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 (2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline) to protect the brain against the neuronal death caused by glutamate agonists was examined. Glutamate agonists and NBQX were co-injected into the dorsal region of the rat hippocampus and 4 days later the brain was examined histochemically for the loss of neurons. 95 nmol NBQX prevented the toxicity of glutamate agonists acting on the AMPA receptor (quisqualate and AMPA [L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate]), except for the higher dose of AMPA where toxicity was only partially reduced. This dose of NBQX 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 damage resulted, but was mainly confined to the dentate region. Allowing for this damage, almost complete protection against the toxicity of non-NMDA glutamate agonists was obtained, with a partial protection against NMDA toxicity. Kainate, and a high dose of AMPA (2 nmol), consistently caused neuronal death in other limbic regions of the brain in addition 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 caused 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 kainate. These results suggest that the direct neuronal cytotoxicity of non-NMDA agonists is more readily prevented by NBQX than is the seizure-related damage initiated by these compounds.