Vol. 281, Issue 2, 921-927, 1997

Effects of a Novel Free Radical Scavenger, MCI-186, on Ischemic Brain Damage in the Rat Distal Middle Cerebral Artery Occlusion Model

Hiroshi Kawai, Hiroshi Nakai, Misao Suga, Satoshi Yuki, Toshiaki Watanabe and Ken-Ichi Saito

Pharmaceuticals Laboratory 2 (H.K.), Pharmaceuticals Laboratory 1 (M.S., S.Y., T.W., K.S.), and Pharmacokinetics and Drug Metabolism Laboratory (H.N.), Yokohama Research Center, Mitsubishi Chemical Corporation, 1000, Kamoshida-cho, Aoba-ku Yokohama 227, Japan

We investigated the effects of a free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), on infarct areas, neurological deficits and regional cerebral blood flow (rCBF), with use of a rat thrombotic distal middle cerebral artery (dMCA) occlusion model to elucidate its possible therapeutic effects on focal cerebral ischemia. In addition, we have attempted to measure 2-oxo-3-(phenylhydrazono)-butanoic acid (OPB), which is the major oxidation product of MCI-186, in the penumbral cortex of a thrombotic dMCA occlusion model. Postischemic treatment with MCI-186 (3 mg/kg) significantly (P < .05) decreased the size of the cerebral infarcts 1 day after dMCA occlusion. MCI-186 (3 mg/kg) significantly (P < .05) improved the neurological deficits 1 day after dMCA occlusion. On the contrary, MCI-186 had no effect on rCBF 1 day after dMCA occlusion. MCI-186 mainly reacted into OPB by peroxidation in rat brain homogenates. Furthermore, the increase in OPB content in the ischemic penumbral cortex tissue was confirmed after 90 min of MCI-186 perfusion. These results suggest that MCI-186 has a protective effect on brain ischemia by reacting with oxygen radicals and that oxygen radicals are closely related to postischemic brain injury.