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The Therapeutic Potential of Rho Kinase Inhibitor Fasudil Derivative FaD-1 in Experimental Autoimmune Encephalomyelitis

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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.

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References

  • Benveniste EN (1997) Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med 75:165–173

    Article  CAS  PubMed  Google Scholar 

  • 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 92:4768–4772

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chan CC (2008) Inflammation: beneficial or detrimental after spinal cord injury? Recent Pat CNS Drug Discov 13:189–199

    Article  Google Scholar 

  • 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 110:599–608

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH (2010) T cells in MS and experimental autoimmune encephalomyelitis. Clin Exp Immunol 162:1–11

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fujimoto S, Negishi M, Katoh H (2011) RhoG promotes neural progenitor cell proliferation in mouse cerebral cortex. Mol Biol Cell 20:4941–4950

    Article  Google Scholar 

  • Gensel JC, Nakamura S, Guan Z, van Rooijen N, Ankeny DP, Popovich PG (2009) Macrophages promote axon regeneration with concurrent neurotoxicity. J Neurosci 13:3956–3968

    Article  Google Scholar 

  • Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279:509–514

    Article  CAS  PubMed  Google Scholar 

  • Hauser SL, Chan JR, Oksenberg JR (2013) Multiple sclerosis: prospects and promise. Ann Neurol 74:317–327

    CAS  PubMed  Google Scholar 

  • 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 141:1625–1636

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 12:255–263

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 18:909–917

    Article  CAS  PubMed  Google Scholar 

  • 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 239:61–67

    Article  CAS  PubMed  Google Scholar 

  • 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 58:1619–1629

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 66:390–402

    Article  CAS  PubMed  Google Scholar 

  • 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 173:7070–7077

    Article  CAS  PubMed  Google Scholar 

  • Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 11:13435–13444

    Article  Google Scholar 

  • Li Q, Huang XJ, He W, Ding J, Jia JT, Fu G, Wang HX, Guo LJ (2009) Neuroprotective potential of fasudil mesylate in brain ischemia-reperfusion injury of rats. Cell Mol Neurobiol 29:169–180

    Article  CAS  PubMed  Google Scholar 

  • Liu CY, Li YH, Yu JZ, Feng L, Hou SW, Liu Y, Guo M, Xie Y, Meng J, Zhang H, Xiao B, Ma C (2013) Targeting the shift from M1 to M2 macrophages in experimental autoimmune encephalomyelitis mice treated with Fasudil. PLoS One 8:e54841

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mahurkar S, Suppiah V, O’Doherty C (2014) Pharmacogenomics of interferon beta and glatiramer acetate response: a review of the literature. Autoimmun Rev 13:178–186

    Article  CAS  PubMed  Google Scholar 

  • Minagar A (2013) Current and future therapies for multiple sclerosis. Sci 249101

  • Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJ, Ffrench-Constant C (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16:1211–1218

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mueller BK, Mack H, Teusch N (2005) Rho kinase, a promising drug target for neurological disorders. Nat Rev Drug Discov 4:387–398

    Article  CAS  PubMed  Google Scholar 

  • Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 13:723–737

    Article  Google Scholar 

  • Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S (1996) ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 392:189–193

    Article  CAS  PubMed  Google Scholar 

  • Niederöst B, Oertle T, Fritsche J, McKinney RA, Bandtlow CE (2002) Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoA and Rac1. J Neurosci 22:10368–10376

    PubMed  Google Scholar 

  • Oh J, Calabresi PA (2013) Emerging injectable therapies for multiple sclerosis. Lancet Neurol 12:1115–1126

    Article  CAS  PubMed  Google Scholar 

  • Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, Olson OC, Quick ML, Huse JT, Teijeiro V, Setty M, Leslie CS, Oei Y, Pedraza A, Zhang J, Brennan CW, Sutton JC, Holland EC, Daniel D, Joyce JA (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19:1264–72

    Article  CAS  PubMed  Google Scholar 

  • Reynolds JM, Martinez GJ, Chung Y, Dong C (2012) Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation. Proc Natl Acad Sci U S A 109:13064–13069

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rodriguez-Perez AI, Dominguez-Meijide A, Lanciego JL, Guerra MJ, Labandeira-Garcia JL (2013) Inhibition of Rho kinase mediates the neuroprotective effects of estrogen in the MPTP model of Parkinson’s disease. Neurobiol Dis 58:209–219

    Article  CAS  PubMed  Google Scholar 

  • Roses RE, Xu S, Xu M, Koldovsky U, Koski G, Czerniecki BJ (2008) Differential production of IL-23 and IL-12 by myeloid-derived dendritic cells in response to TLR agonists. J Immunol 181:5120–5127

    Article  CAS  PubMed  Google Scholar 

  • Rozdzial MM, Pleiman CM, Cambier JC, Finkel TH (1998) pp56Lck mediates TCR zeta-chain binding to the microfilament cytoskeleton. J Immunol 161:5491–5499

    CAS  PubMed  Google Scholar 

  • Song Y, Chen X, Wang LY, Gao W, Zhu MJ (2013) Rho kinase inhibitor fasudil protects against β-amyloid-induced hippocampal neurodegeneration in rats. CNS Neurosci Ther 19:603–610

    Article  CAS  PubMed  Google Scholar 

  • Stadelmann CC, Wegner C, Bruck W (2011) Inflammation, demyelination, and degeneration—recent insights from MS pathology. Biochim Biophys Acta 1812:275–282

    Article  CAS  PubMed  Google Scholar 

  • Sun X, Minohara M, Kikuchi H, Ishizu T, Tanaka M, Piao H, Osoegawa M, Ohyagi Y, Shimokawa H, Kira J (2006) The selective Rho-kinase inhibitor Fasudil is protective and therapeutic in experimental autoimmune encephalomyelitis. J Neuroimmunol 180:126–134

    Article  CAS  PubMed  Google Scholar 

  • Takata M, Tanaka H, Kimura M, Nagahara Y, Tanaka K, Kawasaki K, Seto M, Tsuruma K, Shimazawa M, Hara H (2013) Fasudil, a rho kinase inhibitor, limits motor neuron loss in experimental models of amyotrophic lateral sclerosis. Br J Pharmacol 170:341–351

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tharaux PL, Bukoski RC, Rocha PN, Crowley SD, Ruiz P, Nataraj C, Howell DN, Kaibuchi K, Spurney RF, Coffman TM (2003) Rho kinase promotes alloimmune responses by regulating the proliferation and structure of T cells. J Immunol 171:96–105

    Article  CAS  PubMed  Google Scholar 

  • Tönges L, Frank T, Tatenhorst L, Saal KA, Koch JC, Szego ÉM, Bähr M, Weishaupt JH, Lingor P (2012) Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson’s disease. Brain 135:3355–3370

    Article  PubMed Central  PubMed  Google Scholar 

  • van de Veerdonk FL, Teirlinck AC, Kleinnijenhuis J, Kullberg BJ, van Crevel R, van der Meer JW, Joosten LA, Netea MG (2010) Mycobacterium tuberculosis induces IL-17A responses through TLR4 and dectin-1 and is critically dependent on endogenous IL-1. J Leukoc Biol 88:227–232

    Article  PubMed  Google Scholar 

  • van der Valk P, De Groot CJ (2000) Staging of multiple sclerosis (MS) lesions: pathology of the time frame of MS. Neuropathol Appl Neurobiol 26:2–10

    Article  PubMed  Google Scholar 

  • Visser L, Jan de Heer H, Boven LA, van Riel D, van Meurs M, Melief MJ, Zahringer U, van Strijp J, Lambrecht BN, Nieuwenhuis EE, Laman JD (2005) Proinflammatory bacterial peptidoglycan as a cofactor for the development of central nervous system autoimmune disease. J Immunol 174:808–816

    Article  CAS  PubMed  Google Scholar 

  • Weber MS, Starck M, Wagenpfeil S, Meinl E, Hohlfeld R, Farina C (2004) Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain 127:1370–1378

    Article  PubMed  Google Scholar 

  • Yu JZ, Ding J, Ma CG, Sun CH, Sun YF, Lu CZ, Xiao BG (2010) Therapeutic potential of experimental autoimmune encephalomyelitis by Fasudil, a Rho kinase inhibitor. J Neurosci Res 88:1664–1672

    CAS  PubMed  Google Scholar 

  • Zekki H, Feinstein DL, Rivest S (2002) The clinical course of experimental autoimmune encephalomyelitis is associated with a profound and sustained transcriptional activation of the genes encoding toll-like receptor 2 and CD14 in the mouse CNS. Brain Pathol 12:308–319

    Article  CAS  PubMed  Google Scholar 

  • Zhang XM, Lund H, Mia S, Parsa R, Harris RA (2014) Adoptive transfer of cytokine-induced immunomodulatory adult microglia attenuates experimental autoimmune encephalomyelitis in DBA/1 mice. Glia 62:804–17

    Article  PubMed Central  PubMed  Google Scholar 

  • Zhou Y, Ye L, Wan Q, Zhou L, Wang X, Li J, Hu S, Zhou D, Ho W (2009) Activation of Toll-like receptors inhibits herpes simplex virus-1 infection of human neuronal cells. J Neurosci Res 87:2916–2925

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgment

This work was supported by grants from National Natural Science Foundation of China (No. 81070957, No. 81272163 No. 81371414, and No. 81070956) and Shanxi University of Traditional Chinese Medicine (No. 2011PY-1).

Conflict of Interest

The authors declare no conflicts of interest in relationship to performing this study.

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Authors and Affiliations

  1. Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China

    Yong-Fei Zhao, Xiang Zhang, Qing Zhang & Bao-Guo Xiao

  2. Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China

    Zhi-Bin Ding, Xing-Wang Yang, Hui Zhang, Jie-Zhong Yu, Yan-Hua Li, Chun-Yun Liu & Cun-Gen Ma

  3. Department of Neurology, the First Clinical Medical College, Shanxi Medical University, Taiyuan, China

    Zhi-Bin Ding, Hui Zhang & Cun-Gen Ma

  4. “2011” Collaborative Innovation Center/Department of Encephalopathy and National Major Clinical Department of Ministry of Health, Shanxi University of Traditional Chinese Medicine, Taiyuan, China

    Xing-Wang Yang, Hong-Zhen Zhang & Cun-Gen Ma

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  1. Yong-Fei Zhao
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  2. Xiang Zhang
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  3. Zhi-Bin Ding
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  9. Qing Zhang
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  10. Hong-Zhen Zhang
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Correspondence to Cun-Gen Ma or Bao-Guo Xiao.

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Yong-Fei Zhao and Xiang Zhang contributed equally to this work.

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Zhao, YF., Zhang, X., Ding, ZB. et al. The Therapeutic Potential of Rho Kinase Inhibitor Fasudil Derivative FaD-1 in Experimental Autoimmune Encephalomyelitis. J Mol Neurosci 55, 725–732 (2015). https://doi.org/10.1007/s12031-014-0411-7

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