The selective Rho-kinase inhibitor Fasudil is protective and therapeutic in experimental autoimmune encephalomyelitis

Sun, Xiaojia; Minohara, Motozumi; Kikuchi, Hitoshi; Ishizu, Takaaki; Tanaka, Masahito; Piao, Hong‐Guang; Osoegawa, Manabu; Ohyagi, Yasumasa; Shimokawa, Hiroaki; Kira, Jun Ichi

doi:10.1016/j.jneuroim.2006.06.027

Cited by 74 publications

(65 citation statements)

References 48 publications

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“…Some observations in cultured neurons have shown that the activation of Rho/ROCK caused the growth cone to collapse by affecting the actin skeleton system (Hall 1998). The inhibition of ROCK resulted in accelerated regeneration and enhanced functional recovery, and has also proved to be efficacious in animal models of stroke ), MS (Sun et al 2006;Yu et al 2010;Huang et al 2011;Hou et al 2012;Liu et al 2013), ALS (Takata et al 2013), Alzheimer's disease (Song et al 2013), and Parkinson's disease (Tönges et al 2012;Rodriguez-Perez et al 2013). Therefore, ROCK has been considered as a promising drug target for preventing neurodegeneration and stimulating neuroregeneration in several neurological diseases (Mueller et al 2005).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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 MOG 35-55 -induced EAE. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG 35-55 ) 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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Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…Recent studies have demonstrated that ROCK2 regulates the production of both IL-21 and IL-17 and plays an essential role in the development of autoimmunity in mice (10,11). Indeed, pan ROCK inhibition was reported to effectively down-regulate ongoing autoimmune response in animal models (11,12). Additionally, ROCK activity was found to be up-regulated in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) (13,14), when the production of both IL-21 and IL-17 is deregulated, but to date there is no evidence of selective ROCK2 involvement in the regulation of proinflammatory cytokines in humans.…”

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confidence: 99%

Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism

Zanin-Zhorov¹,

Weiss²,

Nyuydzefe³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

191

214

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Rho-associated kinase 2 (ROCK2) regulates the secretion of proinflammatory cytokines and the development of autoimmunity in mice. Data from a phase 1 clinical trial demonstrate that oral administration of KD025, a selective ROCK2 inhibitor, to healthy human subjects down-regulates the ability of T cells to secrete IL-21 and IL-17 by 90% and 60%, respectively, but not IFN-γ in response to T-cell receptor stimulation in vitro. Pharmacological inhibition with KD025 or siRNA-mediated inhibition of ROCK2, but not ROCK1, significantly diminished STAT3 phosphorylation and binding to IL-17 and IL-21 promoters and reduced IFN regulatory factor 4 and nuclear hormone RAR-related orphan receptor γt protein levels in T cells derived from healthy subjects or rheumatoid arthritis patients. Simultaneously, treatment with KD025 also promotes the suppressive function of regulatory T cells through up-regulation of STAT5 phosphorylation and positive regulation of forkhead box p3 expression. The administration of KD025 in vivo down-regulates the progression of collagen-induced arthritis in mice via targeting of the Th17-mediated pathway. Thus, ROCK2 signaling appears to be instrumental in regulating the balance between proinflammatory and regulatory T-cell subsets. Targeting of ROCK2 in man may therefore restore disrupted immune homeostasis and have a role in the treatment of autoimmunity.T he immune response is a delicate balancing act, protecting the integrity of the host organism from foreign invaders while not causing autoimmune reactivity (1). IL-21 and IL-17 are proinflammatory cytokines produced by T-helper 17 (Th17) cells that are involved in the pathogenesis of many autoimmune diseases (2-5). The generation of Th17 cells is induced by a combination of several cytokines including transforming growth factor-β (TGF-β1), IL-1β, IL-6, and IL-23, and involves the activation of transcription factors, such as RAR-related orphan receptor (ROR) γt, RORα, IFN regulatory factor (IRF) 4, and signal transducer and activator of transcription 3 (STAT3) (2, 6, 7). However, the signaling pathways that lead to activation of this transcriptional profile are poorly understood and remain unclear.Rho GTPase-mediated signaling pathways play a central role in the coordination and balancing of T-cell-mediated immune responses, including T-cell receptor (TCR)-mediated signaling, cytoskeletal reorganization, and the acquisition of the appropriate T-cell effector program (8). The Rho kinase family members, consisting of Rho-associated kinase 1 (ROCK1) and ROCK2, are serine-threonine kinases that are activated by Rho GTPases and mediate the phosphorylation of downstream targets in cells (9). Recent studies have demonstrated that ROCK2 regulates the production of both IL-21 and IL-17 and plays an essential role in the development of autoimmunity in mice (10, 11). Indeed, pan ROCK inhibition was reported to effectively down-regulate ongoing autoimmune response in animal models (11,12). Additionally, ROCK activity was found to be up-regulated in patients w...

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“…Our previous study showed that fasudil alleviated the severity of EAE and attenuated demyelination and neuroinflammation, acting possibly through an anti-inflammatory mechanism [24] . In addition, oral administration of fasudil prevented the development of EAE induced by proteolipid protein (PLP) p139-151 in SJL/J mice [25] . The mechanism of action might be the reduction of lymphocyte proliferation triggered by specific PLPs and the down-regulation of IL-17 levels and the IFN-γ/IL-4 ratio [25] .…”

Section: Introductionmentioning

confidence: 99%

“…In addition, oral administration of fasudil prevented the development of EAE induced by proteolipid protein (PLP) p139-151 in SJL/J mice [25] . The mechanism of action might be the reduction of lymphocyte proliferation triggered by specific PLPs and the down-regulation of IL-17 levels and the IFN-γ/IL-4 ratio [25] . Moreover, we observed that the polarization of the M1 macrophage phenotype to the M2 phenotype in fasudil-treated EAE mice was accompanied by the inhibition of Th17 T cells and an increase in Th2 T cells [26] .…”

Section: Introductionmentioning

confidence: 99%

Fasudil regulates T cell responses through polarization of BV-2 cells in mice experimental autoimmune encephalomyelitis

Chen

Zhang

et al. 2014

Acta Pharmacol Sin

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Aim: Fasudil, a selective Rho kinase (ROCK) inhibitor, has been shown to alleviate the severity of experimental autoimmune encephalomyelitis (EAE) via attenuating demyelination and neuroinflammation. The aim of this study was to investigate the effects of fasudil on interactions between macrophages/microglia and T cells in a mice EAE model. Methods: Mouse BV-2 microglia were treated with IFN-γ and fasudil. Cell viability was detected with MTT assay. BV-2 microglia polarization was analyzed using flow cytometry. Cytokines and other proteins were detected with ELISA and Western blotting, respectively. Mice were immunized with MOG 35-55 to induce EAE, and then treated with fasudil (40 mg/kg, ip) every other day from d 3 to d 27 pi. Encephalomyelitic T cells were prepared from the spleen of mice immunized with MOG 35-55 on d 9 pi. Results: Treatment of mouse BV-2 microglia with fasudil (15 μg/mL) induced significant phenotype polarization and functional plasticity, shifting M1 to M2 polarization. When co-cultured with the encephalomyelitic T cells, fasudil-treated BV-2 microglia significantly inhibited the proliferation of antigen-reactive T cells, and down-regulated IL-17-expressing CD4 + T cells and IL-17 production. Furthermore, fasudil-treated BV-2 microglia significantly up-regulated CD4 + CD25 high and CD4 + IL-10 + regulatory T cells (Tregs) and IL-10 production, suggesting that the encephalomyelitic T cells had converted to Tregs. In EAE mice, fasudil administration significantly decreased both CD11b + iNOS + and CD11b + TNF-α + M1 microglia, and increased CD11b + IL-10 + M2 microglia. Conclusion: Fasudil polarizes BV-2 microglia into M2 cells, which convert the encephalomyelitic T cells into Tregs in the mice EAE model.

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The selective Rho-kinase inhibitor Fasudil is protective and therapeutic in experimental autoimmune encephalomyelitis

Cited by 74 publications

References 48 publications

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

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

Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism

Fasudil regulates T cell responses through polarization of BV-2 cells in mice experimental autoimmune encephalomyelitis

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