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      Neuroprotective effect of ketamine against TNF‐α‐induced necroptosis in hippocampal neurons

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          Abstract

          Tumour necrosis factor‐α (TNF‐α), a crucial cytokine, has various homeostatic and pathogenic bioactivities. The aim of this study was to assess the neuroprotective effect of ketamine against TNF‐α‐induced motor dysfunction and neuronal necroptosis in male C57BL/6J mice in vivo and HT‐22 cell lines in vitro. The behavioural testing results of the present study indicate that ketamine ameliorated TNF‐α‐induced neurological dysfunction. Moreover, immunohistochemical staining results showed that TNF‐α‐induced brain dysfunction was caused by necroptosis and microglial activation, which could be attenuated by ketamine pre‐treatment inhibiting reactive oxygen species production and mixed lineage kinase domain‐like phosphorylation in hippocampal neurons. Therefore, we concluded that ketamine may have neuroprotective effects as a potent inhibitor of necroptosis, which provides a new theoretical and experimental basis for the application of ketamine in TNF‐α‐induced necroptosis‐associated diseases.

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          Most cited references47

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          The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

          Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.
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            Neurotoxic reactive astrocytes are induced by activated microglia

            A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.
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              Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase.

              The receptor-interacting serine-threonine kinase 3 (RIP3) is a key signaling molecule in the programmed necrosis (necroptosis) pathway. This pathway plays important roles in a variety of physiological and pathological conditions, including development, tissue damage response, and antiviral immunity. Here, we report the identification of a small molecule called (E)-N-(4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide--hereafter referred to as necrosulfonamide--that specifically blocks necrosis downstream of RIP3 activation. An affinity probe derived from necrosulfonamide and coimmunoprecipitation using anti-RIP3 antibodies both identified the mixed lineage kinase domain-like protein (MLKL) as the interacting target. MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. Treating cells with necrosulfonamide or knocking down MLKL expression arrested necrosis at a specific step at which RIP3 formed discrete punctae in cells. These findings implicate MLKL as a key mediator of necrosis signaling downstream of the kinase RIP3. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                dujiwei1977@163.com
                LCHOU@XAH.XMU.EDU.CN
                Journal
                J Cell Mol Med
                J Cell Mol Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                03 March 2021
                April 2021
                : 25
                : 7 ( doiID: 10.1111/jcmm.v25.7 )
                : 3449-3459
                Affiliations
                [ 1 ] Department of Anesthesiology Xiang'an Hospital of Xiamen University School of Medicine Xiamen University Xiamen China
                [ 2 ] State Key Laboratory of Cellular Stress Biology Xiamen University Xiamen China
                [ 3 ] Medical College of Yan'an University Yan'an China
                [ 4 ] Department of Nursing Xiang'an Hospital of Xiamen University School of Medicine Xiamen University Xiamen China
                Author notes
                [*] [* ] Correspondence

                Jiwei Du, Department of Nursing, Xiang'an Hospital, Xiamen University, No. 2000 Xiang'an dong Road, Xiang'an District, 361101 Xiamen, China.

                Email: dujiwei1977@ 123456163.com

                Lichao Hou, Department of Anesthesiology, Xiang'an Hospital, Xiamen University, No. 2000 Xiang'an dong Road, Xiang'an District, 361101 Xiamen, China.

                Email: LCHOU@ 123456XAH.XMU.EDU.CN

                Author information
                https://orcid.org/0000-0001-7861-6938
                Article
                JCMM16426
                10.1111/jcmm.16426
                8034479
                33660415
                51453b31-0798-4626-9e29-5881f9e6d224
                © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 February 2021
                : 21 February 2020
                : 18 February 2021
                Page count
                Figures: 6, Tables: 0, Pages: 11, Words: 5654
                Funding
                Funded by: the Fundamental Research Funds for the Central Universities
                Award ID: 20720200037
                Funded by: Scientific Research Foundation for Personnel, Xiang’an Hospital of Xiamen University
                Award ID: PM201809170003
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81171839
                Award ID: 81501207
                Award ID: 81701091
                Funded by: the Science and Technology Project of Xiamen municipal Bureau of Science and Technology
                Award ID: 3502Z20194046
                Funded by: Open Research Fund of State Key Laboratory of CeIIular Stress Biology, Xiamen University
                Award ID: SKLCSB2019KF015
                Funded by: Natural Science Foundation of Fujian Province , open-funder-registry 10.13039/501100003392;
                Award ID: 2020J01017
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                April 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.1 mode:remove_FC converted:09.04.2021

                Molecular medicine
                ketamine,necroptosis,reactive oxygen species,systemic inflammatory response syndrome,tumour necrosis factor‐α

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