Glycogen synthase kinase-3beta (GSK-3beta) is a central component in many critical intracellular signaling mechanisms. These include the
phosphatidylinositol 3-kinase/Akt cell survival pathway, which inhibits
GSK-3beta activity.
GSK-3beta itself inhibits the activation of several
transcription factors, which are important cell survival factors, such as heat shock factor 1. These factors likely contribute to the recent revelation that
GSK-3beta is a pro-apoptotic
enzyme. Recently,
lithium has been identified as a selective and direct inhibitor of
GSK-3beta. Based on these findings, we have proposed that part of the
neuroprotectant properties of
lithium is due to its ability to inhibit
GSK-3beta, and thus block the facilitation of apoptosis produced by
GSK-3beta. Since several
anticonvulsants recently have been shown to be effective mood stabilizers, we examined if these agents are capable of protecting cells from GSK-3beta-facilitated apoptosis. In addition to
lithium, both
valproic acid and
lamotrigine, but not
carbamazepine, provided protection from GSK-3beta-facilitated apoptosis in human
neuroblastoma SH-SY5Y cells. These results demonstrate that several drugs therapeutic for
bipolar disorder can provide neuroprotection by inhibiting the pro-apoptotic effects of
GSK-3beta, providing new evidence that dysregulation of
GSK-3beta may contribute to the pathophysiology of
bipolar disorder.