Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection

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.