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      MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway

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          Abstract

          Introduction

          Demyelination causes neurological deficits involving visual, motor, sensory symptoms. Deregulation of several enzymes has been identified in demyelination, which holds potential for the development of treatment strategies for demyelination. However, the specific effect of methionine sulfoxide reductase A (MsrA) on demyelination remains unclear. Hence, this study aims to explore the effect of MsrA on oxidative stress and inflammatory response of microglia in demyelination.

          Methods

          Initially, we established a mouse model with demyelination induced by cuprizone and a cell model provoked by lipopolysaccharide (LPS). The expression of MsrA in wild-type (WT) and MsrA-knockout (MsrA -/-) mice were determined by RT-qPCR and Western blot analysis. In order to further explore the function of MsrA on inflammatory response, and oxidative stress in demyelination, we detected the expression of microglia marker Iba1, inflammatory factors TNF-α and IL-1β and intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) activity, as well as expression of the NOX2-MAPKs/NF-κB signaling pathway-related genes in MsrA -/- mice and LPS-induced microglia following different treatments.

          Results

          MsrA expression was downregulated in MsrA -/- mice. MsrA silencing was shown to produce severely injured motor coordination, increased expressions of Iba1, TNF-α, IL-1β, ROS and NOX2, and extent of ERK, p38, IκBα, and p65 phosphorylation, but reduced SOD activity. Conjointly, our study suggests that Tat-MsrA fusion protein can prevent the cellular inflammatory response and subsequent demyelination through negative regulation of the NOX2-MAPKs/NF-κB signaling pathway.

          Conclusion

          Our data provide a profound insight on the role of endogenous antioxidative defense systems such as MsrA in controlling microglial function.

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          Most cited references 41

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          The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability.

          The outcome of multiple sclerosis (MS), assessed according to the Kurtzke Disability Status Scale (DSS), was reviewed in 1,099 consecutive patients followed in London, Canada, between 1972 and 1984. A geographically based subgroup of 196 patients representing 90% of Middlesex County MS patients as well as a group of 197 patients seen from onset of disease were separately analysed. The clinical course was progressive from onset in 33% of the total population and in 28% of the Middlesex County subgroup. Of those with duration of 6-10 yrs, 30-40% with initially remitting disease developed progressive MS. The cross-sectional distribution of disability was bimodal with peaks at DSS 1 (no disability) and DSS 6 (assistance required for walking). Actuarial analysis showed that the median time to reach DSS 6 from onset of MS was 14.97 +/- 0.31 yrs in the total population and 9.42 +/- 0.44 yrs in the "seen from onset' subgroup. Survival was minimally altered; 87% of patients followed up to 40 yrs were still alive, although ascertainment of cases with this duration of MS was incomplete. Data describing the rate at which disability develops after the onset of a progressive phase of MS are also presented. The implications of these data in planning and interpretation of clinical therapeutic trials are discussed.
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            Demyelinating diseases.

             S Love (2006)
            A diagnosis of demyelination carries important therapeutic and prognostic implications. In most cases the diagnosis is made clinically, and involvement of the histopathologist is largely confined to postmortem confirmation and clinicopathological correlation. However, every now and then, accurate diagnosis of the presence or cause of demyelination before death hinges on the histopathological assessment. Recognition of demyelination depends on an awareness of this as a diagnostic possibility, and on the use of appropriate tinctorial and immunohistochemical stains to identify myelin, axons and inflammatory cells. In biopsy specimens, the critical distinction is usually from ischaemic or neoplastic disease, and the types of demyelinating disease most likely to be encountered are multiple sclerosis, acute-disseminated encephalomyelitis, progressive multifocal leucoencephalopathy and extrapontine myelinolysis. Interpretation of the pathology has to be made in the context of the clinical, radiological and biochemical findings. Freezing of a small amount of fresh tissue allows for later virological studies, and electron microscopy is occasionally helpful for demonstration of viral particles.
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              Pathology of demyelinating diseases.

              There has been significant progress in our understanding of the pathology and pathogenesis of central nervous system inflammatory demyelinating diseases. Neuropathological studies have provided fundamental new insights into the pathogenesis of these disorders and have led to major advances in our understanding of multiple sclerosis (MS) heterogeneity, the substrate of irreversible progressive disability in MS, the relationship between inflammation and neurodegeneration in MS, the neuroimaging correlates of MS lesions, and the pathogenesis of other central nervous system inflammatory disorders, including neuromyelitis optica, acute disseminated encephalomyelitis, and Balo's concentric sclerosis. Herein, we review the pathological features of these central nervous system inflammatory demyelinating disorders and discuss neuropathological studies that have yielded novel insights into potential mechanisms involved in the formation of the demyelinated lesion.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                05 April 2020
                2020
                : 14
                : 1377-1389
                Affiliations
                [1 ]The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology , Luoyang 471000, People’s Republic of China
                [2 ]Department of Pharmacy, Wuhan Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430030, People’s Republic of China
                [3 ]Department of Pharmacy, Ninth Hospital of Xi’an, Affiliated to Medical College of Xi’an Jiaotong University , Xi’an 710054, People’s Republic of China
                Author notes
                Correspondence: Hua Fan The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology , No. 24, Jinghua Road, Jianxi District, Luoyang471000, Henan Province, People’s Republic of ChinaTel +86-18538825892 Email fanhua19851229@126.com
                Qing Shu Department of Pharmacy, Ninth Hospital of Xi’an, Affiliated to Medical College of Xi’an Jiaotong University , No. 151, Eastern Section of South 2nd Ring Road, Xi’an710054, Shaanxi Province, People’s Republic of ChinaTel +86-18627121873 Email shuqinglwz@163.com
                [*]

                These authors contributed equally to this work

                Article
                223218
                10.2147/DDDT.S223218
                7147623
                © 2020 Fan et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 6, Tables: 1, References: 44, Pages: 13
                Funding
                This study was supported by the National Natural Science Foundation of China (Grant/Award Number: U1504808, 81801201 and 81803503) and the Fundamental Research Funds for the Central Universities (Grant/Award Number: XZY012019121).
                Categories
                Original Research

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