Therapeutic potential of experimental autoimmune encephalomyelitis by Fasudil, a Rho kinase inhibitor.
The migration of aberrant inflammatory cells into the central nervous system plays an important role in the pathogenesis of demyelinating diseases potentially through the Rho/Rho-kinase (Rock) pathway, but direct evidence from human and animal models remains inadequate. Here we further confirm that Fasudil, a selective Rock inhibitor, has therapeutic potential in a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). The results show that Fasudil decreased the development of EAE in C57BL/6 mice. Immunohistochemistry disclosed that expression of Rock-II in the perivascular spaces and vascular endothelial cells of spleens, spinal cords, and brains was elevated in EAE and was inhibited in the Fasudil-treated group. T-cell proliferation specific to MOG(35-55) was markedly reduced, together with a significant down-regulation of interleukin (IL)-17, IL-6, and MCP-1. In contrast, secretion of IL-4 was increased, and IL-10 was slightly elevated. There were no differences in the percentages of CD4(+)CD25(+), CD8(+)CD28(-), and CD8(+)CD122(+) in mononuclear cells. Histological staining disclosed a marked decrease of inflammatory cells in spinal cord and brain of Fasudil-treated mice. These results, together with previous studies showing the inhibitory effect of Fasudil on T-cell migration, might expand its clinical application as a new therapy for multiple sclerosis by decreasing cell migration and regulating immune balance.
Yu
Jie-Zhong
JZ
Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
Ding
Jing
J
Ma
Cun-Gen
CG
Sun
Chang-Hai
CH
Sun
Yi-Fu
YF
Lu
Chuan-Zhen
CZ
Xiao
Bao-Guo
BG
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006023:Glycoproteins; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology; D013154:Spleen / Q000166:cytology; D054460:rho-Associated Kinases / Q000378:metabolism*
D016207:Cytokines; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; C445081:myelin oligodendrocyte glycoprotein (35-55); D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases; C049347:fasudil