Chen PS, Peng GS, Li G, Yang S, Wu X, Wang CC et al. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatr 11: 1116-1125

Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
Molecular Psychiatry (Impact Factor: 14.5). 01/2007; 11(12):1116-25. DOI: 10.1038/
Source: PubMed


Valproate (VPA), one of the mood stabilizers and antiepileptic drugs, was recently found to inhibit histone deacetylases (HDAC). Increasing reports demonstrate that VPA has neurotrophic effects in diverse cell types including midbrain dopaminergic (DA) neurons. However, the origin and nature of the mediator of the neurotrophic effects are unclear. We have previously demonstrated that VPA prolongs the survival of midbrain DA neurons in lipopolysaccharide (LPS)-treated neuron-glia cultures through the inhibition of the release of pro-inflammatory factors from microglia. In this study, we report that VPA upregulates the expression of neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) from astrocytes and these effects may play a major role in mediating VPA-induced neurotrophic effects on DA neurons. Moreover, VPA pretreatment protects midbrain DA neurons from LPS or 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. Our study identifies astrocyte as a novel target for VPA to induce neurotrophic and neuroprotective actions in rat midbrain and shows a potential new role of cellular interactions between DA neurons and astrocytes. The neurotrophic and neuroprotective effects of VPA also suggest a utility of this drug for treating neurodegenerative disorders including Parkinson's disease. Moreover, the neurotrophic effects of VPA may contribute to the therapeutic action of this drug in treating bipolar mood disorder that involves a loss of neurons and glia in discrete brain areas.

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    • "HDAC inhibitors are a class of drugs that inhibit histone deacetylases – group of enzymes that deacetylate histones and non-histone proteins. It has been shown that certain HDAC inhibitors have antidepressant actions and regulate BDNF expression [56], for example valproate [42,57-59], TSA [58,60] and SAHA [61]. Since it would be of interest to use our cell lines for screening of other compounds that could epigenetically regulate BDNF expression, we tested response of the reporter gene in BAC cell lines to four HDAC inhibitors. "
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    ABSTRACT: Background Brain derived neurotrophic factor (BDNF) belongs to a family of structurally related proteins called neurotrophins that have been shown to regulate survival and growth of neurons in the developing central and peripheral nervous system and also to take part in synaptic plasticity related processes in adulthood. Since BDNF is associated with several nervous system disorders it would be beneficial to have cellular reporter system for studying its expression regulation. Methods Using modified bacterial artificial chromosome (BAC), we generated several transgenic cell lines expressing humanised Renilla luciferase (hRluc)-EGFP fusion reporter gene under the control of rat BDNF gene regulatory sequences (rBDNF-hRluc-EGFP) in HeLa background. To see if the hRluc-EGFP reporter was regulated in response to known regulators of BDNF expression we treated cell lines with substances known to regulate BDNF and also overexpressed transcription factors known to regulate BDNF gene in established cell lines. Results rBDNF-hRluc-EGFP cell lines had high transgene copy numbers when assayed with qPCR and FISH analysis showed that transgene was maintained episomally in all cell lines. Luciferase activity in transgenic cell lines was induced in response to ionomycin-mediated rise of intracellular calcium levels, treatment with HDAC inhibitors and by over-expression of transcription factors known to increase BDNF expression, indicating that transcription of the transgenic reporter is regulated similarly to the endogenous BDNF gene. Conclusions Generated rBDNF-hRluc-EGFP BAC cell lines respond to known modulators of BDNF expression and could be used for screening of compounds/small molecules or transcription factors altering BDNF expression.
    BMC Neuroscience 06/2014; 15(1):75. DOI:10.1186/1471-2202-15-75 · 2.67 Impact Factor
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    • "In astrocytes, HDAC inhibition in culture leads to an increase in secretion of neurotrophic cytokines, leading to a neuroprotective effect in dopaminergic neurons (Chen et al. 2006) and also stimulates astrocytes to release clusterin, which counteracts amyloid aggregation and plaque formation (Nuutinen et al. 2010). These results indicate that HDAC inhibition exerts a neuroprotective effect through changes in astrocyte regulation, leading to an enhancement of their neurotrophic potential both in Parkinson's and in Alzheimer's disease. "
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    ABSTRACT: Epigenetic regulation shapes the differentiation and response to stimuli of all tissues and cells beyond what genetics would dictate. Epigenetic regulation acts through covalent modifications of DNA and histones while leaving the nucleotide code intact. However, these chromatin modifications are known to be vital components of the regulation of cell fate and response. With regards to the central nervous system (CNS), little is known about how epigenetic regulation shapes the function of neural cell types. The focus of research so far has been on epigenetic regulation of neuronal function and the role of epigenetics in tumorigenesis. However, the glial cell compartment, which makes up 90 % of all CNS cells, has so far received scant attention as to how epigenetics shape their differentiation and function. Here, we highlight current knowledge about epigenetic changes in glial cells occurring during CNS injury, neuroinflammatory conditions and neurodegenerative disease. This review offers an overview of the current understanding of epigenetic regulation in glial cells in CNS disease.
    Cell and Tissue Research 03/2014; 356(3). DOI:10.1007/s00441-014-1815-y · 3.57 Impact Factor
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    • "VPA, an anticonvulsant and mood-stabilizing drug, has been characterized as an HDACi (Göttlicher et al., 2001). Several studies have shown that VPA has neuroprotective effects, suggesting that the therapeutic mechanisms of this drug involve, at least in part, HDAC inhibition (Dou et al., 2003; Chen et al., 2006; Leng et al., 2008). "
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    ABSTRACT: Bipolar disorder is a severe mood disorder with high morbidity and mortality. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, and functional impairment. Some preclinical studies have shown that histone deacetylase inhibitors may act on depressive-like and manic-like behaviors. Therefore, the aim of the present study was to evaluate the effects of sodium butyrate (SB) on behavioral changes in animal models of depression and mania. The animals were submitted to protocols of chronic mild stress or maternal deprivation for induction of depressive-like behaviors and subjected to amphetamine, or ouabain administration for induction of manic-like behaviors. SB reversed the depressive-like and manic-like behaviors evaluated in the animal models. From these results we can suggest that SB may be a potential mood stabilizer.
    Behavioural pharmacology 08/2013; 24(7). DOI:10.1097/FBP.0b013e32836546fc · 2.15 Impact Factor
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