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Volume 20, Issue 6
September 2013
Research Articles| August 30 2013
Subject Area: Endocrinology , Immunology and Allergy , Neurology and Neuroscience
Cong Gao;
Cong Gao
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Li Huang;
Li Huang
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Youming Long;
Youming Long
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Jianzheng Zheng;
Jianzheng Zheng
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Jie Yang;
Jie Yang
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Shuxiang Pu;
Shuxiang Pu
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Longchang Xie
Longchang Xie
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Neuroimmunomodulation (2013) 20 (6): 334–340.
Article history
Received:
February 27 2013
Accepted:
June 05 2013
Published Online:
August 30 2013
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Citation
Cong Gao, Li Huang, Youming Long, Jianzheng Zheng, Jie Yang, Shuxiang Pu, Longchang Xie; Y-39983, a Selective Rho-Kinase Inhibitor, Attenuates Experimental Autoimmune Encephalomyelitis via Inhibition of Demyelination. Neuroimmunomodulation 1 September 2013; 20 (6): 334–340. https://doi.org/10.1159/000353568
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Abstract
Objective: Rho-associated kinase (ROCK) is a serine/threonine kinase and a major downstream effector of the small GTP-binding protein, Rho. Rho-ROCK triggers an intracellular signaling cascade that controls actin cytoskeleton and is essential for cell motility and adhesion, neurite outgrowth and retraction. In chronic disabling disease, multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), demyelination and axonal damage are the major pathological changes contributing to neurological disability. We investigated the protective effect of a specific ROCK inhibitor, Y-39983, on demyelination and axonal damage in chronic EAE. Methods: Western blotting for myelin proteins, electron microscopy and solochrome cyanine staining was performed to evaluate demyelination while neurofilament proteins and cytoskeletal proteins including β-actin and β-tubulin were used to determine axonal damage in a chronic mouse model of EAE treated with Y-39983. Results: Y-39983 significantly suppressed clinical symptoms of EAE and prevented its relapse while increasing the amount of myelin proteins. No significant changes in neurofilaments and cytoskeletal proteins were observed compared with control EAE mice. The inhibition of demyelination by Y-39983 was confirmed by solochrome cyanine staining and electron microscopy. To further study the effect of Y-39983 on demyelination in EAE, we tested three major ROCK substrates, including myosin light chain phosphorylation, LIMK2 and collapsin response mediator protein-2. The activity of these molecules was decreased in EAE animals treated with Y-39983. Conclusion: The inhibitory effect of Y-39983 on demyelination is probably due to the inactivation of ROCK substrates, which are important for neurite outgrowth, growth cone collapse and demyelination of oligodendrocytes.
Keywords:
Axonal regeneration, Experimental autoimmune encephalomyelitis, Multiple sclerosis, Myelination, Neurite outgrowth inhibitors, Rho-kinase inhibitor, ROCK , Y-39983
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© 2013 S. Karger AG, Basel
2013
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