{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T21:20:03Z","timestamp":1791840003561,"version":"4.3.4"},"reference-count":68,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Natural Science Foundation Project of Chongqing Yuzhong District","award":["grant No. 20240130"],"award-info":[{"award-number":["grant No. 20240130"]}]},{"name":"National Training Program of Innovation and Entrepreneurship for Undergraduates","award":["202510631003"],"award-info":[{"award-number":["202510631003"]}]},{"name":"the Tutorial System of Medical Undergraduate Foundation of Experimental Teaching Center in Chongqing Medical University","award":["grant No. LTMCMTS202437 and LTMCMTS202438"],"award-info":[{"award-number":["grant No. LTMCMTS202437 and LTMCMTS202438"]}]},{"name":"the Project of Youth Innovative Talents Training Program of Chongqing","award":["grant No. CY220404"],"award-info":[{"award-number":["grant No. CY220404"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss, motor deficits, and oxidative stress. Emerging evidence suggests that short-chain fatty acids (SCFAs), microbial metabolites derived from gut fermentation, exert neuroprotective effects, but the underlying mechanisms remain incompletely understood. In this study, we investigated the role of SCFAs in modulating astrocytic glutamate clearance and oxidative stress in a PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behavioral tests demonstrated that SCFA treatment significantly improved locomotor activity, grip strength, and coordination, while attenuating dopaminergic neuron loss and tyrosine hydroxylase (TH) reduction in the substantia nigra and striatum. Mechanistically, SCFAs enhanced astrocytic glutamate uptake mediated by excitatory amino acid transporter 2 (EAAT2), suppressed astrocyte reactivity, and reduced neuroinflammation, as evidenced by decreased plasma interleukin-6 (IL-6), interleukin-1 beta (IL-1\u03b2), and tumor necrosis factor-alpha (TNF-\u03b1) levels. SCFAs also restored redox homeostasis by elevating glutathione, reducing malondialdehyde, preserving superoxide dismutase activity, and promoting nuclear factor-erythroid 2\u2013related factor 2 (Nrf2) nuclear translocation with upregulation of downstream antioxidant enzymes like heme oxygenase-1 (HO-1), superoxide dismutase 1 (SOD1), and superoxide dismutase 2 (SOD2). Inhibition of EAAT2 with dihydrokainic acid (DHK) abolished the beneficial effects of SCFAs, highlighting the critical role of EAAT2 in mediating SCFA-driven neuroprotection. Collectively, our findings demonstrate that SCFAs confer neuroprotection in PD by enhancing EAAT2-dependent glutamate clearance, reducing reactive oxygen species (ROS) accumulation, and activating Nrf2-dependent antioxidant pathways, providing a mechanistic basis for SCFA-based therapeutic strategies in PD.<\/jats:p>","DOI":"10.3390\/antiox14121429","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T16:31:52Z","timestamp":1764261112000},"page":"1429","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Short-Chain Fatty Acids Enhance EAAT2-Mediated Glutamate Clearance and Alleviate Oxidative Stress in an MPTP Mouse Model of Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Weiqi","family":"Li","sequence":"first","affiliation":[{"name":"Laboratory of Tissue and Cell Biology, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China"},{"name":"College of First Clinical, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue and Cell Biology, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China"},{"name":"College of First Clinical, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue and Cell Biology, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China"},{"name":"College of First Clinical, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhe","family":"Hu","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue and Cell Biology, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China"},{"name":"International Medical College, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wu","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue and Cell Biology, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China"},{"name":"College of Pediatrics, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songtao","family":"Ding","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue and Cell Biology, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Yu","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue and Cell Biology, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue and Cell Biology, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Handeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue and Cell Biology, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China"},{"name":"Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 400016, China"},{"name":"Center for Neuroscience Research, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s Disease","volume":"397","author":"Bloem","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S0140-6736(23)01478-2","article-title":"The Pathogenesis of Parkinson\u2019s Disease","volume":"403","author":"Morris","year":"2024","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1056\/NEJMra2401857","article-title":"Parkinson\u2019s Disease","volume":"391","author":"Tanner","year":"2024","journal-title":"N. 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