STAUROSPORINE-INDUCED NEURONAL APOPTOSIS

Staurosporine, a nonselective protein kinase inhibitor, has been shown to induce apoptosis in several different nonneuronal cell types. We t ested the hypothesis that staurosporine would also induce apoptosis in central neurons. Exposure of murine cortical cell cultures to 30-100 nM staurosporine induced concentration-dependent selective neuronal de generation over the following day; at higher concentrations, staurospo rine damaged glial cells as well. Staurosporine-induced neuronal death was accompanied by cell body shrinkage, chromatin condensation, and D NA laddering. In contrast, NMDA-induced neuronal death was accompanied by acute cell body swelling without DNA. laddering. Staurosporine-ind uced neuronal death, unlike excitotoxic death, was markedly attenuated by the protein synthesis inhibitor cycloheximide; this protective eff ect was not reversed by a glutathione synthesis inhibitor, buthionine sulfoximine. Interestingly, the glial cell death induced by 1 mu M sta urosporine was markedly potentiated by cycloheximide. Staurosporine-in duced neuronal death was not accompanied by an increase in intracellul ar free Ca2+ and was attenuated by 30 mM K+; this protective effect of high K+ was blocked by nimodipine or Co2+. Present data suggest that staurosporine can induce apoptosis in cultured cortical neurons and th at this apoptosis can be blocked by raising intracellular Ca2+ or by b locking protein synthesis. Staurosporine exposure may be useful as a m odel for studying central neuronal apoptosis in vitro. (C) 1995 Academ ic Press, Inc.