HYDROXYL RADICAL GENERATION AFTER THE 3RD HOUR FOLLOWING ISCHEMIA CONTRIBUTES TO BRAIN-DAMAGE

The purpose of the present study was to determine after what time peri od hydroxyl radical formation contributes most to ischemic brain damag e in focal ischemia, using a hydroxyl radical scavenger, EPC-K-1, L-as corbic acid 2-trimethyl-tridecyl)-2H-1-benzopyran-6yl-hydrogen phospha te] potassium salt. Focal ischemia was produced by thrombotic occlusio n of the left middle cerebral artery in rats. After evaluation of the pharmacokinetics of EPC-K-1 in the brain tissue and plasma following 1 0 mg/kg intravenous bolus treatment of conscious rats, we investigated the neuroprotective effect of EPC-K-1 in the middle cerebral artery o cclusion model. A single intravenous bolus of EPC-K-1 was given immedi ately, 3 or 6 h after ischemia, and cerebral brain damage was measured 24 h after ischemia. When EPC-K-1 was injected 3 h after ischemia, a significant (P < 0.01) reduction of cerebral brain damage was observed . EPC-K-1 delivered by intravenous infusion that started immediately a fter ischemia and lasted for 24 h, also significantly (P < 0.05) reduc ed brain damage, but the efficacy of the neuroprotective effect was th e same as that of the 3 h after ischemia bolus treatment. These result s may indicate that the period of hydroxyl radical formation most crit ical for ischemic brain damage is a few hours after the third hour fol lowing ischemia in this model. (C) 1998 Elsevier Science B.V. All righ ts reserved.