GYKI 52466 protects against non-NMDA receptor-mediated excitotoxicity in primary rat hippocampal cultures.
Glutamate excitotoxicity is mediated by both N-methyl-D-aspartate (NMDA)-receptor and non-NMDA receptor (alpha-amino-3-hydroxy-5-methyl-isoxazolepropionate (AMPA)/kainate (KA)) mechanisms but the lack of specific antagonists has limited the characterization of AMPA/KA receptor-mediated excitotoxicity. The 2,3-benzodiazepine GYKI 52466 is a newly described non-competitive AMPA/KA receptor antagonist. We have investigated the neuroprotective efficacy of GYKI 52466 in an embryonic rat hippocampal culture model of non-NMDA receptor-mediated excitotoxicity using KA as an agonist at the AMPA/KA receptor. Overnight treatment with 500 microM KA resulted in prominent neuronal excitotoxicity as assessed by lactate dehydrogenase efflux. GYKI 52466 attenuated KA excitotoxicity in a dose-dependent manner with an IC50 of 9 microM. Together with competitive antagonists (e.g., various quinoxalinediones), non-competitive antagonists like GYKI 52466 can now be used to dissect mechanisms of non-NMDA receptor mediated excitotoxicity.
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CNS, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Robison
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D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000818:Animals; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects*; D007608:Kainic Acid / Q000037:antagonists & inhibitors; D009498:Neurotoxins / Q000037:antagonists & inhibitors*; D011810:Quinoxalines / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000502:physiology; D018092:Kainic Acid Receptors
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D007608:Kainic Acid; D009498:Neurotoxins; D011810:Quinoxalines; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; C061950:GYKI 52466