Aurintricarboxylic acid prevents NMDA-mediated excitotoxicity: evidence for its action as an NMDA receptor antagonist.
The effect of the endonuclease inhibitor aurintricarboxylic acid (ATA) versus NMDA-mediated delayed cell death was examined in an ex vivo chick retinal preparation. Transient exposure to 100 microM NMDA for 60 min followed by a 24-h recovery period resulted in a sevenfold increase in lactate dehydrogenase (LDH) release into the medium. ATA at 100 microM significantly reduced NMDA-mediated LDH release by 60%. In clarifying the mechanism of protection versus NMDA, ATA was found to inhibit several acute NMDA-mediated effects: ATA attenuated NMDA-mediated GABA release in a dose-dependent manner (IC50 = 29.5 microM), prevented NMDA-stimulated cyclic GMP formation, and blocked NMDA-mediated 22Na+ influx. These acute inhibitory effects of ATA were overcome by increasing the NMDA concentration, which suggested a competitive interaction between NMDA and ATA. In a binding assay using membranes prepared from adult rat forebrain, ATA displaced the competitive NMDA receptor ligand [3H]CGS 19755 with an IC50 of 26.9 microM. Maximal displacement was 88% with 100 microM ATA. These studies demonstrate that ATA protected neurons from NMDA-mediated cell death upstream of endonuclease inhibition, i.e., by antagonizing NMDA receptor activity in a manner consistent with competitive antagonism.
Zeevalk
G D
GD
Department of Neurology, University of Medicine and Dentistry of NJ-Robert Wood Johnson Medical School, Piscataway 08854.
Schoepp
D
D
Nicklas
W J
WJ
D000818:Animals; D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D002642:Chick Embryo; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018756:GABA Antagonists; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018756:GABA Antagonists; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D001312:Aurintricarboxylic Acid; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D006152:Cyclic GMP