DIFFERENTIAL-EFFECTS OF NBQX ON THE DISTAL AND LOCAL TOXICITY OF GLUTAMATE AGONISTS ADMINISTERED INTRA-HIPPOCAMPALLY

The ability of the non-NMDA glutamate antagonist NBQX ihydroxy-6-nitro -7-sulphamoyl-benzo(F)quinoxaline) to protect the brain against the ne uronal death caused by glutamate agonists was examined. Glutamate agon ists and NBQX were co-injected into the dorsal region of the rat hippo campus and 4 days later the brain was examined histochemically for the loss of neurons. 95 nmol NBQX prevented the toxicity of glutamate ago nists acting on the AMPA receptor (quisqualate and AMPA [L-alpha-amino -3-hydroxy-5-methyl-4-isoxazole propionate]), except for the higher do se of AMPA where toxicity was only partially reduced. This dose of NBQ X also prevented about 50% of the toxicity of kainate, but produced a slight increase in the size of the lesions caused by NMDA (N-methyl-D- aspartate). With 190 nmol NBQX, a variable degree of non-specific dama ge resulted, but was mainly confined to the dentate region. Allowing f or this damage, almost complete protection against the toxicity of non -NMDA glutamate agonists was obtained, with a partial protection again st NMDA toxicity. Kainate, and a high dose of AMPA (2 nmol), consisten tly caused neuronal death in other limbic regions of the brain in addi tion to the hippocampal damage. About 50% of rats treated with 15 nmol quisqualate also showed damage to limbic regions. Both doses of NBQX prevented this distal damage caused by quisqualate, but not that cause d by kainate. With AMPA, only the high dose of NBQX blocked the distal toxicity. Diazepam also blocked the distal toxicity of AMPA, but had only a minor effect on the hippocampal damage. A combination of intra- hippocampal NBQX and systemic diazepam or the NMDA antagonist MK 801 ( dizocilpine) largely prevented both the local and distal toxicity of k ainate. These results suggest that the direct neuronal cytotoxicity of non-NMDA agonists is more readily prevented by NBQX than is the seizu re-related damage initiated by these compounds.