Hydroxyl radical generation after the third hour following ischemia contributes to brain damage

The purpose of the present study was to determine after what time period hydroxyl radical formation contributes most to ischemic brain damage in focal ischemia, using a hydroxyl radical scavenger, EPC-K(1), L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-tridecyl)-2H-1-benzopyran-6yl-hydrogen phosphate] potassium salt. Focal ischemia was produced by thrombotic occlusion of the left middle cerebral artery in rats. After evaluation of the pharmacokinetics of EPC-K(1) in the brain tissue and plasma following 10 mg/kg intravenous bolus treatment of conscious rats, we investigated the neuroprotective effect of EPC-K(1) in the middle cerebral artery occlusion model. A single intravenous bolus of EPC-K(1) was given immediately, 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 after ischemia and lasted for 24 h, also significantly (P < 0.05) reduced brain damage, but the efficacy of the neuroprotective effect was the same as that of the 3 h after ischemia bolus treatment. These results may indicate that the period of hydroxyl radical formation most critical for ischemic brain damage is a few hours after the third hour following ischemia in this model. (C) 1998 Elsevier Science B.V. All rights reserved.