Moriguchi Akira, Aoki Toshiaki, Mihara Kayoko, Tojo Nobuteru, Matsuoka Nobuya, Mutoh Seitaro
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co, Ltd, Osaka, Japan.
J Pharmacol Exp Ther. 2004 Mar;308(3):1094-101. doi: 10.1124/jpet.103.058073. Epub 2003 Nov 21.
Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin alpha(IIb)beta3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A(2) synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke.
血小板活化及随后的聚集在缺血性脑损伤的发病机制中起关键作用。最近的研究表明，缺血后也观察到血小板活化增强，提示继发性血栓形成可能参与脑梗死的发展。血小板糖蛋白GPIIb/IIIa（整合素α(IIb)β3）与纤维蛋白原的结合是血小板聚集的最终共同途径。因此，GPIIb/IIIa拮抗剂可能对急性缺血性卒中以及缺血性卒中的二级预防有用。在本研究中，我们使用豚鼠光化学诱导的大脑中动脉（MCA）血栓形成模型，评估了三种化合物，即新型非肽GPIIb/IIIa拮抗剂FK419（(S)-2-乙酰氨基-3-[(R)-[1-[3-(哌啶-4-基)丙酰基]哌啶-3-基羰基]氨基]丙酸三水合物）、选择性血栓素A(2)合酶抑制剂奥扎格雷和凝血酶抑制剂阿加曲班，对MCA通畅情况和缺血性脑损伤的影响。在光照射结束后5分钟给予FK419、奥扎格雷或阿加曲班。FK419在体外抑制ADP诱导的血小板聚集的剂量下，通过减少总闭塞时间、持续再灌注时间和循环血流减少次数，剂量依赖性地改善MCA通畅情况。相比之下，奥扎格雷仅改善了总闭塞时间，而阿加曲班对MCA通畅情况无改善作用。FK419也以剂量依赖性方式减少缺血性脑损伤，而奥扎格雷和阿加曲班则没有。最后，FK419改善了神经功能缺损，而奥扎格雷和阿加曲班则没有。这些结果表明，GPIIb/IIIa拮抗剂FK419通过改善闭塞后MCA通畅情况来减轻缺血性脑损伤，并且FK419是治疗急性缺血性卒中的一个有前景的候选药物。
