Cold Case of Thrombolysis: Cold Recombinant Tissue Plasminogen Activator Confers Enhanced Neuroprotection in Experimental Stroke.
Cold Case of Thrombolysis: Cold Recombinant Tissue Plasminogen Activator Confers Enhanced Neuroprotection in Experimental Stroke.
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DOI：
10.1161/jaha.123.029817
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发表时间：
2023-09-05
影响因子：
5.4
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中科院分区：
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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，由于时间窗有限和不良反应的发生，只有少数患者能够从再通中真正受益。在动脉血栓切除术基础上动脉内注射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神经保护，防止中风。为了提高缺血性脑卒中的再通率，减少微血栓形成、脑水肿和出血等不良反应，我们首次描述了动脉内低温rtPA联合低温溶栓的方法。我们初步建立了成年大鼠大脑中动脉闭塞的低温rtPA的最佳方案。随后，我们通过探测脑组织温度的降低、血脑屏障损伤的衰减和炎症的隔离以及非靶向代谢组学来探索介导低温rtPA的作用机制。低温rtPA改善了大脑中动脉闭塞大鼠的神经功能评分，减少了梗死体积，同时限制了出血转化。低温rtPA的这些治疗结果伴随着脑温度降低、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，其特征为能量代谢和炎症标志物下调。低温rtPA的创新使用增强了它们的组合，而不是单独的神经保护作用，同时减少了缺血性卒中的出血性转化。
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. 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. The innovative use of hypothermic rtPA enhances their combined, as opposed to stand‐alone, neuroprotective effects, while reducing hemorrhagic transformation in ischemic stroke.