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Programmed cell death: its possible contribution to neurotoxicity mediated by calcium channel antagonists
1Department of Psychobiology, University of California Irvine 92717.
Abstract:
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.
Insights
Long-term exposure to calcium channel antagonists may harm neurons. This neuronal degradation, seen in cerebral cortical cultures, is concentration-dependent and linked to protein synthesis, suggesting potential neurotoxicity with clinical use.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Organic calcium channel antagonists are known to protect neurons from ischemic or excitotoxic injury by limiting calcium influx.
- The long-term effects of these antagonists on neuronal survival have not been thoroughly investigated.
Purpose of the Study:
- To investigate the potential neurotoxic effects of chronic exposure to organic calcium channel antagonists.
- To examine the underlying mechanisms of this potential neurotoxicity.
Main Methods:
- Cerebral cortical cultures were exposed to nifedipine, verapamil, diltiazem, or flunarizine for two days.
- The effects of protein synthesis inhibitors (cycloheximide, actinomycin-D) and low calcium media on neuronal survival were assessed.
Main Results:
- Exposure to calcium channel antagonists resulted in concentration-dependent neuronal degradation.
- This degeneration was attenuated by protein synthesis inhibitors.
- Incubation in low calcium media also induced neuronal damage, blocked by cycloheximide.
Conclusions:
- Chronic exposure to calcium channel antagonists may induce neuronal cell death.
- A decrease in intracellular calcium may trigger the synthesis of proteins involved in neuronal death.
- Further research into the neurotoxicity of clinically used calcium channel antagonists is warranted.