Action of the anti-ischemic agent ifenprodil on N-methyl-D-aspartate and kainate-mediated excitotoxicity.
The efficacy of ifenprodil to antagonize N-methyl-D-aspartate (NMDA) and kainate (KA)-induced acute excitotoxicity was evaluated in embryonic day 13 chick retina. Incubation with either 50 microM NMDA or KA produced a characteristic histological lesion and release of endogenous gamma-aminobutyric acid (GABA). Ifenprodil potently attenuated NMDA-induced GABA efflux by 80% (IC50, 1.26 microM). Histology showed protection of all but a subpopulation of amacrine neurons and processes even at 500 microM ifenprodil. MK-801 and CGS 19755, uncompetitive and competitive NMDA antagonists, respectively, protected all NMDA-sensitive amacrines, including the ifenprodil-resistant population, whilst CNQX, a non-NMDA glutamate receptor antagonist, was ineffective. Ifenprodil was less effective versus KA, requiring 10-100-fold higher concentrations to significantly attenuate GABA release. The potent antagonism of NMDA-mediated acute excitotoxicity by ifenprodil may explain its efficacy as an anti-ischemic agent. Ifenprodil does, however, leave unprotected a subpopulation of NMDA-susceptible neurons suggesting a heterogeneity in the NMDA receptor population.
Zeevalk
G D
GD
Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854.
Nicklas
W J
WJ
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D002642:Chick Embryo; D007608:Kainic Acid / Q000633:toxicity*; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D012160:Retina / Q000166:cytology / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D010880:Piperidines; D011810:Quinoxalines; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C010739:ifenprodil; D007608:Kainic Acid