Valproic acid (VPA) is a potent broad spectrum
anticonvulsant with demonstrated efficacy in the treatment of Bipolar
Affective Disorder, but the biochemical basis for VPA's antimanic or mood-stabilizing actions have not been fully elucidated. It has been demonstrated that VPA, at therapeutically relevant concentrations, increases
AP-1 DNA binding activity in cultured cells in vitro. These findings raise the possibility that VPA may produce its mood-stabilizing effects by regulating the expression of subsets of genes via its effects on the
AP-1 family of
transcription factors. To determine if VPA does, in fact, enhance
AP-1 mediated gene expression, the effects of VPA on the expression of a
luciferase reporter gene were studied in transiently transfected rat C6
glioma and human SH-SY5Y
neuroblastoma cells using the pGL2-control vector. The
luciferase gene in the vector is driven by an SV40 promoter which contains well characterized
AP-1 sites. VPA produced a greater than doubling of
luciferase activity in a time- and concentration-dependent manner in both cell lines. Furthermore, mutations of the
AP-1 sites in the SV40 promoter markedly attenuated the VPA-induced increases in
luciferase activity. These effects of VPA on
AP-1 mediated gene expression are very similar to the effects observed with
lithium, and suggest that the temporal regulation of
AP-1 mediated gene expression in critical neuronal circuits may play a role in the long-term therapeutic efficacy of these agents.