title: FSD-C10: A more promising novel ROCK inhibitor than Fasudil for treatment of CNS autoimmunity.
abstract: Rho-Rho kinase (Rho-ROCK) triggers an intracellular signalling cascade that regulates cell survival, death, adhesion, migration, neurite outgrowth and retraction and influences the generation and development of several neurological disorders. Although Fasudil, a ROCK inhibitor, effectively suppressed encephalomyelitis (EAE), certain side effects may limit its clinical use. A novel and efficient ROCK inhibitor, FSD-C10, has been explored. In the present study, we present chemical synthesis and structure of FSD-C10, as well as the relationship between compound concentration and ROCK inhibition. We compared the inhibitory efficiency of ROCKI and ROCK II, the cell cytotoxicity, neurite outgrowth and dendritic formation, neurotrophic factors and vasodilation between Fasudil and FSD-C10. The results demonstrated that FSD-C10, like Fasudil, induced neurite outgrowth of neurons and dendritic formation of BV-2 microglia and enhanced the production of neurotrophic factor brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3). However, the cell cytotoxicity and vasodilation of FSD-C10 were relatively small compared with Fasudil. Although Fasudil inhibited both ROCK I and ROCK II, FSD-C10 more selectively suppressed ROCK II, but not ROCK I, which may be related to vasodilation insensitivity and animal mortality. Thus, FSD-C10 may be a safer and more promising novel ROCK inhibitor than Fasudil for the treatment of several neurological disorders.
authors.affiliation: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong 037009, China.
authors.forename: Yan-Le
authors.initials: YL
authors.lastname: Xin
authors.affiliation: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong 037009, China.
authors.forename: Jie-Zhong
authors.initials: JZ
authors.lastname: Yu
authors.affiliation: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong 037009, China.
authors.forename: Xin-Wang
authors.initials: XW
authors.lastname: Yang
authors.affiliation: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong 037009, China.
authors.forename: Chun-Yun
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong 037009, China.
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Li
authors.affiliation: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong 037009, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Feng
authors.affiliation: "2011" Collaborative Innovation Center/Research Center of Neurobiology, Shanxi University of Traditional Chinese Medicine, Taiyuan 030619, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chai
authors.affiliation: "2011" Collaborative Innovation Center/Research Center of Neurobiology, Shanxi University of Traditional Chinese Medicine, Taiyuan 030619, China.
authors.forename: Wan-Fang
authors.initials: WF
authors.lastname: Yang
authors.affiliation: "2011" Collaborative Innovation Center/Research Center of Neurobiology, Shanxi University of Traditional Chinese Medicine, Taiyuan 030619, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: "2011" Collaborative Innovation Center/Research Center of Neurobiology, Shanxi University of Traditional Chinese Medicine, Taiyuan 030619, China.
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
authors.forename: Guang-Xian
authors.initials: GX
authors.lastname: Zhang
authors.affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200040, China bgxiao@shmu.edu.cn macungen2001@163.com.
authors.forename: Bao-Guo
authors.initials: BG
authors.lastname: Xiao
authors.affiliation: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong 037009, China "2011" Collaborative Innovation Center/Research Center of Neurobiology, Shanxi University of Traditional Chinese Medicine, Taiyuan 030619, China bgxiao@shmu.edu.cn macungen2001@163.com.
authors.forename: Cun-Gen
authors.initials: CG
authors.lastname: Ma
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D015551:Autoimmunity / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004679:Encephalomyelitis / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D014664:Vasodilation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007546:Isoquinolines; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil
keywords: FSD-C10; Fasudil; Rho kinase; Rho kinase inhibitor