Effects of tissue type plasminogen activator in embolic versus mechanical models of focal cerebral ischemia in rats

Tissue type plasminogen activator (tPA) can be effective therapy for emboli c stroke by restoring cerebral perfusion. However, a recent experimental st udy showed that tPA increased infarct size in a mouse model of transient fo cal ischemia, suggesting a possible adverse effect of tPA on ischemic tissu e per se. In this report. the effects of tPA in two rat models of cerebral ischemia were compared. In experiment 1, rats were subjected to focal ische mia via injection of autologous clots into the middle cerebral artery terri tory. Two hours after clot injection, rats were treated with 10 mg/kg tPA o r normal saline. Perfusion-sensitive computed tomography scanning showed th at tPA restored cerebral perfusion in this thromboembolic model. Treatment with tPA significantly reduced ischemic lesion volumes measured at 24 hours by >60%. In experiment 2, three groups of rats were subjected to focal isc hemia via a mechanical approach in which a silicon-coated filament was used intraluminally to occlude the origin of the middle cerebral artery. In two groups, the filament was withdrawn after 2 hours to allow for reperfusion, and then rats were randomly treated with 10 mg/kg tPA or normal saline. in the third group. rats were not treated and the filament was not withdrawn so that permanent focal ischemia was present. In this experiment, tPA did n ot significantly alter lesion volumes after 2 hours of transient focal isch emia. In contrast, permanent ischemia significantly increased lesion volume s by 55% compared with transient ischemia. These results indicate that in t hese rat models of focal cerebral ischemia, tPA did not have detectable neg ative effects. Other potentially negative effects of tPA may be dependent o n choice of animal species and model systems.