IV-methybaspartate Antagonists Prevent Kainate Neurotoxicity in Rat Retinal Ganglion Cells in vitro

Under defined culture conditions, exogenous glutamate (GM), NMDA, or an endogenous Glu-related toxin is lethal to rat retinal ganglion cells; these detrimental effects are NMDA receptor mediated because specific NMDA antagonists can prevent cellular injury. In the presence of an endogenous Glu-like toxin, 125 PM kainate (KA) increases the proportion of retinal ganglion cells that die, but the toxicity (due to both KA and the endogenous toxin) is totally prevented by P-aminoSphosphonovalerate (APV), a specific NMDA receptor antagonist. These findings indicate that the KA-induced portion of retinal ganglion cell death also appears to be mediated via NMDA receptors. There are at least 2 possible mechanisms for this lethal effect. In addition to KA receptors, KA could directly stimulate NMDA receptors. Alternatively, KA might activate its own specific receptor, which in turn leads to a net increase in the release of an endogenous Glu-related toxin; this endogenous substance would then activate NMDA receptors. Patch-clamp electrophysiology experiments have helped to distinguish between these possibilities. Concentrations of APV that completely block the current elicited by maximal nondesensitizing doses of NMDA exert no detectable inhibition of KA-evoked currents. Hence, at the concentrations used, it appears unlikely that KA directly activates NMDA receptors in this preparation. Furthermore, the fraction of toxicity attributed to the addition of KA can be blocked by the relatively specific non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). This finding is consistent with the hypothesis that KA adds an increment of toxicity in this system by directly interacting with KA receptors. Taken together, the evidence suggests that KA receptor stimulation may lead to the next efflux of additional endogenous Glu-related toxin. In turn, this Glu-related substance activates NMDA receptors and its attendant neurotoxicity.