YM872, A NOVEL SELECTIVE LPHA-AMINO-3-HYDROXY-5-METHYLISOXAZOLE-4-PROPIONIC ACID RECEPTOR ANTAGONIST, REDUCES BRAIN-DAMAGE AFTER PERMANENT FOCAL CEREBRAL-ISCHEMIA IN CATS

YM872 -6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]-acetic acid monohydr ate}, a selective, potent and highly water-soluble competitive lpha-am ino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antag onist, was investigated for its neuroprotective effect against focal c erebral ischemia in halothane-anesthetized cats. Cats were subjected t o permanent occlusion of the left middle cerebral artery for 6 h, then sacrificed and examined histologically. The electroencephalogram and cerebral blood flow were monitored. Intravenous infusion of YM872 star ting 10 min after the onset of ischemia at a rate of 2 mg/kg/h for 6 h markedly reduced the volume of ischemic damage by 61% (from 2604 +/- 202 mm(3) of the cerebral hemisphere in saline-treated cats to 1025 +/ - 277 mm(3) in YM872-treated cats; P <.01), as assessed in 12 stereota xically determined coronal sections. No significant differences were o bserved between YM872- and saline-treated cats concerning physiologica l variables including brain temperature. No precipitation of YM872 in the kidney was seen in any YM872-treated animal. The present data furt her support the notion that the AMPA receptor plays an important role in the progression of focal ischemic damage in a gyrencephalic model. This evidence for the neuroprotective efficacy of YM872 suggests its t herapeutic potential in the treatment of acute stroke in humans.