LY341122 (2-(3, 5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-methylethylaminomethyl-ph enylox y)ethyl)oxazole) is a potent inhibitor of lipid peroxidation which has been shown to protect against global ischemia and traumatic brain injury in rats. The purpose of this study was to examine the effect of LY341122 on ischemic injury in a highly reproducible model of focal cerebral ischemia in rats. Male Sprague-Dawley rats were anesthetized with halothane and subjected to 120 min of temporary middle cerebral artery occlusion by retrograde insertion of an intraluminal nylon suture coated with poly-L-lysine. The drug (LY341122, n=19) or vehicle (phosphate-buffered saline (PBS), n=10) was administered i.v. (as a 5 or 10 mg/kg bolus followed by a 5 or 10 mg/kg/h infusion for 20 h, respectively, starting 1 or 2 h after the onset of middle cerebral artery occlusion). Neurological status was evaluated during middle cerebral artery occlusion (60 min) and daily for 3 days thereafter. Three days after ischemia, brains were perfusion-fixed and infarct volumes and brain edema were determined. LY341122 significantly improved the neurological score compared to vehicle at 24, 48 and 72 h after middle cerebral artery occlusion. Treatment with LY341122 significantly reduced total infarct volume in all treated groups compared to vehicle rats. Cortical infarct volume was significantly reduced by LY341122 treatment in the 10 mg/kg (1 h) and LY341122 10 mg/kg (2 h) groups compared to vehicle rats (14.7+/-9.5 vs. 106.8+/-20.9 mm(3), and 36.9+/-20.1 vs. 106. 8+/-20.9 mm(3), respectively (mean+/-S.E.M.)). Striatal infarct volume was also significantly reduced by treatment with LY341122 in the 10 mg/kg (1 h) group compared to vehicle (23.7+/-3.4 vs. 68. 2+/-6.7 mm(3)). These results demonstrate the neuroprotective efficacy of LY341122 in focal cerebral ischemia.