The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3

Valproic acid (VPA) is a potent broad-spectrum antiepileptic with demonstrated efficacy in the treatment of bipolar affective disorder. It has previously been demonstrated that both VPA and lithium increase activator protein-1 (AP-1) DNA binding activity, but the mechanisms underlying these effects have not been elucidated. However, it is known that phosphorylation of c-jun by glycogen synthase kinase (GSK)-3 beta inhibits AP-I DNA binding activity, and lithium has recently been demonstrated to inhibit GSK-3 beta. These results suggest that lithium may increase AP-1 DNA binding activity by inhibiting GSK-3 beta. In the present study, we sought to determine if VPA, like lithium, regulates GSK-3. We have found that VPA concentration-dependently inhibits both GSK-3 alpha and -3 beta, with significant effects observed at concentrations of VPA similar to those attained clinically. Incubation of intact human neuroblastoma SH-SY5Y cells with VPA results in an increase in the subsequent in vitro recombinant GSK-3 beta-mediated P-32 incorporation into two putative GSK-3 substrates (similar to 85 and 200 kDa), compatible with inhibition of endogenous GSK-3 beta by VPA. Consistent with GSK-3 beta inhibition, incubation of SH-SY5Y cells with VPA results in a significant time-dependent increase in both cytosolic and nuclear beta-catenin levers. GSK-3 beta plays a critical role in the CNS by regulating various cytoskeletal processes as well as long-term nuclear events and is a common target for both lithium and VPA; inhibition of GSK-3 beta in the CNS may thus underlie some of the long-term therapeutic effects of mood-stabilizing agents.