Department of Radiology and Nuclear Medicine, Institute of Cerebrovascular Diseases Research Xuanwu Hospital of Capital Medical University Beijing China.
Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases Beijing China.
J Am Heart Assoc. 2023 Sep 5;12(17):e029817. doi: 10.1161/JAHA.123.029817. Epub 2023 Sep 1.
Background Thrombolysis and endovascular thrombectomy are the primary treatment for ischemic stroke. However, due to the limited time window and the occurrence of adverse effects, only a small number of patients can genuinely benefit from recanalization. Intraarterial injection of rtPA (recombinant tissue plasminogen activator) based on arterial thrombectomy could improve the prognosis of patients with acute ischemic stroke, but it could not reduce the incidence of recanalization-related adverse effects. Recently, selective brain hypothermia has been shown to offer neuroprotection against stroke. To enhance the recanalization rate of ischemic stroke and reduce the adverse effects such as tiny thrombosis, brain edema, and hemorrhage, we described for the first time a combined approach of hypothermia and thrombolysis via intraarterial hypothermic rtPA. Methods and Results We initially established the optimal regimen of hypothermic rtPA in adult rats subjected to middle cerebral artery occlusion. Subsequently, we explored the mechanism of action mediating hypothermic rtPA by probing reduction of brain tissue temperature, attenuation of blood-brain barrier damage, and sequestration of inflammation coupled with untargeted metabolomics. Hypothermic rtPA improved neurological scores and reduced infarct volume, while limiting hemorrhagic transformation in middle cerebral artery occlusion rats. These therapeutic outcomes of hypothermic rtPA were accompanied by reduced brain temperature, glucose metabolism, and blood-brain barrier damage. A unique metabolomic profile emerged in hypothermic rtPA-treated middle cerebral artery occlusion rats characterized by downregulated markers for energy metabolism and inflammation. Conclusions The innovative use of hypothermic rtPA enhances their combined, as opposed to stand-alone, neuroprotective effects, while reducing hemorrhagic transformation in ischemic stroke.
溶栓和血管内血栓切除术是缺血性脑卒中的主要治疗方法。然而，由于时间窗有限和不良反应的发生，只有少数患者能够真正受益于再通。基于动脉血栓切除术的动脉内注射 rtPA（重组组织型纤溶酶原激活剂）可以改善急性缺血性脑卒中患者的预后，但不能降低再通相关不良反应的发生率。最近，选择性脑低温已被证明对脑卒中具有神经保护作用。为了提高缺血性脑卒中的再通率，减少微小血栓形成、脑水肿和出血等不良反应，我们首次描述了通过动脉内低温 rtPA 联合低温治疗的方法。
我们首先在成年大鼠大脑中动脉闭塞模型中建立了低温 rtPA 的最佳方案。随后，我们通过探测脑组织温度降低、血脑屏障损伤减轻以及炎症隔离与非靶向代谢组学相结合，探讨了低温 rtPA 的作用机制。低温 rtPA 可改善神经功能评分，减少梗死体积，同时限制大脑中动脉闭塞大鼠的出血性转化。低温 rtPA 的这些治疗效果伴随着脑温、葡萄糖代谢和血脑屏障损伤的降低。低温 rtPA 治疗大脑中动脉闭塞大鼠的独特代谢组学特征表现为能量代谢和炎症标志物下调。
低温 rtPA 的创新应用增强了它们的联合而非单独的神经保护作用，同时减少了缺血性脑卒中的出血性转化。
