Caspase-dependent apoptosis induced by calcineurin inhibitors was prevented by glycogen synthase kinase-3 inhibitors in cultured rat cortical cells.
Calcineurin is selectively enriched within neurons of the central nervous system. The mechanism of calcineurin inhibitor-induced neurotoxicity remains poorly understood. The purpose of this study is to examine whether glycogen synthase-3 (GSK-3) is involved in calcineurin inhibitor-induced apoptosis. Calcineurin inhibitors such as cyclosporine A (CsA) and FK506 increased apoptotic cell death with morphological changes characterized by cell shrinkage, nuclear condensation of fragmentation, and internucleosomal DNA fragmentation. Alsteropaullone and 1-azakenpaullone, GSK-3 inhibitors, prevented calcineurin inhibitor-induced apoptosis. In addition, insulin growth factor-I (IGF-I) and cycloheximide completely blocked cell death. Moreover, caspase-3 activation was accompanied by calcineurin inhibitor-induced cell death. These results suggest that calcineurin inhibitors induce caspase-dependent apoptosis and activation of GSK-3 is involved in cell death in rat cortical neurons.
Takadera
Tsuneo
T
Department of Clinical Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan. t-takadera@hokuriku-u.ac.jp
Ohyashiki
Takao
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D020169:Caspases / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000633:toxicity*; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000633:toxicity; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D016559:Tacrolimus / Q000633:toxicity
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007334:Insulin-Like Growth Factor I; D016572:Cyclosporine; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin; D020169:Caspases; D016559:Tacrolimus