Induction of Neurotrophic and Differentiation Factors in Neural Stem Cells by Valproic Acid

Valproic acid (VPA), a short-chain fatty acid, is used clinically as an anticonvulsant and mood stabilizer. Valproic acid also inhibits histone deacetylase activity, which is associated with histone hyperacetylation and changes in gene expression. In this study, we examined the effects of VPA on the expression of selected neurotrophic and differentiation factors in C17.2 neural stem cells. Reverse transcription-polymerase chain reaction analysis revealed a significant increase in conserved dopamine neurotrophic factor (CDNF) and glial cell line-derived neurotrophic factor mRNA expression, after treatment with clinically relevant concentrations of VPA (0.5 or 1.0 mM) for 24 hr. Increases in the protein expression of CDNF and mesencephalic astrocyte-derived neurotrophic factor were also observed, after similar treatment with VPA. In addition, significant increases in the mRNA levels of the early dopaminergic neuron marker, nuclear receptor-related protein 1(Nurr1), and the transcriptional regulator, early growth response protein 1 (Egr1), were observed after treatment with VPA for 24 hr. C17.2 neural stem cells exhibited high basal mRNA expression of brain-derived neurotrophic factor and SRY (sex determining region Y)-box 2 (Sox2), which was not altered by VPA treatment. Western analysis revealed hyperacetylation of histone H3 proteins in C17.2 cells after VPA treatment for 24 hr or 48 hr, suggesting involvement of an epigenetic mechanism in the observed gene induction by this drug. These findings support a role for VPA in modulating neurotrophic and differentiation factor expression, in keeping with its reported neuroprotective and neurodevelopmental effects.