AMPA ANTAGONISTS - DO THEY HOLD MORE PROMISE FOR CLINICAL STROKE TRIALS THAN NMDA ANTAGONISTS

The cytoprotective effects of MK-801 and NBQX, selective N-methyl-D-as partate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propioni c acid (AMPA) receptor antagonists, respectively, were compared both s ingularly and in combination in models of transient severe forebrain a nd transient focal cerebral ischemia. After 10 minutes of four-vessel occlusion ischemia, the sodium salt of NBQX (30 mg/kg IF) given at the time of reperfusion and, subsequently, 15 and 30 minutes later produc ed a dramatic reduction in CA1 hippocampal necrosis at 7 days. This ef fect was not obtained with the intraperitoneal administration of eithe r MK-801 (1 mg/kgx3) or the combination of both NBQX and MK-801 given at the same time intervals. This effect of intraperitoneal NBQX alone was reproduced in a two-vessel occlusion/hypotension model using this same drug administration. Delayed treatment with both NBQX and GYKI 52 466, but neither MK-801 nor the combination of NBQX and MK-801 given a fter a delay, produced a significant reduction in the mean volume of n eocortical infarction after transient focal ischemia. We conclude that the AMPA receptor may play a more important role than the NMDA recept or in both selective ischemic necrosis of hippocampal neurons and in n eocortical infarction. AMPA antagonists should be subjected to clinica l stroke trials.