ArticleAntioxidants (Basel, Switzerland)2025
Short-Chain Fatty Acids Enhance EAAT2-Mediated Glutamate Clearance and Alleviate Oxidative Stress in an MPTP Mouse Model of Parkinson's Disease.
Article in Antioxidants (Basel, Switzerland), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Gut-Brain Axis Modulation by Short-Chain Fatty Acids Exerts Disease-Modifying Effects in a Murine Model of Drug-Resistant Epilepsy.Annals of neurology · 2026Article
- Epilepsy-Linked Gut Microbiota and Metabolic Signatures in Acquired Epilepsy: The Focus on Short-Chain Fatty Acid and Tryptophan Metabolism.Biomolecules · 2026Review
- Environmental Factors Drive Neurodegenerative Diseases Through Glutamate Excitotoxicity: A Convergent Mechanistic Pathway.Neuroscience bulletin · 2026Review
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Authors and funding
9 authors.
Funding
Abstract
Parkinson's 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-1β), and tumor necrosis factor-alpha (TNF-α) levels. SCFAs also restored redox homeostasis by elevating glutathione, reducing malondialdehyde, preserving superoxide dismutase activity, and promoting nuclear factor-erythroid 2-related 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.
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