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.
Takadera
Tsuneo
T
Department of Clinical Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa 920-1148, Japan. t-takadera@hokuriku-u.ac.jp
Ohyashiki
Takao
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002540:Cerebral Cortex / Q000166:cytology*; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D013997:Time Factors
D001552:Benzazepines; D007211:Indoles; D008301:Maleimides; C417521:SB 216763; C120793:alsterpaullone; D003994:Bucladesine; D038362:Glycogen Synthase Kinase 3; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D010751:Phosphopyruvate Hydratase; D015232:Dinoprostone