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Vol. 284, Issue 2, 467-473, February 1998

YM872, a Novel Selective alpha -Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptor Antagonist, Reduces Brain Damage after Permanent Focal Cerebral Ischemia in Cats

Masayasu Takahashi, Jian Wei Ni, Sachiko Kawasaki-Yatsugi, Takashi Toya, Sin-Ichi Yatsugi, Masao Shimizu-Sasamata, Kazuo Koshiya, Jun-Ichi Shishikura, Shuichi Sakamoto and Tokio Yamaguchi

Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki 305, Japan

YM872 {[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]-acetic acid monohydrate}, a selective, potent and highly water-soluble competitive alpha -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, was investigated for its neuroprotective effect against focal cerebral ischemia in halothane-anesthetized cats. Cats were subjected to 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 starting 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 mm3 of the cerebral hemisphere in saline-treated cats to 1025 ± 277 mm3 in YM872-treated cats; P < .01), as assessed in 12 stereotaxically determined coronal sections. No significant differences were observed between YM872- and saline-treated cats concerning physiological variables including brain temperature. No precipitation of YM872 in the kidney was seen in any YM872-treated animal. The present data further 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 therapeutic potential in the treatment of acute stroke in humans.

0022-3565/98/2842-0467$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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