title: Protective effect of a novel Rho kinase inhibitor WAR-5 in experimental autoimmune encephalomyelitis by modulating inflammatory response and neurotrophic factors.
abstract: The Rho-kinase (ROCK) inhibitor Fasudil has proven beneficial in experimental autoimmune encephalomyelitis (EAE). Given the small safety window of Fasudil, we are looking for novel ROCK inhibitors, which have similar or stronger effect on EAE with greater safety. In this study, we report that WAR-5, a Y-27632 derivative, alleviates the clinical symptoms, attenuates myelin damage and reduces CNS inflammatory responses in EAE C57BL/6 mice at an extent similar to Fasudil, while exhibits less vasodilator and adverse reaction in vivo. WAR-5 inhibits ROCK activity, and selectively suppresses the expression of ROCK II in spleen, brain and spinal cord of EAE mice, especially in spinal cord, accompanied by decreased expression of Nogo. WAR-5 also regulates the imbalance of Th1/Th17 T cells and regulatory T cells, inhibits inflammatory microenvironment induced with NF-κB-IL-1β pathway. Importantly, WAR-5 converts M1 toward M2 microglia/macrophages that are positively correlated with BDNF and NT-3 production. Taken together, WAR-5 exhibits therapeutic potential in EAE by more selectively inhibits ROCK II, with a greater safety than Fasudil, and is worthy of further clinical study to clarify its clinical value.
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: 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: 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: 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: Jian-chun
authors.initials: JC
authors.lastname: Liu
authors.affiliation: "2011" Collaborative Innovation Center/Research Center of Neurobiology, Shanxi University of Traditional Chinese Medicine, Taiyuan 030619, China.
authors.forename: Hong-zhen
authors.initials: HZ
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Guang-Xian
authors.initials: GX
authors.lastname: Zhang
authors.affiliation: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong 037009, China; Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200025, China. Electronic address: bgxiao@shmu.edu.cn.
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. Electronic address: 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; D000577:Amides / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D000631:Aminopyridines; D016207:Cytokines; D009414:Nerve Growth Factors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C000604476:WAR-5 compound; C108830:Y 27632; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil
keywords: Experimental autoimmune encephalomyelitis; NF–κB signaling; Rho-kinase; Y-27632 derivatives