Roles of Metformin and Pioglitazone in Regulating A1-like Astrocyte Activation in EAE Mice

BACKGROUND: Neuroinflammation serves as a pivotal driver of pathology in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) - 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: 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.