Wang Chen Xu, Ding Xiuqing, Shuaib Ashfaq
Stroke Research Laboratory, Department of Medicine, University of Alberta, Edmonton, Canada.
Exp Neurol. 2008 Sep;213(1):171-5. doi: 10.1016/j.expneurol.2008.05.020. Epub 2008 Jun 7.
Melagatran is a potent direct thrombin inhibitor and it is an effective agent in the prevention of stroke in patients with atrial fibrillation (AF); however, there are no data about its actions in the treatment of acute ischemic stroke. In the present study, we evaluated the neuroprotective actions of melagatran using an embolic model of stroke in rats. We first examined protective effects at increasing doses of melagatran. Then, we examined the effects of melagatran administered at different time points following middle cerebral artery (MCA) occlusion. We also evaluated the effects of combination therapy with melagatran and tissue plasminogen activator (tPA) in this model. Finally, we examined if melagatran can improve compromised microcirculation in the ischemic injured brain. The medication alone or in combination with tPA was well tolerated. Melagatran reduced ischemic brain injury in a dose-response manner, and also in a time dependent manner. Combination treatment of melagatran and tPA was superior to either treatment alone. There was no significant increase in symptomatic or asymptomatic hemorrhages in the treated animals. Melagatran treatment also reduced perfusion deficits in the ischemic injured brain. The present study is the first report on the usefulness of melagatran in embolic ischemic stroke. Our research shows that melagatran is an effective agent in the treatment of ischemic brain injury. The protective effects of this medication are likely due to its actions in enhancing thrombus dissolution and preventing formation of microthrombosis in the ischemic injured brain. Finally, the combination with melagatran and tPA appears safe and superior to each treatment offered alone.
美拉加群是一种强效的直接凝血酶抑制剂，是预防心房颤动（AF）患者中风的有效药物；然而，尚无关于其治疗急性缺血性中风作用的数据。在本研究中，我们使用大鼠栓塞性中风模型评估了美拉加群的神经保护作用。我们首先研究了美拉加群递增剂量的保护作用。然后，我们研究了大脑中动脉（MCA）闭塞后不同时间点给予美拉加群的效果。我们还评估了在该模型中美拉加群与组织型纤溶酶原激活剂（tPA）联合治疗的效果。最后，我们研究了美拉加群是否能改善缺血性损伤脑的微循环障碍。单独用药或与tPA联合用药耐受性良好。美拉加群以剂量反应方式和时间依赖性方式减少缺血性脑损伤。美拉加群与tPA联合治疗优于单独任何一种治疗。治疗动物的症状性或无症状性出血均无显著增加。美拉加群治疗还减少了缺血性损伤脑的灌注不足。本研究是关于美拉加群在栓塞性缺血性中风中有效性的首次报道。我们的研究表明，美拉加群是治疗缺血性脑损伤的有效药物。这种药物的保护作用可能是由于其增强血栓溶解和防止缺血性损伤脑中微血栓形成的作用。最后，美拉加群与tPA联合使用似乎安全且优于单独提供的每种治疗。
