The Therapeutic Potential of Rho Kinase Inhibitor Fasudil Derivative FaD-1 in Experimental Autoimmune Encephalomyelitis
详细信息 查看全文
- 作者：Yong-Fei Zhao ; Xiang Zhang ; Zhi-Bin Ding…
- 关键词：Rho kinase inhibitor ; Fasudil derivative ; FaD ; 1 ; Immunomodulation ; Experimental autoimmune encephalomyelitis
- 刊名：Journal of Molecular Neuroscience
- 出版年：2015
- 出版时间：March 2015
- 年：2015
- 卷：55
- 期：3
- 页码：725-732
- 全文大小：828 KB
- 参考文献：1. Benveniste EN (1997) Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med 75:165-73 CrossRef
2. Caplan S, Zeliger S, Wang L, Baniyash M (1995) Cell-surface-expressed T-cell antigen-receptor zeta chain is associated with the cytoskeleton. Proc Natl Acad Sci U S A 92:4768-772 CrossRef
3. Chan CC (2008) Inflammation: beneficial or detrimental after spinal cord injury? Recent Pat CNS Drug Discov 13:189-99 CrossRef
4. Dou W, Zhang J, Sun A, Zhang E, Ding L, Mukherjee S, Wei X, Chou G, Wang ZT, Mani S (2013) Protective effect of naringenin against experimental colitis via suppression of Toll-like receptor 4/NF-κB signalling. Br J Nutr 110:599-08 CrossRef
5. Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH (2010) T cells in MS and experimental autoimmune encephalomyelitis. Clin Exp Immunol 162:1-1 CrossRef
6. Fujimoto S, Negishi M, Katoh H (2011) RhoG promotes neural progenitor cell proliferation in mouse cerebral cortex. Mol Biol Cell 20:4941-950 CrossRef
7. Gensel JC, Nakamura S, Guan Z, van Rooijen N, Ankeny DP, Popovich PG (2009) Macrophages promote axon regeneration with concurrent neurotoxicity. J Neurosci 13:3956-968 CrossRef
8. Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279:509-14 CrossRef
9. Hauser SL, Chan JR, Oksenberg JR (2013) Multiple sclerosis: prospects and promise. Ann Neurol 74:317-27
10. Hirose M, Ishizaki T, Watanabe N, Uehata M, Kranenburg O, Moolenaar WH, Matsumura F, Maekawa M, Bito H, Narumiya S (1998) Molecular dissection of the Rho-associated protein kinase (p160ROCK)-regulated neurite remodeling in neuroblastoma N1E-115 cells. J Cell Biol 141:1625-636 CrossRef
11. Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, Ahlfors H, Wilhelm C, Tolaini M, Menzel U, Garefalaki A, Potocnik AJ, Stockinger B (2011) Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 12:255-63 CrossRef
12. Hou SW, Liu CY, Li YH, Yu JZ, Feng L, Liu YT, Guo MF, Xie Y, Meng J, Zhang HF, Xiao BG, Ma CG (2012) Fasudil ameliorates disease progression in experimental autoimmune encephalomyelitis, acting possibly through antiinflammatory effect. CNS Neurosci Ther 18:909-17 CrossRef
13. Huang XN, Fu J, Wang WZ (2011) The effects of fasudil on the permeability of the rat blood–brain barrier and blood-spinal cord barrier following experimental autoimmune encephalomyelitis. J Neuroimmunol 239:61-7 CrossRef
14. Kattah MG, Wong MT, Yocum MD, Utz PJ (2008) Cytokines secreted in response to Toll-like receptor ligand stimulation modulate differentiation of human Th17 cells. Arthritis Rheum 58:1619-629 CrossRef
15. Kebir H, Ifergan I, Alvarez JI, Bernard M, Poirier J, Arbour N, Duquette P, Prat A (2009) Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Ann Neurol 66:390-02 CrossRef
16. Kerfoot SM, Long EM, Hickey MJ, Andonegui G, Lapointe BM, Zanardo RC, Bonder C, James WG, Robbins SM, Kubes P (2004) TLR4 contributes to disease-inducing mechanisms resulting in central nervous system autoimmune disease. J Immunol 173:7070-077
文摘
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 MOG35-5-induced EAE. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG35-5) 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.