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Hypoglycaemic brain damage: effect of a dihydropyridine calcium channel antagonist in rats
1Department of Pathology, University of Calgary, Alberta, Canada.
Abstract:
Hypoglycaemic brain damage consists of selective necrosis of cerebral neurons related to the extracellular release of excitatory amino acids. Neuronal excitatory amino acid receptors are activated and calcium channels are opened. The present investigation was designed to test the effectiveness of dihydropyridine blockade of voltage-sensitive calcium channels in hypoglycaemic brain damage. Sixty-four rats were given either high-dose nimodipine, consisting of an initial bolus of 300 micrograms/kg nimodipine administered at the stage of EEG slowing (blood glucose levels of 1.0-1.5 mmol/l), followed by continuous intravenous nimodipine infusion at 1.5 micrograms.kg-1.min-1, low-dose nimodipine, consisting of an initial bolus of 30 micrograms/kg at the time of EEG slowing, followed by 0.15 microgram.kg-1.min-1, an equal volume of vehicle solution, or 154 mmol/l NaCl. Animals receiving either low- or high-dose nimodipine had higher mortality, and increased brain damage compared with controls. Examination of the perfusion-fixed brains 1 week after recovery with glucose revealed that quantitated neuronal necrosis was worsened by nimodipine in the hippocampus, caudate nucleus and cerebral cortex. The present results in profound hypoglycaemia (accompanied by a flat EEG) contrast with the beneficial effect of nimodipine in brain ischaemia.
Insights
Nimodipine worsened brain damage and increased mortality in rats experiencing profound hypoglycemia. This contrasts with nimodipine's known benefits in cases of brain ischemia.
Area of Science:
- Neuroscience
- Pharmacology
- Pathophysiology
Background:
- Hypoglycemic brain damage involves neuronal necrosis due to excitatory amino acid release.
- Activation of neuronal excitatory amino acid receptors opens calcium channels, contributing to neuronal injury.
Purpose of the Study:
- To evaluate the efficacy of nimodipine, a dihydropyridine calcium channel blocker, in mitigating hypoglycemic brain damage.
- To investigate the effects of nimodipine on neuronal survival during severe hypoglycemia.
Main Methods:
- Sixty-four rats were administered varying doses of nimodipine (high-dose and low-dose) or control solutions (vehicle or saline).
- Nimodipine administration involved an initial bolus at electroencephalogram (EEG) slowing, followed by continuous intravenous infusion.
- Brain damage was assessed one week post-recovery by quantifying neuronal necrosis in specific brain regions.
Main Results:
- Both high- and low-dose nimodipine treatments resulted in increased mortality rates compared to control groups.
- Nimodipine administration exacerbated neuronal necrosis in the hippocampus, caudate nucleus, and cerebral cortex.
- The detrimental effects of nimodipine were observed in profound hypoglycemia, characterized by a flat EEG.
Conclusions:
- Nimodipine blockade of voltage-sensitive calcium channels is ineffective and harmful in treating hypoglycemic brain damage.
- The findings in profound hypoglycemia contrast sharply with the previously observed beneficial effects of nimodipine in brain ischemia.
- These results suggest that nimodipine should not be used in clinical scenarios involving severe hypoglycemia-induced brain injury.