Extension Of The Therapeutic Time Window For For Rt-PA Coadministered With MCI-186 In A Rat Model Of Embolic Stroke

In recent years, many different animal stroke models have been described in the Chinese and English literatures, such as Animal stroke models which based on photochemically induced MCA-occlusion, on surgical occlusion, on vessel occlusion by electrical cauterization or thread-occlusion. Most of these models reproduced only some aspects of human ischemic stroke, and studies on thrombolytic therapy or reperfusion damage based on these models were not possible.The investigation of the method to produce an ideal animal model that is based on thromboembolic occlusion and resembles human embolic stroke as close as possible will facilitate the studies of the effects of thrombolytic therapy and the pathophysiology of cerebral ischemia.In our study, A Wistar rat model of embolic stroke was set up by occlusion of one side middle cerebral artery with the use of a single fibrin-rich clot made from a donor rat arterial blood. Combination treatments of rt-PA and MCI-186 in the rat model at different time were performed to test the hypothesis that the combination treatment withrt-PA and MCI-186 could extend the treatment window to 6 hours, Neurological deficit score, infarct volume and hemorrhagic transfomation rate were measured, and histopathologic changes were evaluated on the hematoxylin and eosin-stained coronal sections. Quantitative analysis of free radicals and apoptosis in rat brain sections suggested that the combination treatment may extend the time window of thrombolytic therapy for embolic stroke.Part I A study on a Wistar rat model of thromboembolic stroke and thrombolytic therapyPurpose To investigate the possibility that combination treatment with rt-PA and free radical scavenger MCI-186 could extend the therapeutic window to 6 hours after stroke onset. Methods Male Wistar rats were subjected to middle cerebral artery occlusion (MCAO) by a single fibrin-rich clot made from a donor rat arterial blood, the rat model of embolic stroke was successfully produced. The ischemic lesion and neurologic deficits were evident, and the lesion regions were consistent. In addition, rt-PA and MCI-186 were coadminstrationed at different time windows in rat models. The neurological deficit, lesion volume, hemorrhagic transformation rate and HE-stained section were analyzed. Results Effect of the combination treatment was significant without increasing hemorrhagic transformation rate. Conclusions Our data suggested that the combination treatment with rt-PA and MCI-186extend the therapeutic time window for embolic stroke to at least 6 hours. stroke; thrombolysis; free radical scavenger; combination treatment. Part II Effect of the free radical scavenger MCI-186 alone and in combination with rt-PA on a Wistar rat model of embolic strokePurpose To evaluate the effects that MCI-186 alone and in combination with rt-PA directly scavenge free radicals in a Wistar rat model of embolic stroke. Methods The lipid peroxidation product malondialdehyde(MDA), superoxidase (SOD) and nitric oxide (NO) in rat brain homogenates were measured. Results The concentrations of MDA and NO in brain homogenates of rats treated with MCI-186 alone and in combination with rt-PA at 3,6 hours after stroke onset were significantly decreased compaired with untreated controls. The concentration of SOD was correlated with severity of rat brain infarction. Conclusions The present study indicates that the free radical scavenger MCI-186 alone and in combination with rt-PA at various therapeutic time windows may significantly suppress rat brain damage caused by free radicals.Part m Effects of combination therapy of thrombolytic...