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

Abstract

Valproic acid (VPA) is a potent broad-spectrum anti-epileptic 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)-3beta inhibits AP-1 DNA binding activity, and lithium has recently been demonstrated to inhibit GSK-3beta. These results suggest that lithium may increase AP-1 DNA binding activity by inhibiting GSK-3beta. 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-3alpha and -3beta, 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-3beta-mediated 32P incorporation into two putative GSK-3 substrates (approximately 85 and 200 kDa), compatible with inhibition of endogenous GSK-3beta by VPA. Consistent with GSK-3beta inhibition, incubation of SH-SY5Y cells with VPA results in a significant time-dependent increase in both cytosolic and nuclear beta-catenin levels. GSK-3beta 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-3beta in the CNS may thus underlie some of the long-term therapeutic effects of mood-stabilizing agents.

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

“…Mechanisms of action of VPA include blockade of voltagedependent sodium channels and increase of gammaaminobutyric acid (GABA), leading to an overall reduction of neuronal activity (Loscher, 2002). VPA has also been shown to inhibit GSK3b indirectly (Chen et al, 1999;De Sarno et al, 2002), and to block the activity of histone deacetylases (HDACs). Given the results of our study, in which VPA shortened period similarly in both neurons and fibroblasts (which lack DA and its receptors), the effects of VPA on circadian rhythms must be independent of DA receptor signaling.…”

The Pivotal Roles of GSK3β in Glioma Biology

“…It was proposed that VPA activates Wnt-dependent gene expression through inhibition of HDAC, which generated interest for its use in cancer therapy (Phiel et al, 2001). Apart from this, VPA, like LiCl, exerts significant inhibitory effects on the activity of GSK3β both directly in vitro and also on endogenous GSK3β in intact human neuroblastoma SY5Y cells (Chen et al, 1999) (Figure 4). The dual inhibition of HDAC and GSK3β by VPA may provide a basis for its anticancer activity.…”

“…Furthermore, addition of LiCl at therapeutic concentrations results in additive inhibitory effects to that of VPA. These additive effects of LiCl and VPA on GSK3β suggest that the 2 drugs may exert their effects at different sites, but additional studies will be necessary to establish this definitively (Chen et al, 1999).…”

Lithium regulates adult hippocampal progenitor development through canonical Wnt pathway activation

“…17,32 Since all three mood stabilizers alter inositol signaling, but not GSK-3b, we tested whether these drugs were equally effective at increasing AHP proliferation. We applied clinically effective concentrations of carbamazepine (50 mM), valproic acid (500 mM) and lithium (2 mM) to AHP for 48 h then pulsed with BrdU for 1 h prior to fixation ( Figure 3a).…”