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Diverse mechanisms of neuronal protection by nimodipine in experimental rabbit brain ischemia
J W Lazarewicz1, R Pluta, M Puka
1Department of Neurochemistry, Polish Academy of Sciences, Warsaw.
Abstract:
The purpose of this study was to verify the possible involvement of nimodipine-sensitive calcium channels in ischemic Ca2+ influx to hippocampal neurons to assess their role in nimodipine neuroprotection. We induced 15-minute global cerebral ischemia in pentobarbital-anesthetized and relaxed rabbits, which had been implanted with a transhippocampal dialysis probe, by intrathoracic artery occlusion combined with hypotension. A part from electroencephalographic and morphologic observations, changes in the extracellular concentrations of calcium, amino acids, and blood-brain barrier permeability to fluorescein were detected by microdialysis of the hippocampus. Nimodipine was applied either intravenously or locally to the hippocampus before, during, and after ischemia. Application of nimodipine locally or systemically, which had no effect on extracellular amino acids, enhanced recovery and normalization of the electroencephalographic activity and protected hippocampal neurons from early morphologic changes. Intravenous nimodipine reduced the ischemia-evoked drop of extracellular Ca2+ and completely prevented postischemic leakage of the blood-brain barrier, whereas local nimodipine infusion did not modify these ischemic disturbances. Our results suggest that nimodipine-sensitive Ca2+ channels play a minor role in the ischemic calcium influx to hippocampal neurons. Nimodipine, apart from a potent vasotropic action, may also directly protect brain neurons by intracellular calcium antagonism rather than by inhibition of calcium influx.
Insights
Nimodipine aids brain recovery after ischemia by protecting neurons, but not by blocking calcium influx. It may offer neuroprotection through intracellular calcium antagonism, not just vasodilation.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Global cerebral ischemia can lead to neuronal damage and impaired brain function.
- Calcium influx into neurons plays a critical role in ischemic brain injury.
- Nimodipine is a calcium channel blocker used to treat certain neurological conditions.
Purpose of the Study:
- To investigate the role of nimodipine-sensitive calcium channels in ischemic calcium influx.
- To determine the mechanism of nimodipine's neuroprotective effects in the hippocampus.
- To assess nimodipine's impact on neuronal survival and blood-brain barrier integrity during and after ischemia.
Main Methods:
- Global cerebral ischemia was induced in rabbits using arterial occlusion and hypotension.
- Hippocampal microdialysis was used to measure extracellular calcium, amino acids, and blood-brain barrier permeability.
- Nimodipine was administered systemically (intravenously) or locally to the hippocampus.
Main Results:
- Nimodipine administration, both systemic and local, improved electroencephalographic recovery and protected hippocampal neurons from morphological damage.
- Systemic nimodipine reduced the decrease in extracellular calcium and prevented blood-brain barrier leakage post-ischemia.
- Local nimodipine did not affect extracellular calcium levels or blood-brain barrier permeability, suggesting a non-channel blocking mechanism.
Conclusions:
- Nimodipine-sensitive calcium channels have a limited role in ischemic calcium influx to hippocampal neurons.
- Nimodipine's neuroprotective effects may stem from direct intracellular calcium antagonism rather than solely from inhibiting calcium influx.
- Nimodipine exhibits both vasotropic actions and direct neuronal protection, highlighting its complex therapeutic potential in ischemic stroke.