Staurosporine-induced neuronal apoptosis.
Staurosporine, a nonselective protein kinase inhibitor, has been shown to induce apoptosis in several different nonneuronal cell types. We tested 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 degeneration over the following day; at higher concentrations, staurosporine damaged glial cells as well. Staurosporine-induced neuronal death was accompanied by cell body shrinkage, chromatin condensation, and DNA laddering. In contrast, NMDA-induced neuronal death was accompanied by acute cell body swelling without DNA laddering. Staurosporine-induced neuronal death, unlike excitotoxic death, was markedly attenuated by the protein synthesis inhibitor cycloheximide; this protective effect was not reversed by a glutathione synthesis inhibitor, buthionine sulfoximine. Interestingly, the glial cell death induced by 1 microM staurosporine was markedly potentiated by cycloheximide. Staurosporine-induced neuronal death was not accompanied by an increase in intracellular 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 that this apoptosis can be blocked by raising intracellular Ca2+ or by blocking protein synthesis. Staurosporine exposure may be useful as a model for studying central neuronal apoptosis in vitro.
Koh
J Y
JY
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Wie
M B
MB
Gwag
B J
BJ
Sensi
S L
SL
Canzoniero
L M
LM
Demaro
J
J
Csernansky
C
C
Choi
D W
DW
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000494:pharmacology; D009410:Nerve Degeneration; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure*; D019311:Staurosporine; D013997:Time Factors
D000470:Alkaloids; D004791:Enzyme Inhibitors; D016202:N-Methylaspartate; D019311:Staurosporine; D007608:Kainic Acid