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

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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Abbreviations

ACM:

astrocyte-conditioned medium

BDNF:

brain-derived neurotrophic factor

DA:

dopaminerigc

FBS:

fetal bovine serum

GDNF:

glial cell line-derived neurotrophic factor

HDAC:

histone deacetylase

LPS:

lipopolysaccharide

MPP+:

1-methyl-4-phenylpyridinium

PD:

Parkinson's disease

TH-IR:

tyrosine hydroxylase-immunoreactive

VPA:

valproate

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Acknowledgements

We are grateful to Dr Sung-Jen Wei for technical assistance; Dr Carl D Bortner and Dr Wei Zhang for careful reading of the manuscript.

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Correspondence to J-S Hong.

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Chen, PS., Peng, GS., Li, G. et al. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry 11, 1116–1125 (2006). https://doi.org/10.1038/sj.mp.4001893

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Keywords

  • BDNF
  • GDNF
  • valproate
  • astrocytes
  • dopaminergic neurons
  • neurotrophic effects

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