Usefulness of postischemic thrombolysis with or without neuroprotection in a focal embolic model of cerebral ischemia

Abstract

Object. Recent studies have shown that the use of thrombolysis in the setting of acute stroke is associated with an increased risk of cerebral hemorrhage. The time of onset of symptoms to initiation of medication and the dose levels of the thrombolytic agents are important determinants for the risk of cerebral hemorrhage. The authors evaluated the time course of thrombolysis-related hemorrhages in experimental settings and tested whether the addition of neuroprotective medication augments the efficacy of thrombolysis and reduces the incidence of hemorrhages.Methods. Male Wistar rats were subjected to right middle cerebral artery embolization with an autologous thrombus and were then randomly assigned to one of the following groups: Group 1, saline-treated (2 hours after ischemic insult) animals as controls; Groups 2 to 4, high-dose urokinase (5000 U/kg) at 2, 3, and 6 hours after the insult; Group 5, low-dose urokinase (2500 U/kg) at 2 hours after the insult; Group 6, 20 mg/kg topiramate (TPM) at 2 hours after the insult; Group 7, a combination of 20 mg/kg TPM at 2 hours and low-dose urokinase (2500 U/kg) at 6 hours after the insult; and Group 8, 20 mg/kg TPM (20 mg/kg) at 2 hours and high-dose urokinase (5000 U/kg) at 2 hours after the insult. Neurological behavior and the infarct volume in the brain were assessed following cerebral embolism and the various treatments.All animals in the single therapy and low-dose combination groups survived surgery. Three of eight animals treated with high-dose urokinase alone at 6 hours and three of six animals in the combined high-dose urokinase and TPM group developed fatal intracerebral hemorrhages. There was a significantly better neurological outcome at 24 hours in the animals treated with either medication compared with controls. The volume of the infarct in the saline-treated group was 54.2 ± 9%. The use of TPM at 2 hours led to a decrease in the infarct to 20.1 ± 11.2% (p < 0.01). Treatment with urokinase at 6 hours after the occlusion showed a trend toward protection; the infarct volume was 31.9 ± 14.1% (p < 0.05). The addition of TPM to low- or high-dose urokinase achieved better neuroprotection (8.2 ± 6% and 11.9 ± 10.7%, respectively; both p < 0.01).Conclusions. In this study the authors show that the volume of the infarct can be significantly decreased with 2 to 6-hour delayed intraarterial thrombolysis with urokinase and that the efficacy of thrombolysis may be enhanced by combining neuroprotective agents like TPM. It is also shown that low-dose combination therapy may decrease the likelihood of cerebral hemorrhage.