Intranasal delivery of FSD-C10, a novel Rho kinase inhibitor, exhibits therapeutic potential in experimental autoimmune encephalomyelitis

Authors

  • Yan-Hua Li,

    1. Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, China
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  • Jie-Zhong Yu,

    1. Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, China
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  • Chun-Yun Liu,

    1. Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, China
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  • Hui Zhang,

    1. Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, China
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  • Hai-Fei Zhang,

    1. Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, China
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  • Wan-Fang Yang,

    1. Department of Encephalopathy and National Major Clinical Department of the Ministry of Health, Third Hospital, Shanxi University of Traditional Chinese Medicine, Taiyuan, China
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  • Jun-Lian Li,

    1. Department of Encephalopathy and National Major Clinical Department of the Ministry of Health, Third Hospital, Shanxi University of Traditional Chinese Medicine, Taiyuan, China
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  • Qian-Jin Feng,

    1. Department of Encephalopathy and National Major Clinical Department of the Ministry of Health, Third Hospital, Shanxi University of Traditional Chinese Medicine, Taiyuan, China
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  • Ling Feng,

    1. Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, China
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  • Guang-Xian Zhang,

    1. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA
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  • Bao-Guo Xiao,

    Corresponding author
    1. Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
    • Correspondence: Bao-guo Xiao, Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200025, China.

      Emails: bgxiao@shmu.edu.cn;

      Or

      Cun-gen Ma, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, 037009, China and Shanxi University of Traditional Chinese Medicine, Taiyuan, 030024, China.

      Email: macungen2001@163.com

      Senior author: Guang-xian Zhang,

      email: guang-xian.zhang@jefferson.edu

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  • Cun-Gen Ma

    Corresponding author
    1. Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, China
    2. Department of Encephalopathy and National Major Clinical Department of the Ministry of Health, Third Hospital, Shanxi University of Traditional Chinese Medicine, Taiyuan, China
    • Correspondence: Bao-guo Xiao, Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200025, China.

      Emails: bgxiao@shmu.edu.cn;

      Or

      Cun-gen Ma, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, 037009, China and Shanxi University of Traditional Chinese Medicine, Taiyuan, 030024, China.

      Email: macungen2001@163.com

      Senior author: Guang-xian Zhang,

      email: guang-xian.zhang@jefferson.edu

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Summary

Viewing multiple sclerosis (MS) as both neuroinflammation and neurodegeneration has major implications for therapy, with neuroprotection and neurorepair needed in addition to controlling neuroinflammation in the central nervous system (CNS). While Fasudil, an inhibitor of Rho kinase (ROCK), is known to suppress experimental autoimmune encephalomyelitis (EAE), an animal model of MS, it relies on multiple, short-term injections, with a narrow safety window. In this study, we explored the therapeutic effect of a novel ROCK inhibitor FSD-C10, a Fasudil derivative, on EAE. An important advantage of this derivative is that it can be used via non-injection routes; intranasal delivery is the preferred route because of its efficient CNS delivery and the much lower dose compared with oral delivery. Our results showed that intranasal delivery of FSD-C10 effectively ameliorated the clinical severity of EAE and CNS inflammatory infiltration and promoted neuroprotection. FSD-C10 effectively induced CNS production of the immunoregulatory cytokine interleukin-10 and boosted expression of nerve growth factor and brain-derived neurotrophic factor proteins, while inhibiting activation of p-nuclear factor-κB/p65 on astrocytes and production of multiple pro-inflammatory cytokines. In addition, FSD-C10 treatment effectively induced CD4+ CD25+, CD4+ FOXP3+ regulatory T cells. Together, our results demonstrate that intranasal delivery of the novel ROCK inhibitor FSD-C10 has therapeutic potential in EAE, through mechanisms that possibly involve both inhibiting CNS inflammation and promoting neuroprotection.

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