Neuroprotection by LY341122, a novel inhibitor of lipid peroxidation, against focal ischemic brain damage in rats

LY341122 (2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-methylethylaminomethyl -phenyloxy)ethyl)oxazole) is a potent inhibitor of lipid peroxidation which has been shown to protect against global ischemia and traumatic brain inju ry 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 ischem ia in rats. Male Sprague-Dawley rats were anesthetized with halothane and s ubjected to 120 min of temporary middle cerebral artery occlusion by retrog rade insertion of an intraluminal nylon suture coated with poly-L-lysine. T he drug (LY341122, n = 19) or vehicle (phosphate-buffered saline (PBS), n = 10) was administered i.v. las 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 dur ing middle cerebral artery occlusion (60 min) and daily for 3 days thereaft er. Three days after ischemia, brains were perfusion-fixed and infarct volu mes and brain edema were determined. LY341122 significantly improved the ne urological score compared to vehicle at 24, 48 and 72 h after middle cerebr al artery occlusion. Treatment with LY341122 significantly reduced total in farct volume in all treated groups compared to vehicle rats. Cortical infar ct 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), r espectively (mean +/- S.E.M.)). Striatal infarct volume was also significan tly 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 demonstrat e the neuroprotective efficacy of LY341122 in focal cerebral ischemia. (C) 2000 Elsevier Science B.V. All rights reserved.