Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA, 17033, USA.
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong, 226000, China.
Sci Rep. 2023 Feb 4;13(1):2030. doi: 10.1038/s41598-023-29235-2.
Phosphoinositide 3-kinase beta (PI3Kβ) plays an important role in platelet activation and thrombosis, but its role in stroke pathology remains unknown. In this study, we investigated whether inhibition of PI3Kβ protects against cerebral ischemia/reperfusion (I/R) injury by preventing circulating platelet activation and downstream microvascular thrombosis. We used a rat intraluminal filament model of transient middle cerebral artery occlusion (tMCAO) because the rapid restoration of cerebral blood flow to the ischemic area in both tMCAO and endovascular thrombectomy provides clinical relevance for this model. The results showed that TGX221, a selective PI3Kβ inhibitor, treatment immediately before the onset of reperfusion dose-dependently reduced infarct volume and improved neurological function. The protective effects were associated with blocking platelet activation and thrombotic response, thereby reducing downstream microvascular thrombosis, and maintaining reperfusion efficiency. These results suggest that PI3Kβ might be a promising target for treating downstream microvascular thrombosis induced by cerebral I/R injury and offer a novel adjunctive treatment to improve reperfusion therapy for acute ischemic stroke.
磷酸肌醇 3-激酶β（PI3Kβ）在血小板激活和血栓形成中发挥重要作用，但它在中风发病机制中的作用尚不清楚。在这项研究中，我们通过防止循环血小板激活和下游微血管血栓形成，研究了抑制 PI3Kβ 是否可以通过防止循环血小板激活和下游微血管血栓形成来预防脑缺血/再灌注（I/R）损伤。我们使用大鼠大脑中动脉闭塞（tMCAO）管腔内纤维蛋白模型，因为 tMCAO 和血管内血栓切除术都迅速恢复缺血区的脑血流，这使得该模型具有临床相关性。结果表明，选择性 PI3Kβ 抑制剂 TGX221 在再灌注开始前立即给药可剂量依赖性地减少梗死体积并改善神经功能。保护作用与阻断血小板激活和血栓形成反应有关，从而减少下游微血管血栓形成，并维持再灌注效率。这些结果表明，PI3Kβ 可能是治疗脑 I/R 损伤引起的下游微血管血栓形成的有前途的靶点，并提供了一种新的辅助治疗方法，以改善急性缺血性中风的再灌注治疗。
