Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes

Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
Molecular Psychiatry (Impact Factor: 15.15). 01/2007; 11(12):1116-25. DOI: 10.1038/
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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Available from: Po-Wu Gean, Jul 28, 2015
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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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    • "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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    • "For example, Drevets [2000] reported that chronic treatment with valproate largely suppressed the reduction in brain volume bipolar disorder patients [Drevets, 2000]. Upregulation of the expression of BDNF from astrocytes was reported to be responsible of the neurotrophic effect induced by valproate on dopaminergic neurons [Chen et al., 2006a]. The positive genetic association in our study supports that neurodegeneration may play a role in pathogenesis of bipolar disorder. "
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