Blocking of PI3-kinase beta protects against cerebral ischemia/reperfusion injury by reducing platelet activation and downstream microvascular thrombosis in rats.
Blocking of PI3-kinase beta protects against cerebral ischemia/reperfusion injury by reducing platelet activation and downstream microvascular thrombosis in rats.
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DOI：
10.1038/s41598-023-29235-2
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发表时间：
2023-02-04
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
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磷酸肌醇 3-激酶 β (PI3Kβ) 在血小板活化和血栓形成中发挥重要作用，但其在中风病理学中的作用仍不清楚。在这项研究中，我们研究了抑制 PI3Kβ 是否可以通过阻止循环血小板活化和下游微血管血栓形成来预防脑缺血/再灌注 (I/R) 损伤。我们使用短暂性大脑中动脉闭塞（tMCAO）的大鼠管腔内细丝模型，因为在 tMCAO 和血管内血栓切除术中，脑血流快速恢复到缺血区域，为该模型提供了临床相关性。结果表明，TGX221（一种选择性 PI3Kβ 抑制剂）在再灌注开始前立即进行治疗，可剂量依赖性地减少梗塞体积并改善神经功能。保护作用与阻断血小板活化和血栓反应有关，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可能是治疗脑缺血再灌注损伤引起的下游微血管血栓形成的一个有前景的靶点，并为改善急性缺血性卒中的再灌注治疗提供一种新的辅助治疗。
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.
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DOI：
10.2147/dddt.s56071
发表时间：
2015
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Fluri F;Schuhmann MK;Kleinschnitz C
通讯作者：
Kleinschnitz C
影响因子：
20.3
作者：
Laurent, Pierre-Alexandre;Severin, Sonia;Gratacap, Marie-Pierre
通讯作者：
Gratacap, Marie-Pierre
影响因子：
20.3
作者：
Canobbio, Ilaria;Stefanini, Lucia;Torti, Mauro
通讯作者：
Torti, Mauro
影响因子：
20.3
作者：
Martin, Valerie;Guillermet-Guibert, Julie;Gratacap, Marie-Pierre
通讯作者：
Gratacap, Marie-Pierre
影响因子：
82.9
作者：
Jackson, SP;Schoenwaelder, SM;Salem, HH
通讯作者：
Salem, HH