Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, China.
Cell Mol Neurobiol. 2012 Oct;32(7):1187-97. doi: 10.1007/s10571-012-9845-z. Epub 2012 May 3.
Recently, some studies suggested that inhibition of Rho-kinase (ROCK) prevented cerebral ischemia injury through inhibiting inflammatory reaction, increasing cerebral blood flow, modulating the neuronal actin cytoskeleton polymerization, and preventing tau hyperphosphorylation and p25/CDK5 increase. However, there is little information regarding the effects of ROCK inhibitor on the neuronal apoptosis in ischemic brain injury. In this study, we determined whether ROCK inhibitor, fasudil, inhibited ischemic neuronal apoptosis through phosphatase and tensin homolog deleted on chromosome10 (PTEN)/Akt/signal pathway in vivo. Adult male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion. Rats received ROCK inhibitor, fasudil (10 mg/kg), at 30 min before middle cerebral artery occlusion. The infarct area, neuronal apoptosis and caspase-3 activity was significantly decreased by fasudil with improvement of neurological deterioration. However, the beneficial effects of fasudil were attenuated by the co-application of LY294002 (PI3K inhibitor). Fasudil maintained postischemic Akt activity at relatively proper level and decreased the augmentation of PTEN and ROCK activity in the penumbra area. Furthermore, fasudil inhibited attenuation of GSK-β and Bad phosphorylation in the penumbra area. In conclusion, the findings provide another consideration that fasudil protects the brain against ischemia injury through decreasing neuronal apoptosis and reveals the link between the ROCK inhibition and the PTEN/Akt pathway.
最近的一些研究表明，通过抑制炎症反应、增加脑血流量、调节神经元肌动蛋白细胞骨架聚合、防止 tau 过度磷酸化和 p25/CDK5 增加，Rho 激酶（ROCK）抑制剂可预防脑缺血损伤。然而，关于 ROCK 抑制剂对缺血性脑损伤中神经元凋亡的影响的信息较少。在这项研究中，我们确定了 ROCK 抑制剂法舒地尔是否通过磷酸酶和张力蛋白同源物缺失的染色体 10（PTEN）/Akt/信号通路在体内抑制缺血性神经元凋亡。成年雄性 Sprague-Dawley 大鼠接受永久性大脑中动脉闭塞。大鼠在大脑中动脉闭塞前 30 分钟给予 ROCK 抑制剂法舒地尔（10mg/kg）。法舒地尔可显著减少梗塞面积、神经元凋亡和 caspase-3 活性，并改善神经功能恶化。然而，LY294002（PI3K 抑制剂）的共同应用减弱了法舒地尔的有益作用。法舒地尔维持了缺血后 Akt 活性在相对适当的水平，并降低了半影区中 PTEN 和 ROCK 活性的增加。此外，法舒地尔抑制了半影区中 GSK-β和 Bad 磷酸化的减弱。总之，这些发现提供了另一种考虑，即法舒地尔通过减少神经元凋亡来保护大脑免受缺血性损伤，并揭示了 ROCK 抑制与 PTEN/Akt 通路之间的联系。
