Prevention of rat cortical neurons from prostaglandin E2-induced apoptosis by glycogen synthase kinase-3 inhibitors.

Cyclooxygenase-2 (COX-2) induction and prostaglandin E(2) (PGE(2)) elevation have been reported to occur after cerebral ischemic insult. PGE(2) induces apoptosis through the PGE(2) EP2 receptor by a cAMP-dependent pathway. Glycogen synthase kinase-3 (GSK-3) affects many fundamental cellular functions. We examined whether GSK-3 is involved in PGE(2)-induced cell death by using GSK-3 inhibitors in rat cultured cortical neurons. Cells treated with 12.5 microM PGE(2) for 2 days shrank. The injured cells underwent chromatin condensation and nuclear fragmentation detected by staining with Hoechst33258, indicating apoptotic cell death. We assayed the effects of selective GSK-3 inhibitors SB216763 and alsteropaullone on PGE(2)-induced apoptosis. These inhibitors completely protected the cells from apoptosis induced by PGE(2). Moreover, dibutyryl cAMP (a cell permeable cAMP)-induced apoptosis was also prevented by alsteropaullone. In addition, GSK-3 inhibitors inhibited caspase-3 activation accompanied by PGE(2)-induced apoptosis. We showed in this report that PGE(2)-induced apoptosis is prevented by GSK-3 inhibitors, suggesting that PGE(2) induces caspase-dependent apoptosis mediated through GSK-3 activation in rat cultured cortical neurons.