Tirilazad prevention of reperfusion edema after focal ischemia in cynomolgus monkeys

Background: The purpose of the present investigation was to determine if post-ischemic treatment with the 21-aminosteroid lipid peroxidation inhibitor tirilazad mesylate (U-74006F) could affect reperfusion brain edema during the first 3 h following a 3 h period of middle cerebral artery occlusion-induced focal ischemia in cynomolgus monkeys. Methods: Adult female cynomolgus monkeys (N = 14) were subjected under halothane anesthesia to a 3 h period of middle cerebral artery occlusion, followed by 3 h of reperfusion. U-74006F, 3.0 mg/kg i.v. or citrate vehicle, was administered 10 min before beginning reperfusion. Multiple spin-echo (8 echoes: TE = 26.3 msec; TR = 3.0 secs; 2.35 Tesla) magnetic resonance imaging was performed every 30 min, beginning at 1 h after reperfusion. Transverse relaxation rates (T2) for the caudate, putamen, cortex, insular cortex, parietal cortex and central white matter were calculated as an index of focal brain edema. After the final images, corresponding regions were removed for determination of water content by the wet weight/dry weight method. Results: The T2 measurements strongly suggested the presence of post-reperfusion edema in all gray matter, but not white matter, regions at 1 h after reperfusion in vehicle-treated animals. Significant attenuation of edema development was seen in the putamen and insular cortex in U-74006F-treated animals. An effect was also observed in the parietal cortex, but none in the caudate. The measurement of water content at 3 h after reperfusion yielded similar results. Conclusions: These results showing the ability of U-74006F to attenuate post-reperfusion brain edema support the concept that lipid peroxidation is a significant mediator of reperfusion brain edema after focal ischemia. The therapeutic window for U-74006F's anti-edema effect appears to be at least 3 h after the onset of focal ischemia since delaying treatment until just before reperfusion largely prevented subsequent edema in cortical regions and the putamen. The effects of U-74006F on edema may play a mechanistic role in the compound's reported neuroprotective efficacy in a variety of focal ischemia models.