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Various Ca2+ entry blockers prevent glutamate-induced neurotoxicity
1Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Italy.
Abstract:
In the present study we investigated the effect of different Ca2+ entry blockers on the onset of neuronal damage induced by glutamate, kainate or alpha-amino-3-hydroxy-5-methyl-5-isoxazolo propionate (AMPA) in primary culture of rat cerebellar granule cells. We found that the dihydropyridine derivative, nifedipine used at 100 nM concentration, significantly counteracted the neuronal death induced by 15 min application of 50 microM glutamate. This effect was dependent on the presence of nifedipine before the exposure of granule cells to glutamate and was dose-related (IC50 = 10 nM). The nifedipine response was reproduced by isradipine and by verapamil with IC50 values of 9 and 100 nM, respectively. The activation of voltage sensitive Ca2+ channels elicited by 100 nM Bay K 8644, greatly enhanced glutamate-mediated neurotoxicity. Moreover, 100 nM isradipine was significantly active in blocking the neuronal death produced by 24 h exposure of cerebellar granule cells to 10 microM AMPA or 60 microM kainate. These results reveal a 'preventive' role of the Ca2+ entry blockers on the development of the neurodegeneration induced by overstimulation of various glutamate receptor subtypes.
Insights
Calcium entry blockers, such as nifedipine, protect rat cerebellar neurons from glutamate-induced damage. These findings suggest a preventive role for these blockers against neurodegeneration caused by glutamate receptor overstimulation.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Glutamate receptor overstimulation is a key factor in neuronal damage.
- Calcium (Ca2+) influx plays a critical role in excitotoxicity.
Purpose of the Study:
- To investigate the neuroprotective effects of various Ca2+ entry blockers against excitotoxicity in primary rat cerebellar granule cells.
- To determine the efficacy of specific blockers against damage induced by glutamate, kainate, and alpha-amino-3-hydroxy-5-methyl-5-isoxazolo propionate (AMPA).
Main Methods:
- Primary culture of rat cerebellar granule cells.
- Induction of neuronal damage using glutamate, kainate, or AMPA.
- Application of different Ca2+ entry blockers, including nifedipine, isradipine, and verapamil, at varying concentrations.
- Dose-response analysis to determine IC50 values.
Main Results:
- Nifedipine (100 nM) significantly prevented glutamate-induced neuronal death, with a dose-dependent effect (IC50 = 10 nM).
- Isradipine and verapamil also demonstrated neuroprotective effects against glutamate toxicity.
- Activation of voltage-sensitive Ca2+ channels enhanced glutamate neurotoxicity.
- Isradipine protected against AMPA- and kainate-induced neuronal death.
Conclusions:
- Ca2+ entry blockers exhibit a preventive role in neurodegeneration.
- These findings highlight the therapeutic potential of Ca2+ entry blockers in conditions involving glutamate receptor overactivation.