Various Ca2+ entry blockers prevent glutamate-induced neurotoxicity

In the present study we investigated the effect of different Ca²⁺ entry blockers on the onset of neuronal damage induced by glutamate, kainate or α-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 μM 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 μM AMPA or 60 μM 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.