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 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.
Pizzi
M
M
Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Italy.
Ribola
M
M
Valerio
A
A
Memo
M
M
Spano
P
P
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates / Q000633:toxicity; D018698:Glutamic Acid; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000633:toxicity; D017275:Isradipine; D007608:Kainic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D009410:Nerve Degeneration / Q000187:drug effects; D009422:Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control*; D009543:Nifedipine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014700:Verapamil / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D007051:Ibotenic Acid; D018698:Glutamic Acid; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D014700:Verapamil; D009543:Nifedipine; D007608:Kainic Acid; D017275:Isradipine