Zhang R L, Zhang L, Jiang Q, Zhang Z G, Goussev A, Chopp M
Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Brain Res. 2000 Sep 29;878(1-2):64-71. doi: 10.1016/s0006-8993(00)02693-7.
To simulate human stroke, we developed a model of focal cerebral embolic ischemia in the unanesthetized rat. Using this model, we tested the hypothesis that intra-arterial administration of TNK-tPA, a fibrin specific second generation thrombolytic agent, is effective in reducing ischemic volume without increasing intra-cerebral hemorrhage.
Under anesthesia, a catheter was inserted to the origin of the MCA of male Wistar rats. Forty-five minutes after recovery from anesthesia, the MCA was occluded in the awake rat by a single fibrin rich clot placed via the catheter. TNK-tPA (1.5 mg/kg) was administered intraarterially via the catheter at either 2 h or 4 h after stroke. All rats were sacrificed at 48 h after ischemia. Neurological deficits, gross hemorrhage and ischemic lesion volume were measured.
A clot was detected at the origin of the MCA 4 h after MCA occlusion in the awake rats (n=4). Rats (n=12) subjected to MCA occlusion showed immediate neurological deficits which persisted for 48 h of ischemia. Ischemic rats had a lesion volume of 38.2+/-3.8% and 25% of rats exhibited gross hemorrhage. Ischemic rats (n=10) treated with TNK-tPA at 2 h showed a significant (P<0.05) reduction of neurological deficits, body weight loss and infarct volume (22.8+/-2.1%) without an increase in gross hemorrhage (10%) compared with the non treated ischemic rats (25%). Although treatment with TNK-tPA of ischemic rats (n=12) at 4 h did not significantly (P=0.06) reduce infarct volume (28.6+/-3.0%), it also did not increase gross hemorrhage (25%) compared with the control group (25%).
This study demonstrates that intraarterial administration of TNK-tPA at 2 h of ischemia in the unanesthesthetized rat is effective in reducing neurological deficits and ischemic lesion volume without increasing hemorrhagic transformation and that administration of TNK-tPA at 4 h of ischemia does not increase the incidence of hemorrhagic transformation.
为模拟人类中风，我们建立了未麻醉大鼠局灶性脑栓塞缺血模型。利用该模型，我们检验了以下假设：动脉内给予纤维蛋白特异性第二代溶栓剂替奈普酶（TNK-tPA）可有效减少缺血体积，而不增加脑出血。
在麻醉状态下，将导管插入雄性Wistar大鼠大脑中动脉（MCA）起始处。麻醉苏醒45分钟后，通过导管向清醒大鼠的MCA内注入一个富含纤维蛋白的凝块，使其闭塞。在中风后2小时或4小时，经导管动脉内给予TNK-tPA（1.5毫克/千克）。所有大鼠在缺血48小时后处死。测量神经功能缺损、肉眼可见的出血情况及缺血性病变体积。
清醒大鼠MCA闭塞4小时后，在MCA起始处检测到一个凝块（n = 4）。接受MCA闭塞的大鼠（n = 12）立即出现神经功能缺损，并持续至缺血48小时。缺血大鼠的病变体积为38.2%±3.8%，25%的大鼠出现肉眼可见的出血。与未治疗的缺血大鼠（25%）相比，缺血2小时接受TNK-tPA治疗的大鼠（n = 10）神经功能缺损、体重减轻及梗死体积显著减少（P < 0.05）（22.8%±2.1%），且肉眼可见出血未增加（10%）。虽然缺血4小时接受TNK-tPA治疗的大鼠（n = 12）梗死体积没有显著减少（P = 0.06）（28.6%±3.0%），但与对照组（25%）相比，肉眼可见出血也未增加（25%）。
本研究表明，在未麻醉大鼠缺血2小时时动脉内给予TNK-tPA可有效减少神经功能缺损和缺血性病变体积，且不增加出血性转化，而在缺血4小时给予TNK-tPA不会增加出血性转化的发生率。
