Programmed cell death: its possible contribution to neurotoxicity mediated by calcium channel antagonists.
Organic calcium channel antagonists attenuate ischemic or excitotoxic neuronal injury, probably by limiting Ca2+ influx through the voltage-gated calcium channels. However, the possibility that calcium channel antagonists may compromise neuronal survival with long-term exposure has not been systemically examined. In the present study, we report that cerebral cortical cultures exposed for 2 days to either nifedipine, verapamil, diltiazem, or flunarizine, undergo selective neuronal degradation in a concentration-dependent fashion. This degeneration could be attenuated by protein synthesis inhibitors cycloheximide and actinomycin-D. Cortical cultures incubated for 2 days in low calcium media also exhibit widespread neuronal damage, which is similarly blocked by cycloheximide. Although we cannot exclude other possibilities, these findings suggest that a decrease in intraneuronal calcium levels may trigger synthesis of proteins mediating neuronal cell death. Regardless of the exact toxic mechanisms involved, additional studies on neurotoxicity of calcium channel antagonists seem warranted since some of these compounds are currently being clinically used.
Koh
J Y
JY
Department of Psychobiology, University of California Irvine 92717.
Cotman
C W
CW
D000818:Animals; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003470:Culture Media; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D005260:Female; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D009410:Nerve Degeneration / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D011247:Pregnancy
D002121:Calcium Channel Blockers; D003470:Culture Media; D003609:Dactinomycin; D003513:Cycloheximide; D007770:L-Lactate Dehydrogenase; D002118:Calcium