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      Role of inflammation in neurological damage and regeneration following spinal cord injury and its therapeutic implications

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          Abstract

          Spinal cord injury (SCI) is an incurable trauma that frequently results in partial or complete loss of motor and sensory function. Massive neurons are damaged after the initial mechanical insult. Secondary injuries, which are triggered by immunological and inflammatory responses, also result in neuronal loss and axon retraction. This results in defects in the neural circuit and a deficiency in the processing of information. Although inflammatory responses are necessary for spinal cord recovery, conflicting evidence of their contributions to specific biological processes have made it difficult to define the specific role of inflammation in SCI. This review summarizes our understanding of the complex role of inflammation in neural circuit events following SCI, such as cell death, axon regeneration and neural remodeling. We also review the drugs that regulate immune responses and inflammation in the treatment of SCI and discuss the roles of these drugs in the modulation of neural circuits. Finally, we provide evidence about the critical role of inflammation in facilitating spinal cord neural circuit regeneration in zebrafish, an animal model with robust regenerative capacity, to provide insights into the regeneration of the mammalian central nervous system.

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          Traumatic spinal cord injury

          Traumatic spinal cord injury (SCI) has devastating consequences for the physical, social and vocational well-being of patients. The demographic of SCIs is shifting such that an increasing proportion of older individuals are being affected. Pathophysiologically, the initial mechanical trauma (the primary injury) permeabilizes neurons and glia and initiates a secondary injury cascade that leads to progressive cell death and spinal cord damage over the subsequent weeks. Over time, the lesion remodels and is composed of cystic cavitations and a glial scar, both of which potently inhibit regeneration. Several animal models and complementary behavioural tests of SCI have been developed to mimic this pathological process and form the basis for the development of preclinical and translational neuroprotective and neuroregenerative strategies. Diagnosis requires a thorough patient history, standardized neurological physical examination and radiographic imaging of the spinal cord. Following diagnosis, several interventions need to be rapidly applied, including haemodynamic monitoring in the intensive care unit, early surgical decompression, blood pressure augmentation and, potentially, the administration of methylprednisolone. Managing the complications of SCI, such as bowel and bladder dysfunction, the formation of pressure sores and infections, is key to address all facets of the patient's injury experience.
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            Traumatic Spinal Cord Injury: An Overview of Pathophysiology, Models and Acute Injury Mechanisms

            Traumatic spinal cord injury (SCI) is a life changing neurological condition with substantial socioeconomic implications for patients and their care-givers. Recent advances in medical management of SCI has significantly improved diagnosis, stabilization, survival rate and well-being of SCI patients. However, there has been small progress on treatment options for improving the neurological outcomes of SCI patients. This incremental success mainly reflects the complexity of SCI pathophysiology and the diverse biochemical and physiological changes that occur in the injured spinal cord. Therefore, in the past few decades, considerable efforts have been made by SCI researchers to elucidate the pathophysiology of SCI and unravel the underlying cellular and molecular mechanisms of tissue degeneration and repair in the injured spinal cord. To this end, a number of preclinical animal and injury models have been developed to more closely recapitulate the primary and secondary injury processes of SCI. In this review, we will provide a comprehensive overview of the recent advances in our understanding of the pathophysiology of SCI. We will also discuss the neurological outcomes of human SCI and the available experimental model systems that have been employed to identify SCI mechanisms and develop therapeutic strategies for this condition.
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              The Biology of Regeneration Failure and Success After Spinal Cord Injury.

              Since no approved therapies to restore mobility and sensation following spinal cord injury (SCI) currently exist, a better understanding of the cellular and molecular mechanisms following SCI that compromise regeneration or neuroplasticity is needed to develop new strategies to promote axonal regrowth and restore function. Physical trauma to the spinal cord results in vascular disruption that, in turn, causes blood-spinal cord barrier rupture leading to hemorrhage and ischemia, followed by rampant local cell death. As subsequent edema and inflammation occur, neuronal and glial necrosis and apoptosis spread well beyond the initial site of impact, ultimately resolving into a cavity surrounded by glial/fibrotic scarring. The glial scar, which stabilizes the spread of secondary injury, also acts as a chronic, physical, and chemo-entrapping barrier that prevents axonal regeneration. Understanding the formative events in glial scarring helps guide strategies towards the development of potential therapies to enhance axon regeneration and functional recovery at both acute and chronic stages following SCI. This review will also discuss the perineuronal net and how chondroitin sulfate proteoglycans (CSPGs) deposited in both the glial scar and net impede axonal outgrowth at the level of the growth cone. We will end the review with a summary of current CSPG-targeting strategies that help to foster axonal regeneration, neuroplasticity/sprouting, and functional recovery following SCI.
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                Author and article information

                Contributors
                Journal
                Burns Trauma
                Burns Trauma
                burnst
                Burns & Trauma
                Oxford University Press
                2321-3868
                2321-3876
                2023
                28 February 2023
                28 February 2023
                : 11
                : tkac054
                Affiliations
                Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,Nantong University , Nantong 226006, China
                School of Life Sciences, Nantong University , Nantong 226019, China
                Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,Nantong University , Nantong 226006, China
                School of Medicine, Nantong University , Nantong 226006, China
                NICM Health Research Institute, Western Sydney University , Westmead, NSW 2145, Australia
                Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,Nantong University , Nantong 226006, China
                Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education , Guangzhou 510275, China
                Co-innovation Center of Neuroregeneration, Nantong University , Nantong 226006, China
                Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,Nantong University , Nantong 226006, China
                School of Medicine, Nantong University , Nantong 226006, China
                Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,Nantong University , Nantong 226006, China
                Author notes
                Correspondence. Lingyan Xing, Email: xlyan011@ 123456163.com ; Gang Chen, Email: chengang6626@ 123456ntu.edu.cn

                Yan Jin, Yixing Song and Jiaqi Lin authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-0078-2394
                https://orcid.org/0000-0002-7646-2522
                Article
                tkac054
                10.1093/burnst/tkac054
                9976751
                36873284
                18523fee-a807-4c92-868e-b39732cd4c54
                © The Author(s) 2023. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 May 2022
                : 7 July 2022
                : 1 December 2022
                Page count
                Pages: 10
                Funding
                Funded by: National Key Research and Development Program of China, DOI 10.13039/501100012166;
                Award ID: 2022YFA1105900
                Funded by: National Natural Science Foundation of China, DOI 10.13039/501100001809;
                Award ID: 81701127
                Funded by: Nantong Science and Technology Foundation of China;
                Award ID: JC2021058
                Funded by: Large Instruments Open Foundation of Nantong University;
                Award ID: KFJN2231
                Award ID: KFJN2275
                Funded by: National Health and Medical Research Council, DOI 10.13039/501100000925;
                Award ID: 1112258
                Funded by: WSU Vice-Chancellor’s Senior Research Fellowship;
                Categories
                Review
                AcademicSubjects/MED00010

                inflammation,immune response,spinal cord injury,axon regeneration,cell death,zebrafish,inflammatory drugs,trauma,neurological damage

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