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Abstract：
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.
摘要：
背景溶栓和血管内血栓切除术是缺血性卒中的主要治疗方法。然而,由于时间窗口有限和不良反应的发生，只有少数患者可以真正受益于再通。动脉内注射rtPA(重组组织型纤溶酶原激活剂)可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可以提供针对中风的神经保护。提高缺血性脑卒中的再通率，减少微小血栓形成等不良反应，脑水肿,出血，我们首次描述了通过动脉内低温rtPA进行低温和溶栓的联合方法。方法和结果我们初步建立了成年大鼠大脑中动脉阻塞的低温rtPA的最佳方案。随后，我们通过探测降低脑组织温度来探索介导低温rtPA的作用机制，减弱血脑屏障损伤，和炎症的隔离以及非靶向代谢组学。低温rtPA改善神经评分，减少梗死体积，同时限制了大脑中动脉阻塞大鼠的出血性转化。这些低温rtPA的治疗结果伴随着大脑温度的降低，葡萄糖代谢，和血脑屏障损伤。在低温rtPA治疗的大脑中动脉闭塞大鼠中出现了独特的代谢组学特征，其特征是能量代谢和炎症的标志物下调。结论低温rtPA的创新使用增强了它们的联合，而不是独立的，神经保护作用,同时减少缺血性中风的出血性转化。
