Abstract: Objective To investigate the effects of recombinant tissue-type plasminogen activator (rt-PA) combined with mild hypothermia on the hemorrhagic transformation after cerebral ischemia-reperfusion within or out of the therapeutic time window in rats.Methods The focal cerebral ischemia-reperfusion 3 and 4 hours models of rats were established by middle cerebral artery occlusion (MCAO) 3 or 4 hours. The rats were randomly divided into the normal saline group (group NS), normothermia rt-PA group (group rt-PA), rt-PA combined with hypothermia group (group rt-PA +HT), and sham-operation group. Brain mild hypothermia was achieved after ischemia reperfusion and maintained 3 hours. Rats were sacrificed 24 h after ischemia reperfusion, and the amount of bleeding was measured.Results The amount of bleeding significantly reduced in the group rt-PA+HT compared with group rt-PA, which obviously increased in the group rt-PA compared with group NS ( P<0.05); there was a significant difference between rt-PA groups MCAO 3 hours and 4 hours ( P<0.05).Conclusion rt-PA can increase hemorrhagic transformation volume; hemorrhagic transformation volume is higher if treated by rt-PA within 3 h therapeutic time window than treated beyond the time window; mild hypothermia should possibly prevent the development of hemorrhagic transformation and prolong the therapeutic time window of thrombolytic intervention in ischemic stroke.

Key words: cerebral ischemia-reperfusion, hemorrhagic transformation, recombinant tissue-type plasminogen activator (rt-PA), mild hypothermia