title: The therapeutic potential of Rho kinase inhibitor fasudil derivative FaD-1 in experimental autoimmune encephalomyelitis.
abstract: Although therapeutic potential of fasudil in EAE is promising, action mechanism and clinical limitations are still not fully understood and resolved. In this study, we observed the therapeutic potential of a novel Rho kinase (ROCK) inhibitor FaD-1, a fasudil derivative, and explored possible mechanism in MOG35-55-induced EAE. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG35-55) immunization. The pathology of spinal cord was measured by immunohistochemistry and neurological impairment was evaluated using clinical scores. FaD-1, as a novel ROCK inhibitor, inhibited the expression of ROCK II that is mainly expressed in the CNS. We show here that FaD-1 ameliorates the neurological defects and the severity of MOG-induced EAE in mice, accompanied by the protection of demyelination and the inhibition of neuroinflammation in spinal cord of EAE. In addition, FaD-1 dampened TLR2 and TLR4 signaling as well as Th1 (IFN-γ) and Th17 (IL-17) responses in spinal cord of EAE. FaD-1 also prevented the expression of iNOS and production of inflammatory cytokine IL-1β, IL-6, and TNF-α which are specific markers for M1 inflammatory microglia/macrophages. This study highlights the therapeutic potential of FaD-1 as a ROCK inhibitor for the treatment of human autoimmune diseases with both inflammatory and autoimmune components.
authors.affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: Yong-Fei
authors.initials: YF
authors.lastname: Zhao
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhi-Bin
authors.initials: ZB
authors.lastname: Ding
authors.forename: Xing-Wang
authors.initials: XW
authors.lastname: Yang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Jie-Zhong
authors.initials: JZ
authors.lastname: Yu
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Li
authors.forename: Chun-Yun
authors.initials: CY
authors.lastname: Liu
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Hong-Zhen
authors.initials: HZ
authors.lastname: Zhang
authors.forename: Cun-Gen
authors.initials: CG
authors.lastname: Ma
authors.forename: Bao-Guo
authors.initials: BG
authors.lastname: Xiao
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D007378:Interleukins; D047428:Protein Kinase Inhibitors; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D052247:Nitric Oxide Synthase Type II; D054460:rho-Associated Kinases; C049347:fasudil