Akt Specific Activator SC79 Protects against Early Brain Injury following Subarachnoid Hemorrhage.
Akt Specific Activator SC79 Protects against Early Brain Injury following Subarachnoid Hemorrhage.
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Akt 特异性激活剂 SC79 可预防蛛网膜下腔出血后的早期脑损伤。
DOI：
10.1021/acschemneuro.5b00306
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Hang Chun-Hua
中科院分区：
文献类型：
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作者：
Zhang Ding-Ding;Zhang Hua-Sheng;Hao Shuang-Ying;Yan Hui-Ying;Zhang Zi-Huan;Hu Yang-Chun;Zhuang Zong;Li Wei;Zhou Meng-Liang;Li Kuan-Yu;Hang Chun-Hua
越来越多的证据表明，Akt可作为治疗蛛网膜下腔出血(SAH)后早期脑损伤的治疗靶点。本研究旨在评价Akt特异性激活剂SC79对实验性蛛网膜下腔出血大鼠的神经保护作用。将30 0μL血注入视交叉前池诱发蛛网膜下腔出血。脑室注射SC79(SAH后30min)可诱导p-Akt(Ser473)的表达，并呈剂量依赖关系。单次脑室注射SC79(100μg/只)可显著增加Bcl2和p-GSK-3β的表达，降低Bax、胞浆细胞色素和caspase-3的蛋白表达，提示SC79具有抗细胞凋亡作用。结果表明，SAH后24 h细胞凋亡数明显减少。此外，SC79治疗减轻了SAH诱导的氧化应激，恢复了线粒体的形态，并改善了神经功能障碍。值得注意的是，SC79的治疗效果良好，治疗窗至少是SAH后4h的脑室注射和30min的SAH后的腹腔注射。综上所述，SC79可能通过抗氧化和抗细胞凋亡的双重作用发挥其神经保护作用。这些数据为考虑将SC79作为治疗SAH的新型治疗剂提供了基础平台。
A growing body of evidence demonstrates that Akt may serve as a therapeutic target for treatment of early brain injury following subarachnoid hemorrhage (SAH). The purpose of the current study was to evaluate the neuroprotective effect of Akt specific activator SC79 in an experimental rat model of SAH. SAH was induced by injecting 300 μL of blood into the prechiasmatic cistern. Intracerebroventricular (ICV) injection of SC79 (30 min post-SAH) induced the p-Akt (Ser473) expression in a dose-dependent manner. A single ICV dose treatment of SC79 (100 μg/rat) significantly increased the expression of Bcl-2 and p-GSK-3β (Ser9), decreased the protein levels of Bax, cytoplasm cytochromec, and cleaved caspase-3, indicating the antiapoptotic effect of SC79. As a result, the number of apoptotic cells was reduced 24 h post SAH. Moreover, SC79 treatment alleviated SAH-induced oxidative stress, restored mitochondrial morphology, and improved neurological deficits. Strikingly, treatment of SC79 provided a beneficial outcome against neurologic deficit with a therapeutic window of at least 4 h post SAH by ICV injection and 30 min post SAH by intraperitoneal injection. Collectively, SC79 exerts its neuroprotective effect likely through the dual activities of antioxidation and antiapoptosis. These data provide a basic platform to consider SC79 as a novel therapeutic agent for treatment of SAH.