title: The inhibition of Rho kinase blocks cell migration and accumulation possibly by challenging inflammatory cytokines and chemokines on astrocytes.
abstract: Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by the immune-mediated demyelination and neurodegeneration of the CNS. Our previous studies showed that Rho kinase inhibitor Fasudil can delay onset, and ameliorate severity of EAE, accompanied by the improvement in myelination and the inhibition of inflammatory responses in the CNS. In this study, we found that Fasudil inhibited the migration of T cells indirectly by affecting the production of inflammatory factors and the expression of chemokines in astrocytes functions, indicating that Fasudil treatment reduced inflammatory cytokines such as TNF-α and IL-6, reactive oxygen species (NO) and chemokines like MIP-3α (CCL-20), RANTES (CCL5), MIP-1α (CCL-3) and MCP-1 (CCL2) in vitro, and blocked the chemotaxis of reactive mononuclear cells in EAE mice. Further studies found that Fasudil treatment reduced the infiltration and accumulation of pathogenic T cells into the CNS. Astrocytes expressing GFAP and CCL-20 were inhibited in Fasudil-treated EAE compared with control mice. These results demonstrate that Fasudil alleviates the pathogenesis of EAE possibly by blocking astrocyte-derived chemokine-mediated migration of inflammatory macrophages and pathogenic T cells, and might be used to treat MS.
authors: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China.
authors: Min-Fang
authors: MF
authors: Guo
authors: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China.
authors: Jian
authors: J
authors: Meng
authors: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China.
authors: Yan-Hua
authors: YH
authors: Li
authors: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China.
authors: Jie-Zhong
authors: JZ
authors: Yu
authors: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China.
authors: Chun-Yun
authors: CY
authors: Liu
authors: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China.
authors: Ling
authors: L
authors: Feng
authors: Department of Encephalopathy and National Major Clinical Department of Ministry of Health, Third Hospital, Department of Neurology, Shanxi University of Traditional Chinese Medicine, Taiyuan, China.
authors: Wan-Fang
authors: WF
authors: Yang
authors: Department of Encephalopathy and National Major Clinical Department of Ministry of Health, Third Hospital, Department of Neurology, Shanxi University of Traditional Chinese Medicine, Taiyuan, China.
authors: Jun-Lian
authors: JL
authors: Li
authors: Department of Encephalopathy and National Major Clinical Department of Ministry of Health, Third Hospital, Department of Neurology, Shanxi University of Traditional Chinese Medicine, Taiyuan, China.
authors: Qian-Jin
authors: QJ
authors: Feng
authors: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. Electronic address: bgxiao@shmu.edu.cn.
authors: Bao-Guo
authors: BG
authors: Xiao
authors: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China; Department of Encephalopathy and National Major Clinical Department of Ministry of Health, Third Hospital, Department of Neurology, Shanxi University of Traditional Chinese Medicine, Taiyuan, China. Electronic address: macungen2001@163.com.
authors: Cun-Gen
authors: CG
authors: Ma
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D009573:Nitrites / Q000097:blood; D010446:Peptide Fragments / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D063308:Myelin-Oligodendrocyte Glycoprotein; D009573:Nitrites; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C445081:myelin oligodendrocyte glycoprotein (35-55); D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil
keywords: Astrocytes; Chemokines; Cytokines; Experimental autoimmune encephalomyelitis; Fasudil; Rho kinase inhibitor