The mood stabilizer valproate activates human FGF1 gene promoter through inhibiting HDAC and GSK‐3 activities

Abstract

Valproic acid (VPA) is the primary mood-stabilizing drug to exert neuroprotective effects and to treat bipolar disorder in clinic. Fibroblast growth factor 1 (FGF1) has been shown to regulate cell proliferation, cell division, and neurogenesis. Human FGF1 gene 1B promoter (À540 to +31)-driven green fluorescence (F1BGFP) has been shown to recapitulate endogenous FGF1 gene expression and facilitates the isolation of neural stem/progenitor cells (NSPCs) from developing and adult mouse brains. In this study, we provide several lines of evidence to demonstrate the underlying mechanisms of VPA in activating FGF-1B promoter activity: (i) VPA significantly increased the FGF-1B mRNA expression and the percentage of F1BGFP(+) cells; (ii) the increase of F1BGFP expression by VPA involves changes of regulatory factor X (RFX) 1-3 transcriptional complexes and the increase of histone H3 acetylation on the 18-bp cis-element of FGF-1B promoter; (iii) treatments of other histone deacetylases (HDAC) inhibitors, sodium butyrate and trichostatin A, significantly increased the expression levels of FGF-1B, RFX2, and RFX3 transcripts; (iv) treatments of glycogen synthase kinase 3 (GSK-3) inhibitor, lithium, or GSK-3 siRNAs also significantly activated FGF-1B promoter; (v) VPA specifically enhanced neuronal differentiation in F1BGFP(+) embryonic stem cells and NSPCs rather than GFP(À) cells. This study suggested, for the first time, that VPA activates human FGF1 gene promoter through inhibiting HDAC and GSK-3 activities.

An Update on the Epigenetics of Psychotic Diseases and Autism

“…Lithium also increases H3 ac and phosphoacetylation in the central nucleus of amygdala in rats that can be augmented by HDAC inhibitors [113]. Valproate and lithium could also activate the promoter of FGF1, which plays important roles in cell division and neurogenesis, via the inhibition of HDAC and GSK-3 activities [114]. Lamotrigine was also shown to increase H3 and H4 acetylation in a dose-and time-dependent manner in rat cerebellar granule cells, and via the induction of Bcl-2 protects neurons against glutamate excitotoxicity.…”

Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

“…Valproate which is a simple branched-chain fatty acid has established efficacy in manic, mixed and depressive episodes, and although with regards to GSK3 inhibition there is conflicting evidence, it is a well-studied histone deacetylase (HDAC) inhibitor. HDAC inhibition increases Akt phosphorylation, with resulting inactivation of GSK3 and this mechanism enhances the mood stabilizing effect of lithium 43). In addition, chronic valproate treatment has been found to induce changes in the level of microRNAs (miRNAs) in the rat hippocampus, and the targets of some of these miRNAs are proteins involved in the canonical Wnt pathway 44).…”

Dysregulated fibroblast growth factor (FGF) signaling in neurological and psychiatric disorders

“…Interestingly, mood stabilizers can alter the FGF system by epigenetic mechanisms. The primary mood stabilizer for bipolar disorder, valproate, has recently been shown to increase FGF1 expression by inhibiting HDAC activity [84]. The HDAC enzyme, which removes acetyl groups from histones, typically has an inhibitory role on gene expression.…”