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This research reports that early ɑ2-adrenergic receptor agonist treatment drives microglia toward a homeostatic phenotype within the post-injury scar. The approach reduces inhibitory extracellular matrix deposition and converts inhibitory substrates into permissive conditions for axonal regrowth. Anatomical analyses show regeneration of the reticulospinal tract and synaptic connectivity with thoracolumbar circuits, enabling motor recovery in complete SCI, supporting pharmacological glial-neural circuit repair.",{"@graph":69,"@context":121},[70,84,104],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/pharmacological-microglial-inhibition-remodels-the-scar-microenvironment-to-support-reticulospinal-circuit-reconstruction-after-spinal-cord-injury/439614/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":98,"encodingFormat":97,"isAccessibleForFree":99,"interactionStatistic":100},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/pharmacological-microglial-inhibition-remodels-the-scar-microenvironment-to-support-reticulospinal-circuit-reconstruction-after-spinal-cord-injury/439614.png","ImageObject",300,407,{"name":92,"@type":93},"Aditya","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-29",true,{"@type":101,"interactionType":102,"userInteractionCount":14},"InteractionCounter",{"@type":103},"ViewAction",{"@type":105,"mainEntity":106},"FAQPage",[107,113,117],{"name":108,"@type":109,"acceptedAnswer":110},"Why does spinal cord injury often lead to long-term neurological dysfunction?","Question",{"text":111,"@type":112},"SCI creates an inhibitory scar microenvironment at the lesion site that suppresses neural circuit reconstruction, secondary degeneration, and functional recovery.","Answer",{"name":114,"@type":109,"acceptedAnswer":115},"What treatment is described to modulate microglia after SCI?",{"text":116,"@type":112},"Early ɑ2-adrenergic receptor agonist treatment is reported to drive microglia toward a homeostatic phenotype within the post-SCI scar.",{"name":118,"@type":109,"acceptedAnswer":119},"How does microglial modulation support motor recovery in complete SCI?",{"text":120,"@type":112},"The intervention reduces inhibitory extracellular matrix deposition, promotes axonal regrowth, and enables reticulospinal tract regeneration with synaptic connectivity to thoracolumbar circuits that mediate motor recovery.","https://schema.org",{"og:url":83,"og:type":123,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":125,"canonical":83},"index,follow",{"doc_id":127,"site_id":62},439614,1790725604,{"code":4,"msg":5,"data":130},{"doc_id":127,"user_id":131,"nickname":92,"user_avatar":132,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":133,"file_id":134,"file_url":135,"file_type":136,"file_size":137,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":138,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},962085564549,"https://ap-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","RESEARCH ARTICLE  \n[www.advancedscience.com](www.advancedscience.com)  \nPharmacological Microglial Inhibition Remodels the Scar Microenvironment to Support Reticulospinal Circuit Reconstruction After Spinal Cord Injury  \nRun Li, Hongyuan Xing, Yifan Shen, Meng Chen, Bowen Lyu, Xiaofeng Yang, Li Sun, Chao Jiang, Jianyu Lv, Xin Ding,* Zhongyang Gao,* and Yue Wang*  \nDue to an inhibitory scar microenvironment that prevents neural circuit reconstruction, spinal cord injury (SCI) often leads to persistent neurological dysfunction. Although neonatal murine models demonstrate that microglial inhibition enables scar remodeling to support neuroregeneration and functional recovery, effective pharmacological suppression of microglial activation in adult SCI remain elusive. Here, this work demonstrates that early 􀀂2-adrenergic receptor agonist treatment drives microglial transition to a homeostatic phenotype within the post-SCI scar. This intervention reduces inhibitory extracellular matrix deposition and transforms the inhibitory microenvironments into permissive substrates for axonal regrowth. Anatomical analyses reveal regeneration ofthe reticulospinal tract, which establishes synaptic connectivity with thoracolumbar circuits to mediate motor recovery in a complete SCI. These findings elucidate the therapeutic potential and neural circuit mechanisms underlying pharmacological microglial modulation for SCI repair, establishing a glial-neural circuit reparative paradigm.  \nThe pathological cascade following SCI features progressive scar formation at the lesion site,[3,4] comprising aberrantly proliferating astrocytes, pericytes, fibroblasts, activated microglia, and multiple inhibitory factors of neural regeneration. [5] This inhibitory scar environment serves as a principal contributor to secondary neurodegeneration, suppresses axonal regeneration and ultimately leads to failure of functional recovery.[6] Consequently, remodeling the scar microenvironment has emerged as a promising therapeutic strategy to promote central nervous system (CNS) axon regeneration and functional recovery.[5–8] Recent studies indicate that targeting microglial activation is a promising therapeutic approach to remodel the scar environment after SCI. [9,10] Upon activation, microglia secrete various pro-inflammatory mediators, such as cytokines, chemokines, and reactive oxygen,[11] to establish an inflammatory microenvironment at the SCI  \n1. Introduction  \nSpinal cord injury (SCI) is a devastating neurological disorder that results in permanent loss of sensory and motor functions[1,2]  \nsite. Moreover, activated microglia induces secondary activation of neighboring astroglia cells. Intriguingly, neonatal murine models exhibit intrinsic microglial phenotypic plasticity, whereby activated microglia spontaneously return to a resting state. [12–15]  \nR. Li, H. Xing, Y. Shen, B. Lyu, Z. Gao, Y. Wang Department of Orthopedic Surgery The First Affiliated Hospital  \nZhejiang University School of Medicine Hangzhou 310003, China  \nE-mail: [zhongyang.gao@zju.edu.cn](zhongyang.gao@zju.edu.cn); [wangyuespine@zju.edu.cn](wangyuespine@zju.edu.cn)  \nM. Chen  \nM.S. E  \nJohns Hopkins University  \n3400 North Charles Street, Hopkins, MD 21218, USA  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202503966](https://doi.org/10.1002/advs.202503966)[ ](https://doi.org/10.1002/advs.202503966)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \nDOI: 10.1002/advs.202503966  \nX. Yang, L. Sun  \nSoochow Key Laboratory of Prevention and Treatment of Child Brain injury  \nChildren’s Hospital of Soochow University Suzhou 215025, China  \nC. Jiang  \nDepartment of Orthopedics  \nTaizhou Hospital of Zhejiang Province Affi","cbCaip8OFvVb1mpU","https://ap.wps.com/l/cbCaip8OFvVb1mpU","pdf",20925112,17,"English","# Introduction\n## SCI and inhibitory scar microenvironment\n## Microglial activation and phenotypic plasticity\n## Rationale for pharmacological microglial modulation\n# Materials and Methods\n## (Not present in provided text)\n# Results\n## Microglial transition within the post-SCI scar\n## Reduction of inhibitory ECM deposition and axonal regrowth\n## Reticulospinal tract regeneration and synaptic connectivity\n# Discussion\n## Therapeutic potential and repair paradigm","[{\"question\":\"Why does spinal cord injury often lead to long-term neurological dysfunction?\",\"answer\":\"SCI creates an inhibitory scar microenvironment at the lesion site that suppresses neural circuit reconstruction, secondary degeneration, and functional recovery.\"},{\"question\":\"What treatment is described to modulate microglia after SCI?\",\"answer\":\"Early ɑ2-adrenergic receptor agonist treatment is reported to drive microglia toward a homeostatic phenotype within the post-SCI scar.\"},{\"question\":\"How does microglial modulation support motor recovery in complete SCI?\",\"answer\":\"The intervention reduces inhibitory extracellular matrix deposition, promotes axonal regrowth, and enables reticulospinal tract regeneration with synaptic connectivity to thoracolumbar circuits that mediate motor recovery.\"}]","Pharmacological Microglial Inhibition Remodels the Scar Microenvironment to Support Reticulospinal Circuit Reconstruction After Spinal Cord Injury | PDF",1790689501,43]