Glycogen synthase kinase-3 inhibitors prevent caspase-dependent apoptosis induced by ethanol in cultured rat cortical neurons.
The effect of ethanol on cell viability was examined in rat cultured cortical neurons. Ethanol induced apoptosis, which was characterized by cell shrinkage, nuclear condensation or fragmentation and internucleosomal DNA fragmentation. Ethanol-induced apoptosis was prevented by N-methyl-d-aspartate (NMDA), an agonist of the NMDA receptor, which is a subtype of ionotropic glutamate receptors. Incubation with glycogen synthase kinase-3 (GSK-3) inhibitors 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) and alsteropaullone, but not a cyclin-dependent protein kinase 5 inhibitor roscovitine, completely protected the neurons from ethanol-induced apoptosis. Apoptosis was accompanied by the activation of caspase-3 and prevented by a caspase-3 inhibitor. These results suggest that ethanol induces caspase-dependent apoptosis mediated by glycogen synthase kinase-3 activation in cultured rat cortical neurons.
Takadera
Tsuneo
T
Department of Clinical Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1148, Japan. t-takadera@hokuriku-u.ca.jp
Ohyashiki
Takao
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D010455:Peptides; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D000077546:Roscovitine
D061945:Caspase Inhibitors; D007211:Indoles; D008301:Maleimides; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011687:Purines; C417521:SB 216763; C430227:acetyl-AAVALLPAVLLALLAP-DEVD-CHO; D000077546:Roscovitine; D000431:Ethanol; D016202:N-Methylaspartate; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002118:Calcium