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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

Department of Psychiatry, National Cheng Kung University, 臺南市, Taiwan, Taiwan
Molecular Psychiatry (Impact Factor: 14.5). 01/2007; 11(12):1116-25. DOI: 10.1038/sj.mp.4001893
Source: PubMed

ABSTRACT

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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    • "Several drugs, including valproic acid (VPA), vorinostat, MS-275, sodium butyrate, and phenyl butyrate have been shown to cross the blood-brain barrier making these compounds suitable candidates to be tested in treating brain disorders[160]. Clinical evidences showed that VPA can reduce brain inflammation by inducing microglia apoptosis[162,163,164]and promote neurotrophin production by astrocytes[165,166]suggesting a potential therapeutic relevance of HDAC inhibitors in CNS pathologies[160]. Accordingly, in a mouse model of Alzheimer's disease (AD), injections of the inhibitors sodium valproate, sodium butyrate, or vorinostat completely restored contextual memory indicating that targeted inhibition of class I HDAC isoforms would be promising for treating the cognitive deficits associated with early stage AD[167]. "
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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.
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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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