Induction Of Neurotrophic and Differentiation Genes in Neural Stem Cells by Valproic Acid M.Sc. Thesis

The short-chain branched fatty acid, valproic acid (2-propylpentanoicacid), has long been in use clinically as an anticonvulsant and mood-stabilizing drug. Recently, VPA has been shown to inhibit the activity of histone deacetylases (HDACs), resulting in chromatin remodelling and changes in gene expression. Although the molecular mechanism for VPA action in the central nervous system (CNS) is not well understood, many signalling pathways have been suggested to serve as targets for this HDAC inhibitor. For instance, VPA was found to induce differentiation in adult hippocampal neural progenitor cells via the β-catenin-Ras-ERK pathway. VPA was also shown to up regulate Bcl-2, a neurotrophic/neuroprotective protein, with association of extracellular signal-regulated kinase (ERK-1) and phosphatidylinositol 3-kinase (PI3) pathway activation. In this study, C17.2 neural stem cells were used to examine the effects of VPA on the expression of the novel neurotrophic factors; cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF). Also the effect of VPA on other genes including; glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), the orphan nuclear receptor-related factor1 (Nurr-1), the early growth response protein 1(Egr-1), and the sex determining region Y-box-2 (Sox-2) were examined. Histone H3 acetylation and the ERK1/2 pathway were examined as possible targets for VPA action. Treatment with clinically relevant concentrations of VPA (1mM, and 3 mM) induced a significant increase of CDNF protein concentrations. Also, an increase in the mRNA expressions of GDNF, Nurr-1, and Egr-1 were detected following 24 hours VPA treatment at clinically relevant concentrations. Also, an increase of histone H3 acetylation was noticed, suggesting HDAC inhibition as a potential mechanism mediated by VPA to induce gene expression in C17.2 NSCs. These findings might support the role of VPA in neuronal development, differentiation and neuroprotection.