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

Bernd Kallmünzer,Rainer Kollmar,Stefan Schwab

doi:10.1186/2040-7378-4-3

Bernd Kallmünzer, Rainer Kollmar + Show 1 more

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https://doi.org/10.1186/2040-7378-4-3

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Abstract

BackgroundHypothermia is neuroprotective in experimental stroke and may extend the so far limited therapeutic time window for thrombolysis. Therefore, hypothermia of 34°C and its effects on delayed thrombolysis including reperfusion-associated injury were investigated in a model of thromboembolic stroke (TE).MethodsMale 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.ResultsThe 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.ConclusionsTherapeutic hypothermia reduced side-effects of rt-PA associated treatment and reperfusion in our model of TE.

Highlights

Thrombolysis by recombinant tissue-plasminogen activator is the preferable causal therapy for acute ischemic stroke, but only a minority of all stroke patients is eligible for treatment [1]
Preliminary study The mortality rate was the highest in group 2. 10 animals died before reaching 24 hours. 7 of 16 animals died in group 1, 9 of 16 animals died in group 2, 6 of 16 animals died in group 3 and only one animal died in group 4
Main Study Physiological parameters There was no significant difference for the measured physiological parameters with the exception of the desired body temperature according to the treatment group

Summary

Introduction

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]. Clinical and animal data suggest an increased risk for intracerebral hemorrhage and brain edema after delayed thrombolysis [4,5]. Hypothermia might be a promising candidate for combination therapy with rt-PA because of its multiple neuroprotective effects and capacity to reduce reperfusion associated injury [10,11]. It is the only strategy that succeeded in acute brain injury so far: moderate hypothermia (33°C) improved functional outcome and survival of cardiac arrest patients when applied directly after successful resuscitation [12]. Hypothermia of 34°C and its effects on delayed thrombolysis including reperfusion-associated injury were investigated in a model of thromboembolic stroke (TE)

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