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Integr. Neurosci."],"abstract":"<jats:p>Background: Neuroinflammation serves as a pivotal driver of pathology in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) \u2013 the widely used animal model of MS. A key contributor to this pathological process is neurotoxic A1-like reactive astrocytes, which play an essential role in disease progression. Although the antidiabetic drugs Metformin (Met) and Pioglitazone (Pio) exhibit anti-inflammatory properties, the effects of Met and Pio on A1-like reactive astrocytes in MS, as well as the underlying mechanisms, remain poorly defined. In this study, we investigated whether Met and Pio can attenuate neuroinflammation by modulating A1-like astrocyte activation to uncover the underlying signaling pathways involved in the process. Methods: Primary astrocytes were isolated from mice and then treated with interleukin\u201117 (IL-17) to induce an A1-like reactive state. The effects of Met and Pio on A1-like astrocyte activation and inflammatory responses were evaluated. The role of the protein kinase B \/mammalian target of rapamycin \/signal transducer and activator of transcription 3 (AKT\/mTOR\/STAT3) signaling pathway was examined using Western blotting and immunofluorescence assay. Meanwhile, the experiments in vivo were performed in EAE mice, where Met and Pio administration was used to assess the therapeutic effects on neuroinflammation, demyelination, and disease progression. Results: Both Met and Pio significantly suppressed the production of inflammatory cytokines and attenuated A1-like astrocyte activation in IL-17-stimulated primary astrocytes. These effects were mediated by the inhibition of the AKT\/mTOR\/STAT3 pathway. In EAE mice, drug treatment markedly reduced neuroinflammation and demyelination, thereby leading to a significant alleviation of clinical symptoms and pathological damage. Conclusion: Our findings suggest that Met and Pio downregulate the activated astrocyte-mediated inflammatory reaction to alleviate EAE pathogenesis through suppression of the AKT\/mTOR\/STAT3 pathway. Collectively, these results demonstrate a novel mechanism underlying the potential therapeutic effects of these drugs in MS and other neuroinflammatory disorders.<\/jats:p>","DOI":"10.31083\/jin47364","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T08:26:43Z","timestamp":1777451203000},"source":"Crossref","is-referenced-by-count":1,"title":["Roles of Metformin and Pioglitazone in Regulating A1-like Astrocyte Activation in EAE Mice"],"prefix":"10.31083","volume":"25","author":[{"given":"Suping","family":"Qin","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, School of Basic Medical Sciences, Xuzhou Medical University, 221004 Xuzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Guo","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, School of Basic Medical Sciences, Xuzhou Medical University, 221004 Xuzhou, Jiangsu, China"},{"name":"Clinical Laboratory, Shiyan Hospital of Integrated Traditional and Western Medicine, 442001 Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohui","family":"Yuan","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, School of Basic Medical Sciences, Xuzhou Medical University, 221004 Xuzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, School of Basic Medical Sciences, Xuzhou Medical University, 221004 Xuzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuowei","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, School of Basic Medical Sciences, Xuzhou Medical University, 221004 Xuzhou, Jiangsu, China"},{"name":"First Clinical Medical College, Xuzhou Medical University, 221004 Xuzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Ding","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, School of Basic Medical Sciences, Xuzhou Medical University, 221004 Xuzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, School of Basic Medical Sciences, Xuzhou Medical University, 221004 Xuzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotian","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, School of Basic Medical Sciences, Xuzhou Medical University, 221004 Xuzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dexu","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Xuzhou Medical University, 221004 Xuzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8469-5548","authenticated-orcid":true,"given":"Feng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, School of Basic Medical Sciences, Xuzhou Medical University, 221004 Xuzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0607-218X","authenticated-orcid":true,"given":"Xiaomei","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, School of Basic Medical Sciences, Xuzhou Medical University, 221004 Xuzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Charabati M, Wheeler MA, Weiner HL, Quintana FJ. 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