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 (HbSo2), 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 HbSo2 (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 HbSo2 (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 CO2 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.