1 adipocytes were treated with Mt protein. Conclusions: These data suggest that Mt2a might be involved in insulin resistance through the up-regulation of Mt gene expression, which may lead to the modulation of insulin action in fat cells. These results suggest the concept of considering Mt proteins as markers and potential targets in type 2 diabetes. [Copyright &y& Elsevier]