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.