Zhang Li, Zhang Zheng Gang, Zhang Ruilan, Morris Daniel, Lu Mei, Coller Barry S, Chopp Michael
Department of Neurology, Henry Ford Health Sciences Center, Detroit, Mich, USA.
Circulation. 2003 Jun 10;107(22):2837-43. doi: 10.1161/01.CIR.0000068374.57764.EB. Epub 2003 May 19.
Platelet aggregation and fibrin deposition are key events leading to microvascular thrombosis and progressive impairment of downstream microvascular perfusion after stroke. We tested the hypothesis that inhibition of platelet function with a GP IIb/IIIa receptor antagonist would increase the efficacy and safety and increase the time window for thrombolytic therapy for stroke with full- and half-dose tissue plasminogen activator (tPA).
Rats were subjected to embolic middle cerebral artery occlusion. Four hours after ischemia, rats were treated with 7E3 F(ab')2 (6 mg/kg) in combination with tPA at doses of 10 and 5 mg/kg, tPA alone at a dose of 10 or 5 mg/kg, 7E3 F(ab')2 (6 mg/kg) alone, or saline. Combination treatment with 7E3 F(ab')2 and tPA (full- or half-dose) significantly (P<0.05) reduced infarct volume and neurological deficits compared with saline-treated rats. However, treatment with 7E3 F(ab')2 or tPA (full- or half-dose) alone did not reduce infarct volume. Quantitative measurements of cerebral microvessels perfused by FITC-dextran revealed that combination treatment with 7E3 F(ab')2 and full-dose tPA significantly (P<0.05) increased the percentage of FITC-dextran-perfused vessels compared with saline and full-dose tPA-treated rats. In addition, treatment with 7E3 F(ab')2 in combination with full-dose tPA significantly (P<0.05) decreased microvascular platelet accumulation and matrix metalloproteinase 9 immunoreactivity and protected against loss of collagen IV immunoreactivity.
Combination treatment with 7E3 F(ab')2 with full- and half-dose tPA at 4 hours after ischemia significantly reduces infarct volume and improves neurological outcome. Enhancement of patency and integrity of cerebral microvessels most likely contributes to the benefits observed with this combination therapy.
血小板聚集和纤维蛋白沉积是导致微血管血栓形成以及中风后下游微血管灌注进行性受损的关键事件。我们检验了这样一个假设，即使用糖蛋白IIb/IIIa受体拮抗剂抑制血小板功能可提高疗效和安全性，并延长使用全剂量和半剂量组织型纤溶酶原激活剂（tPA）进行中风溶栓治疗的时间窗。
对大鼠进行栓塞性大脑中动脉闭塞。缺血4小时后，大鼠分别接受7E3 F(ab')2（6毫克/千克）与剂量为10和5毫克/千克的tPA联合治疗、单独使用剂量为10或5毫克/千克的tPA治疗、单独使用7E3 F(ab')2（6毫克/千克）治疗或生理盐水治疗。与生理盐水治疗的大鼠相比，7E3 F(ab')2与tPA（全剂量或半剂量）联合治疗显著（P<0.05）减少了梗死体积和神经功能缺损。然而，单独使用7E3 F(ab')2或tPA（全剂量或半剂量）治疗并未减少梗死体积。对用异硫氰酸荧光素标记的葡聚糖灌注的脑微血管进行定量测量显示，与生理盐水和全剂量tPA治疗的大鼠相比，7E3 F(ab')2与全剂量tPA联合治疗显著（P<0.05）增加了异硫氰酸荧光素标记的葡聚糖灌注血管的百分比。此外，7E3 F(ab')2与全剂量tPA联合治疗显著（P<0.05）减少了微血管血小板聚集和基质金属蛋白酶9免疫反应性，并防止了IV型胶原免疫反应性的丧失。
缺血4小时后，7E3 F(ab')2与全剂量和半剂量tPA联合治疗可显著减少梗死体积并改善神经功能结局。脑微血管通畅性和完整性的增强很可能是这种联合治疗所观察到的益处的原因。
