Effect of U74389G on Neurological Deficit and the Formation of Brain Edema after Focal Ischemia in Rats

ABSTRACT

In the early stage of the development of ischemic brain injury, oxygen free radical-mediated lipid peroxidation is suspected to play an important role. U74389G is considered as one of the effective scavengers of free radicals and inhibitors of lipid peroxidation. However, the cytoprotective effect of U74389G in rodent models of neocortical infarction still remains controversial. Forty-four adult Sprague-Dawley rats weighing 250-300gm were subjected to permanent or transient middle cerebral artery occlusion(MCAO) using modified Longa's method while anesthetized with ketamine and xylazine. In the permanent MCAO groups, the animals were subjected to 4-hours of occlusion and were treated with vehicle(control, n=9), 3mg/kg U74389G(low-dose treatment, n=9) or 7mg/kg U74389G(high-dose treatment, n=10) intravenously at the time of occlusion and then half of the initial dose was administered 30 minuites after occlusion respectively. In the transient MCAO groups, the animals were subjected to 0.5 hours of occlusion and 3.5-hours of reperfusion and were treated with vehicle(control, n=8) or 3mg/kg U74389G(treatment, n=8) intravenously at the time of occlusion and then half of the initial dose was administered at the time of reperfusion respectively. Four hours after occlusion neurological evaluation was performed and then the animals were sacrificed immediately to determine brain water content. In the rats of permanent MCAO, treatment with both low and high-dose U74389G did not protect them against neurological deficit;however, treatment with high-dose U74389G was found to reduce brain edema in the ischemic core(19%, p<0.05) and intermediate regions(23%, p<0.05). In the rats of transient MCAO, treatment with U74389G was found to protect them against neurological deficit(p<0.05) and reduce brain edema in the ischemic core region(58%, p<0.05). These results suggest that free radical-mediated lipid peroxidation plays a significant role in focal ischemic reperfusion brain injury and that 21-aminosteroids might have the potential to be a useful supplementary drug as a cerebral protective agent for the thrombolytic therapy of acute cerebral infarction.