Valproate robustly enhances AP-1 mediated gene expression

Valproic acid (VPA) is a potent broad spectrum anticonvulsant with demonstr ated efficacy in the treatment of Bipolar Affective Disorder, but the bioch emical basis for VPA's antimanic or mood-stabilizing actions have not been fully elucidated. It has been demonstrated that VPA, at therapeutically rel evant concentrations, increases AP-I DNA binding activity in cultured cells in vitro. These findings raise the possibility that VPA may produce its mo od-stabilizing effects by regulating the expression of subsets of genes via its effects on the AP-1 family of transcription factors. To determine if V PA does, in fact, enhance AP-I mediated gene expression, the effects of VPA on the expression of a luciferase reporter gene were studied in transientl y transfected rat CG glioma and human SH-SY5Y neuroblastoma cells using the pGL2-control vector. The luciferase gene in the vector is driven by an SV4 0 promoter which contains well characterized AP-I sites. VPA produced a gre ater than doubling of luciferase activity in a time- and concentration-depe ndent manner in both cell lines. Furthermore, mutations of the AP-1 sites i n the SV40 promoter markedly attenuated the VPA-induced increases in lucife rase activity. These effects of VPA on AP-1 mediated gene expression are ve ry similar to the effects observed with lithium, and suggest that the tempo ral regulation of AP-I mediated,gene expression in critical neuronal circui ts may play a role in the long-term therapeutic efficacy of these agents. ( C) 1999 Elsevier Science B.V. All rights reserved.