• apoptosis;
  • glycogen synthase kinase-3β;
  • lamotrigine;
  • lithium;
  • neuroprotection;
  • valproate

Glycogen synthase kinase-3β (GSK-3β) is a central component in many critical intracellular signaling mechanisms. These include the phosphatidylinositol 3-kinase/Akt cell survival pathway, which inhibits GSK-3β activity. GSK-3β 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-3β is a pro-apoptotic enzyme. Recently, lithium has been identified as a selective and direct inhibitor of GSK-3β. Based on these findings, we have proposed that part of the neuroprotectant properties of lithium is due to its ability to inhibit GSK-3β, and thus block the facilitation of apoptosis produced by GSK-3β. Since several anticonvulsants recently have been shown to be effective mood stabilizers, we examined if these agents are capable of protecting cells from GSK-3β-facilitated apoptosis. In addition to lithium, both valproic acid and lamotrigine, but not carbamazepine, provided protection from GSK-3β-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-3β, providing new evidence that dysregulation of GSK-3β may contribute to the pathophysiology of bipolar disorder.