Selective reduction in domoic acid toxicity in vivo by a novel non-N-methyl-D-aspartate receptor antagonist

Our objective was to characterize the neurotoxic actions of systemically administered domoic acid on different excitatory amino acid receptors, and to compare the receptor selectivity of domoate with the related compound kainic acid. Groups of mice were injected with various ligands selective for N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid-kainate (AMPA/kainate) receptors prior to injection of equitoxic doses of domoic acid or kainic acid. Domoic acid toxicity was not significantly altered by pretreatment with any NMDA receptor selective antagonists, with the exception of 3-(2-carboxypiperazine-4-yl)propyl-1 -phosphonic acid. Consistent with its characterization as an AMPA/kainate agonist, domoate toxicity was significantly antagonized by all non-NMDA receptor antagonists tested. Non-NMDA receptor antagonists that do not distinguish between high- and low-affinity [3H]kainic acid binding (i.e., quinoxalinediones) were equally effective at reducing domoic acid and kainic acid toxicity. However, the novel isatinoxime NS-102, which has been shown to interact selectively with low-affinity [3H]kainic acid binding sites, produced a selective dose-related antagonism of domoic acid toxicity relative to kainic acid. NS-102 produced significant reductions in overall toxicity, onset of motor seizures, and hippocampal CA3 cell damage induced by domoic acid at NS-102 doses that did not antagonize kainic acid induced toxicity. We conclude that domoic acid toxicity in vivo is mediated largely by a subclass of non-NMDA receptors that are selectively antagonized by NS-102.