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.