Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Shanghai, 200080, PR China; Department of Clinical Pharmacy, Henan Provincial People's Hospital, Zhengzhou 450000, PR China; Department of Clinical Pharmacy, Fuwai Central China Cardiovascular Hospital, Zhengzhou 450000, PR China.
Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Shanghai, 200080, PR China.
J Pharmacol Sci. 2018 Oct;138(2):107-115. doi: 10.1016/j.jphs.2018.08.012. Epub 2018 Sep 22.
The current study investigated whether a Rho-kinase inhibitor alleviated impairments in a rat model of chronic cerebral ischemia and examined the specific pathological mechanisms by which Rho-kinase impacts neuronal damage and cognitive dysfunction. Adult Sprague-Dawley rats underwent permanent bilateral carotid artery occlusion (BCAO) to establish our chronic cerebral ischemia model. Chronic Y27632 administration reversed the abnormal behaviors of BCAO-treated rats in the Morris water maze. We performed Western blot analyses of the apoptosis-related proteins Bcl-2 and Bax to examine the potential mechanism underlying the beneficial effects of Y27632 on cerebral ischemia and showed for the first time that Y27632 reversed the decrease in the Bcl-2/Bax ratio in BCAO model rats. Y27632 restored the depression of NR2A- and NR2B-containing N-methyl-d-aspartate receptors (NMDARs) in the cerebral cortex of BCAO model rats. We also investigated these effects on middle cerebral artery occlusion (MCAO) model rats and observed some differences between the two models. In summary, our data provide evidence supporting the hypothesis that Rho-kinase inhibitors exert neuroprotective effects on cerebral ischemia. The Bcl-2/Bax-NMDAR signaling pathway in the cerebral cortex may be responsible for the protective effects of the Rho-kinase inhibitor, and this pathway may represent a pharmacological target for curative clinical strategies.
本研究旨在探讨 Rho 激酶抑制剂是否能改善慢性大脑局部缺血模型大鼠的损伤，并探讨 Rho 激酶影响神经元损伤和认知功能障碍的具体病理机制。成年 Sprague-Dawley 大鼠接受永久性双侧颈总动脉闭塞（BCAO）以建立我们的慢性大脑局部缺血模型。慢性 Y27632 给药逆转了 BCAO 处理大鼠在 Morris 水迷宫中的异常行为。我们进行了与凋亡相关的蛋白 Bcl-2 和 Bax 的 Western blot 分析，以研究 Y27632 对大脑局部缺血有益作用的潜在机制，并首次表明 Y27632 逆转了 BCAO 模型大鼠中 Bcl-2/Bax 比值的降低。Y27632 恢复了 BCAO 模型大鼠大脑皮质中包含 NR2A 和 NR2B 的 N-甲基-D-天冬氨酸受体（NMDAR）的抑制。我们还研究了 Y27632 对大脑中动脉闭塞（MCAO）模型大鼠的这些影响，并观察到两种模型之间的一些差异。总之，我们的数据提供了 Rho 激酶抑制剂对大脑局部缺血具有神经保护作用的证据。大脑皮质中的 Bcl-2/Bax-NMDAR 信号通路可能是 Rho 激酶抑制剂的保护作用的原因，并且该通路可能代表了治疗策略的药理学靶点。
