快速选择性动脉内低温对恒河猴急性缺血性卒中缺血再灌注损伤的作用及机制研究

In patients with acute ischemic stroke related to large-artery occlusions, rapid treatment with mechanical thrombectomy by using stent retrievers for vessel recanalization reduces mortality and improves functional outcome according to the recent release of landmark randomized controlled trials. However, reperfusion of ischemic brain tissue may also induce additional tissue damage and hemorrhagic transformation, which potentially limit the benefits of such recanalization therapies. Neuroprotective effects of hypothermia in cerebral ischemia are substantiated by numerous animal experiments. Systemic cooling, however, requires longer time to reach target temperature and has many adverse effects. In the past, our experiment with rodent animal showed the use of local intra-arterial infusions of solutions and drugs into ischemic brain regions via a microcatheter to provide stronger neuroprotection comparing with systemic hypothermia. Considering the complications resulted from over loading volume of low temperature of saline, we developed a new device which could cool arterial blood quickly and infused through the catheter in internal artery into ischemic cerebral tissue again to induce hypothermia. We first will develope acute ischemic model with non human primate by inserting the thrombus to the middle cerebral artery, and then infuse cooled blood by our new device through internal artery to ischemic cerebral tissue after recanalizing the occluded middle cerebral artery. We will test its neuroprotective effects and try to find specific microRNA as a new early biomark to further investigate its mechanism with selective intraarteial hypothermia intervention, and hope to find a new strategy for the treatment of acute ischemic stroke in the future.

大血管闭塞导致的急性缺血性卒中，血管再通不一定表示预后良好。部分病人的血管再通还会产生严重的缺血再灌注损伤如出血转化、恶性脑水肿等，反而加重病情。如何筛选出这部分病人并进行有效的干预，具有重要的意义。我们前期小动物实验，发现血管再通即刻，经动脉内灌注低温液体可快速实现缺血脑组织区域性低温，降低缺血再灌注损伤，提高血管再通效果，避免全身低温副作用，前瞻性临床实验也证实了其安全性和可行性。但该方法仍存在低温诱导维持时间短等局限性。本课题拟建立可重复、稳定的恒河猴急性大脑中动脉血栓梗死模型，利用自主开发的新型血管内低温诱导装置，在大脑中动脉开通即刻，将股动脉血冷却后经颈内动脉重新回输灌注缺血脑组织，实现长程快速选择性动脉内低温脑保护作用，减轻严重缺血再灌注损伤，同时利用各种分子生物学技术筛选可作为严重缺血再灌注损伤早期预警生物标志物的microRNA，探讨快速选择性动脉内低温对其干预的新机制。

建立可重复、稳定的恒河猴急性大脑中动脉血栓梗死模型，在此基础上，建立非人灵长类动物急性缺血性卒中神经、运动功能评分系统，保证恒河猴模型及脑梗死治疗评价的标准化；利用自主开发的新型血管内低温诱导装置，在大脑中动脉开通即刻，将股动脉血冷却后经颈内动脉重新回输灌注缺血脑组织，实现长程快速选择性动脉内低温脑保护作用，减轻严重缺血再灌注损伤，同时利用各种分子生物学技术筛选可作为严重缺血再灌注损伤早期预警生物标志物的microRNA，发现circulating mml-let-7g可能是急性缺血性卒中干预的新靶点，将进一步验证其是否为快速选择性动脉内低温的神经保护新机制。