SELECTIVE PROTECTION AGAINST AMPA-EVOKED AND KAINATE-EVOKED NEUROTOXICITY BY ZOLE-5-YL)ETHYL]DECAHYDROISOQUINOLINE-3-CARBOXYLIC ACID (LY293558) AND ITS RACEMATE (LY215490)

Glutamate receptor-mediated excitotoxicity is linked to the activation of multiple receptors including those activated by alpha-amino-3-hydr oxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-D-aspartate ( NMDA), and kainate. In this study, the novel glutamate receptor antago nist, as its active isomer zole-5-yl)ethyl]decahydroisoquinoline-3-car boxylic acid ((-)LY293558) and it's +/- racemate (LY215490), was exami ned for neuroprotectant effects against excitotoxic injury in vitro an d in vivo. This agent selectively protected against AMPA and kainate i njury in cultured primary rat hippocampal neurons, an in vivo rat stri atal neurotoxicity model, and against agonist-evoked seizures in mice. Thus, azole-5-yl)ethyl]decahydroisguinoline-3-carboxylic acid represe nts a novel receptor selective and potent systemically active AMPA/kai nate receptor antagonist for exploring neuroprotection via non-NMDA re ceptor mechanisms.