Antioxidant LY231617 enhances electrophysiologic recovery after global cerebral ischemia in dogs

OBJECTIVE: The potent antioxidant LY231617 (2,6-bis(1,1-dimethylethyl)-4-(1-ethyl)amino]methyl]phenol hydrochloride) is cytoprotective in models of focal and global cerebral ischemia. We tested the hypothesis that administration of LY231617, before the insult, would improve recovery of cerebral electrical activity and metabolic function after transient global cerebral ischemia by improving cerebral blood flow (CBF) during the reperfusion period. DESIGN: Randomized, controlled, prospective study. SETTING: Research laboratory at a university teaching hospital. SUBJECTS: Twenty-four male beagle dogs. INTERVENTIONS: All experiments were performed under pentobarbital anesthesia and controlled conditions of normoxia, normocarbia, and normothermia. Twelve control dogs received 20 mL/kg saline (vehicle) bolus into the right atrium and 0.01 mL/kg/min i.v., beginning 20 mins before 13 mins of global cerebral ischemia (by aortic occlusion). The dogs in the drug-treated group received LY231617 as a 10-mg/kg bolus 20 mins before ischemia and 5 mg/kg/hr throughout reperfusion (n = 12). CBF was measured using radiolabeled microspheres. MEASUREMENTS AND MAIN RESULTS: Total CBF, cerebral oxygen consumption, and somatosensory evoked potentials (SEP) were measured during 240 mins of reperfusion. CBF was similar in both vehicle- and LY231617-treated animals at baseline and throughout the experimental period. In all animals, SEP became isoelectric between 60 and 100 secs after cross-clamping of the ascending aorta. SEP amplitude recovery was significantly higher in drug-treated animals compared with controls (73%+/-15% vs. 39%+/-14% mean+/-SEM] from baseline at 120 mins p<.05] and 86%+/-12% vs. 49%+/-14% from baseline at 240 mins p< .05]). CONCLUSIONS: LY231617 improves recovery of cerebral electrical function after complete transient global ischemia via mechanisms unrelated to cerebral circulatory effects.