NEUROPROTECTIVE EFFECT OF YM90K, AN AMPA-RECEPTOR ANTAGONIST, AGAINSTDELAYED NEURONAL DEATH INDUCED BY TRANSIENT GLOBAL CEREBRAL-ISCHEMIA IN GERBILS AND RATS

We investigated the neuroprotective effect of the pha-amino-3-hydroxy- 5-methylisoxazole-4-propionate (AMPA)-receptor antagonist YM90K in tra nsient global ischemia models. In a gerbil model, transient ischemia w as induced by bilateral common carotid artery (CCA) occlusion for 5 mi n. On administration at 1 hr after ischemia, the AMPA antagonists NBQX (30 mg/kg, i.p. x 3) and YM90K (15 mg/kg, i.p. x 3 or 30 mg/kg, i.p. x 3) significantly reduced the delayed neuronal death in the hippocamp al CA1 region from 4 days after bilateral CCA occlusion. Furthermore, YM90K (30 mg/kg, i.p. x 3) showed a neuroprotective effect even when g iven at 6 hr after ischemia. In contrast, the N-methyl-D-aspartate rec eptor antagonists CGS19755, MNQX (30 mg/kg, i.p. x 3, each) and (+/-)M K-801 (10 mg/kg, i.p.) were not effective on injection at 1 hr after i schemia in this model. In a rat model, ischemia was induced by 4-vesse l occlusion (4-VO) for 10 min. YM90K was administered 60 min after rep erfusion. Rectal and temporal muscle temperatures were maintained at t he same level as in the control group for 6 hr. YM90K markedly prevent ed the development of delayed neuronal death from 7 days after 4-VO at doses of 15 or 30 mg/kg, i.p. x 3, with neuroprotective efficacy simi lar to that in the gerbil model. These results suggest that the AMPA r eceptor plays a critical role in the development of the delayed neuron al death induced by transient global cerebral ischemia. They also sugg est that the neuroprotective effect of YM90K is not related to its hyp othermic effect.