The calcium channel blocker nifedipine attenuates slow excitatory amino acid neurotoxicity.
High concentrations of potent N-methyl-D-aspartate (NMDA) agonists can trigger degeneration of cultured mouse cortical neurons after an exposure of only a few minutes; in contrast, selective non-NMDA agonists or low levels of NMDA agonists require exposures of several hours to induce comparable damage. The dihydropyridine calcium channel antagonist nifedipine was used to test whether this slow neurotoxicity is mediated by a calcium influx through voltage-gated channels. Nifedipine had little effect on the widespread neuronal degeneration induced by brief exposure to high concentrations of NMDA but substantially attenuated the neurotoxicity produced by 24-hour exposure to submaximal concentrations of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate, kainate, or quinolinate. Calcium ion influx through dihydropyridine-sensitive, voltage-dependent calcium channels may be an important step in the neuronal injury induced by the prolonged activation of NMDA or non-NMDA glutamate receptors.
Weiss
J H
JH
Department of Neurology and Neurological Sciences, Stanford University Medical School, CA 94305.
Hartley
D M
DM
Koh
J
J
Choi
D W
DW
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D015220:Calcium Channels / Q000187:drug effects*; D004336:Drug Antagonism; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology*; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000633:toxicity; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D015220:Calcium Channels; D011805:Quinolinic Acids; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D007051:Ibotenic Acid; D001224:Aspartic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D017378:Quinolinic Acid; D009543:Nifedipine; D007608:Kainic Acid