The Mood‐Stabilizing Agent Valproate Inhibits the Activity of Glycogen Synthase Kinase‐3

: Valproic acid (VPA) is a potent broad‐spectrumanti‐epileptic with demonstrated efficacy in the treatment of bipolaraffective disorder. It has previously been demonstrated that both VPA andlithium increase activator protein‐1 (AP‐1) DNA binding activity, but themechanisms underlying these effects have not been elucidated. However, it isknown that phosphorylation of c‐ jun by glycogen synthase kinase(GSK)‐3β inhibits AP‐1 DNA binding activity, and lithium has recentlybeen demonstrated to inhibit GSK‐3β. These results suggest that lithiummay increase AP‐1 DNA binding activity by inhibiting GSK‐3β. In thepresent study, we sought to determine if VPA, like lithium, regulates GSK‐3.We have found that VPA concentration‐dependently inhibits both GSK‐3αand ‐3β, with significant effects observed at concentrations of VPAsimilar to those attained clinically. Incubation of intact human neuroblastomaSH‐SY5Y cells with VPA results in an increase in the subsequent in vitrorecombinant GSK‐3β‐mediated 32 P incorporation into twoputative GSK‐3 substrates (~85 and 200 kDa), compatible with inhibition of endogenous GSK‐3β by VPA. Consistent with GSK‐3β inhibition, incubation of SH‐SY5Y cells with VPA results in a significant time‐dependent increase in both cytosolic and nuclear β‐catenin levels. GSK‐3β 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‐3β in the CNS may thus underlie some of the long‐term therapeutic effects of mood‐stabilizing agents.