The therapeutic effects of Rho-ROCK inhibitors on CNS disorders.
The therapeutic effects of Rho-ROCK inhibitors on CNS disorders.
复制标题
Rho-Rock抑制剂对CNS疾病的治疗作用。
DOI：
10.2147/tcrm.s2907
复制
发表时间：
2008-06
影响因子：
2.8
通讯作者：
Yamashita T
中科院分区：
文献类型：
--
作者：
Kubo T;Yamaguchi A;Iwata N;Yamashita T
Rho-Kinase(ROCK)是一种丝氨酸/苏氨酸激酶，是小分子GTP酶Rho的主要下游效应子之一。Rho-Rock通路参与神经元功能的许多方面，包括轴突生长和回缩。最近发现，Rho-Rock通路与脊髓损伤、中风和阿尔茨海默病(AD)等中枢神经系统疾病的发病机制密切相关，因而成为开发治疗中枢神经系统(CNS)疾病药物的一个有吸引力的靶点。在成人中枢神经系统中，由于存在髓鞘相关的轴突生长抑制物，如髓鞘相关糖蛋白(MAG)、Nogo、少突胶质细胞髓磷脂糖蛋白(OMGp)和新近发现的排斥性引导分子(RGM)，损伤的轴突再生不良。在体外，这些抑制剂的作用可被Rho-Rock通路阻断而逆转，而抑制该通路可促进体内受损中枢神经系统的轴突再生和功能恢复。此外，Rho-Rock抑制剂的治疗效果已在中风的动物模型中得到证实。本文综述了Rho-ROCK通路在脊髓损伤、卒中、AD等中枢神经系统疾病中的作用，并讨论了Rho-ROCK抑制剂在人类中枢神经系统疾病治疗中的潜力。
Rho-kinase (ROCK) is a serine/threonine kinase and one of the major downstream effectors of the small GTPase Rho. The Rho-ROCK pathway is involved in many aspects of neuronal functions including neurite outgrowth and retraction. The Rho-ROCK pathway becomes an attractive target for the development of drugs for treating central nervous system (CNS) disorders, since it has been recently revealed that this pathway is closely related to the pathogenesis of several CNS disorders such as spinal cord injuries, stroke, and Alzheimer’s disease (AD). In the adult CNS, injured axons regenerate poorly due to the presence of myelin-associated axonal growth inhibitors such as myelin-associated glycoprotein (MAG), Nogo, oligodendrocyte-myelin glycoprotein (OMgp), and the recently identified repulsive guidance molecule (RGM). The effects of these inhibitors are reversed by blockade of the Rho-ROCK pathway in vitro, and the inhibition of this pathway promotes axonal regeneration and functional recovery in the injured CNS in vivo. In addition, the therapeutic effects of the Rho-ROCK inhibitors have been demonstrated in animal models of stroke. In this review, we summarize the involvement of the Rho-ROCK pathway in CNS disorders such as spinal cord injuries, stroke, and AD and also discuss the potential of Rho-ROCK inhibitors in the treatment of human CNS disorders.