Mild hypothermia of 34°C reduces side effects of rt-PA treatment after thromboembolic stroke in rats

Male Wistar rats (n = 48) were subjected to TE. The following treatment groups were investigated: control group - normothermia (37°C); thrombolysis group - rt-PA 90 min after TE; hypothermia by 34°C applied 1.5 to 5 hours after TE; combination therapy- hypothermia and rt-PA. After 24 hours infarct size, brain edema and neuroscore were assessed. Protein markers for inflammation and adhesion, gelatinase activity, and blood brain barrier (BBB) disruption were determined. MRI-measurements investigated infarct evolution and blood flow parameters.The infarct volume and brain swelling were smaller in the hypothermia group compared to the other groups (p < 0.05 to p < 0.01). Thrombolysis resulted in larger infarct and brain swelling than all others. Hypothermia in combination with thrombolysis reduced these parameters compared to thrombolysis (p < 0.05). Moreover, the neuroscore improved in the hypothermia group compared to control and thrombolysis. Animals of the combination therapy performed better than after thrombolysis alone (p < 0.05). Lower serum concentration of sICAM-1, and TIMP-1 were shown for hypothermia and combination therapy. Gelatinase activity was decreased by hypothermia in both groups.Therapeutic hypothermia reduced side-effects of rt-PA associated treatment and reperfusion in our model of TE.Thrombolysis by recombinant tissue-plasminogen activator (rt-PA) is the preferable causal therapy for acute ischemic stroke, but only a minority of all stroke patients is eligible for treatment [1]. Its approval is restricted to the first 4.5 hours after symptom onset [2,3]. Delayed administration of rt-PA has less pronounced effects on restoration of cerebral blood flow (CBF) and outcome, but may still be effective [2-4]. However, clinical and animal data suggest an increased risk for intracerebral hemorrhage and brain edema after delayed thrombolysis [4,5]. Possibly, these side effects account to a reperfusion-associated injury [6], pro-apoptotic and neurotoxic sid