Postischemic Application of Lipid Peroxidation Inhibitor U-101033E Reduces Neuronal Damage After Global Cerebral Ischemia in Rats

Abstract

Background and Purpose —The lipid peroxidation inhibitor U-101033E was examined for effects on cerebral blood flow (CBF), cortical tissue hemoglobin oxygen saturation (HbS o 2 ), and neuronal damage. Methods —Fifteen minutes of global cerebral ischemia was induced by two-vessel occlusion and hypobaric hypotension. Wistar rats (n=25) were randomized to receive vehicle (n=9) or 40 mg/kg U-101033E (n=9) intraperitoneally during 2 hours of reperfusion. A sham group (n=7) had neither ischemia nor therapy. Histology was evaluated 7 days after ischemia. Results —During late hyperperfusion (at 17 minutes), vehicle-treated animals had a higher ( P =0.044) cortical tissue HbS o 2 (72.0±1.4%) than did U-101033E–treated animals (65.8±2.5%). Neuronal counts in the superficial cortex layer found after 7 days correlated negatively with rCBF ( r =−0.76; P <0.001) or cortical tissue HbS o 2 ( r =−0.56; P =0.028) assessed during the late hyperperfusion phase. U-101033E reduced neuronal damage in hippocampal CA1 from 64.3±9.2% to 31.2±8.4% ( P =0.020), as well as in the superficial cortical layer from 53.5±14.6% to 12.8±11.7% ( P =0.046). While animals in the vehicle group had reduced counts in all four examined cortex layers ( P <0.05 versus sham group), there was significant cortical neuron loss in the U-101033E group in only one of four areas. U-101033E had no effect on resting CBF or CO 2 reactivity. Conclusions —Postischemic application of U-101033E protects hippocampal CA1 and cortical neurons after 15 minutes of global cerebral ischemia. The results indicate that free radical–induced lipid peroxidation contributes to reperfusion injury, a process that can be inhibited by antioxidants such as U-101033E.