Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
Mol Cell Neurosci. 2010 Feb;43(2):201-8. doi: 10.1016/j.mcn.2009.11.001. Epub 2009 Nov 11.
Rho kinase (ROCK) is important in fundamental processes of cell proliferation and survival. Blockade of ROCK promotes stem cell survival in vitro and axonal regeneration in vivo, exhibiting therapeutic potential such as spinal cord injuries and stroke. Here, we used the model of hypoxia/reoxygenation (H/R) injury to explore the possibility whether Fasudil, a ROCK inhibitor in clinical application for subarachnoid hemorrhage and stroke, mobilizes adult neural stem cells in vivo. Most interestingly, Fasudil triggers neurogenesis especially in the subventricular zone after H/R. The increase of Brdu+ cholinergic neurons was observed in striatum and forebrain cortex of Fasudil-treated mice after 30 days. Further observation demonstrates that both levels of granulocyte colony-stimulating factor (G-CSF) and astrocytes expressing G-CSF were elevated in mice treated with Fasudil, as compared to mice injected with saline. In vitro H/R model of cultured astrocytes, Fasudil promoted astrocytes to produce G-CSF in a dose-dependent manner. In addition, antibody neutralization and receptor blocking of the G-CSF pathway clearly demonstrate that Fasudil-induced neurogenesis was mediated partially through astrocyte-derived G-CSF. Our results indicate that Fasudil might represent a promising therapeutic perspective by mobilizating endogenous adult neural stem cells in the CNS.
Rho 激酶（ROCK）在细胞增殖和存活的基本过程中很重要。ROCK 阻断剂促进体外干细胞存活和体内轴突再生，表现出治疗潜力，如脊髓损伤和中风。在这里，我们使用缺氧/复氧（H/R）损伤模型来探讨 Fasudil（一种临床应用于蛛网膜下腔出血和中风的 ROCK 抑制剂）是否有可能在体内动员成年神经干细胞。最有趣的是，Fasudil 在 H/R 后特别是在侧脑室下区触发神经发生。在 Fasudil 处理的小鼠中，30 天后观察到纹状体和前脑皮质中 Brdu+胆碱能神经元增加。进一步观察表明，与注射生理盐水的小鼠相比，用 Fasudil 处理的小鼠中粒细胞集落刺激因子（G-CSF）的水平和表达 G-CSF 的星形胶质细胞都升高。在体外培养的星形胶质细胞 H/R 模型中，Fasudil 以剂量依赖的方式促进星形胶质细胞产生 G-CSF。此外，G-CSF 通路的抗体中和和受体阻断清楚地表明，Fasudil 诱导的神经发生部分是通过星形胶质细胞衍生的 G-CSF 介导的。我们的结果表明，Fasudil 通过动员中枢神经系统中的内源性成年神经干细胞，可能代表一种有前途的治疗前景。
