Yu Zhonghai, Cai Min, Li Xianting, Zhang Jingsi, Wu Ting, Yang Feng, Zhu Wen, Xiang Yijin, Zhang Wen, Xiang Jun, Cai Dingfang
Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, China; Institute of Neurology, Academy of Integrative Medicine, Fudan University, Shanghai, China.
Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, China; Institute of Neurology, Academy of Integrative Medicine, Fudan University, Shanghai, China.
Brain Res. 2018 Apr 15;1685:9-18. doi: 10.1016/j.brainres.2018.01.036. Epub 2018 Feb 7.
Ischemic stroke brings a huge family and social burden. Although the reperfusion of ischemic cerebral tissue is the most important way to rescue ischemic stroke, ischemia-reperfusion (I/R) injury further results in brain damage and even lead to death. Recent studies demonstrated that Tongxinluo (TXL) helps to protect the brain against focal cerebral I/R injury in rats by reducing neuronal apoptosis, and the MEK1/2/ERK1/2/90 ribosomal S6 kinase (p90RSK) pathway may be involved in this protective effect. Therefore, our present research was designed to identify the potential mechanisms involved. Adult male Sprague-Dawley rats (n = 108) were randomly divided into 4 groups: sham, cerebral ischemia and reperfusion (I/R), I/R plus TXL (TXL), and TXL plus U0126, a highly selective inhibitor of MEK 1 and MEK 2 (TXL + U0126). Brain edema was measured by T2-weighted magnetic resonance imaging (MRI). Pathological destruction of the blood brain barrier (BBB) ultrastructure was assessed by transmission electron microscopy, and proteins involved in the MEK1/2/ERK1/2/p90RSK pathway were detected by immunofluorescence and Western blotting. Our results indicated that TXL significantly improved neurological function, reduced brain edema, ameliorated the destruction of the BBB ultrastructure and markedly reduced neuronal injury. However, these benefits were diminished when the MEK1/2/ERK1/2/p90RSK pathway was inhibited by U0126. We also found that TXL upregulated the expression levels of p-MEK1/2, p-ERK1/2, p-p90RSK and p-bad, which were all significantly reversed by U0126. Collectively, our data demonstrate that TXL provides neuroprotection against cerebral I/R injury and neuronal injury, and that these effects are mediated, in part, by activation of the MEK1/2/ERK1/2/p90RSK pathway.
缺血性中风给家庭和社会带来了巨大负担。尽管缺血脑组织的再灌注是挽救缺血性中风的最重要方法，但缺血再灌注（I/R）损伤会进一步导致脑损伤甚至死亡。最近的研究表明，通心络（TXL）通过减少神经元凋亡有助于保护大鼠大脑免受局灶性脑I/R损伤，并且丝裂原活化蛋白激酶激酶1/2/细胞外信号调节激酶1/2/90核糖体S6激酶（p90RSK）通路可能参与了这种保护作用。因此，我们目前的研究旨在确定其中潜在的机制。成年雄性Sprague-Dawley大鼠（n = 108）被随机分为4组：假手术组、脑缺血再灌注（I/R）组、I/R加TXL（TXL）组以及TXL加U0126组（U0126是MEK 1和MEK 2的高选择性抑制剂，即TXL + U0126组）。通过T2加权磁共振成像（MRI）测量脑水肿。通过透射电子显微镜评估血脑屏障（BBB）超微结构的病理破坏情况，并通过免疫荧光和蛋白质印迹法检测MEK1/2/ERK1/2/p90RSK通路相关蛋白。我们的结果表明，TXL显著改善神经功能，减轻脑水肿，改善BBB超微结构的破坏，并显著减少神经元损伤。然而，当MEK1/2/ERK1/2/p90RSK通路被U0126抑制时，这些益处就会减弱。我们还发现，TXL上调了p-MEK1/2、p-ERK1/2、p-p90RSK和p-bad的表达水平，而这些均被U0126显著逆转。总体而言，我们的数据表明，TXL对脑I/R损伤和神经元损伤具有神经保护作用，并且这些作用部分是由MEK1/2/ERK1/2/p90RSK通路的激活介导的。
