Effect of Tissue Plasminogen Activator on Autologous Arterial Emboli in the Cerebral Circulation of Rabbit Model

Lee, Kyung Jin; Choi, Chang Rak

Abstract

The safety and efficacy of intravenous tissue plasminogen activator(tPA) on the condition of ruling out the significant risk were studied at 6 and 12 hours after cerebral artery embolization in rabbit model. The time selection was chosen to stimulate the analogous clinical situation. The safety and effectiveness of tPA in experimental and clinical treatment of acute coronary thrombosis have been established. Tissue plasminogen activator is an endogenous fibrin-specific serine protease with the potent thrombolytic activity that has been produced recently by recombinant DNA technology. The acute cerebral thromboembolic model was induced by injecting three 0.5X1.0mm fragments of autologous arterial thromi into internal carotid artery through the intra-arterial catheter. The autologous arterial thrombi was obtained from the traumatized arterial endothelium by scratching the lumen of auricular artery using modified spinal needle. The experimental group was divided into four groups : (1) group Ia : saline-treated(1 ml/kg) control group at 6 hours after embolization(n=10), (2) group Ib : tPA-treated(1 mg/kg) at 6 hours after embolization(n=10), (3) group IIa : saline-treated control group 12 hours after embolization(n=10), (4) group Iib : tPA-treated group 12 hours after embolization(n=13). The experimental rabbits were sacrificed at 24 hours after injection of tPA(1 mg/kg) or saline(1 ml/kg) in each group. Brain was cut into 0.5 cm thick coronal sections, which were stained with triphenyltetrazolium chloride to define the areas of infarction. The transparent plastic sheets were placed on the each section, and the total area of the brain slice and the area of infarction were measured by the plannimeter(as outlined by TTC staining). The percentage area of whole brain infarction was calculated as(the sum of infarcted area/the sum of brain slice areas)x100% for each rabbit. We also observed the pathologic findings with hematoxylin-eosin staining. The results were as follows : 1) Only 1 rabbit treated with tPA at 12 hours after occlusion exhibited the gross hemorrhage. 2) The infarcted area was limited to the basal ganglia and cortex in all group. 3) The mean percentage area of whole brain infarction averaged 18.6+/-1.94% in group Ia, 6.32+/-1.02% in group Ib, and 20.8+/-3.34% in group IIa, 6.78+/-1.40% in group IIb. One-way ANOVA test of infarction size showed the significant differences(p<0.05) between the tPA-treated group and the saline-treated control group, but no difference between the groups treated with same agent. 4) Under the study of microscope, infarcted area of saline-treated control group was more extended than that of tPA-treated group. Congulation necrosis and degeneration of neuronal cells could be seen. But the infarcted area of tPA-treated group was smaller than that of saline-treated control group. Only collection of foamy macrophages adjacent the necrotic area could be seen in tPA-treated group. These results suggest that tPA therapy may be safe and efficacious during the interval of 6 to 12 hours after embolization.