AG490 attenuates neuroinflammation in experimental autoimmune encephalomyelitis possible through promoting autophagy

Multiple sclerosis (MS) is an autoimmune inflammatory disorder that affects the central nervous system (CNS) and has been extensively studied in experimental autoimmune encephalomyelitis (EAE) animal models. AG490, which has potent neuroprotective activity, is used to investigate immune disorders associated with the CNS. In this study, we investigated the efficacy of AG490 in EAE mice and our findings revealed that AG490 suppressed NLRP3 inflammasome activation, increased AMPK phosphorylation and SIRT1 expression, as well as regulated Th1/Th17 cell differentiation and restarted autophagy influx in EAE model mice.

Additionally, AG490 upregulated the expressions of LC3-II/I and Beclin 1 (autophagic proteins), while downregulated the p62 and proinflammatory factors, IL-17 A, IL-1β, IFN-γ, and IL-18. Moreover, treatment with AG490 alleviated EAE-related spinal cord demyelination and inflammation; in contrast, 3-MA exacerbated these symptoms and delayed the remission of EAE in mice. Moreover, 3-MA coadministration reversed the therapeutic efficacy of AG490.

In vitro, AG490 suppressed the inflammatory level possible through promoting autophagy and inhibiting the activation of the NLRP3 inflammasome in CD4 + T cells. Overall, AG490 can resist inflammation and demyelination in EAE mice, and its satisfactory therapeutic efficacy is probably imparted by the regulation of autophagy and NLRP3 pathways. These findings suggest that AG490 has potential as a treatment for MS.

This study was supported by the Hebei Provincial Medical Science Research Project [Grant numbers 20240531]. This funding source did not influence the study outcomes, and the authors were free to interpret the data in accordance with a strict scientific rationale. Department of Neurology, Shijiazhuang People’s Hospital, Shijiazhuang, China Yumei Xue, Yu Zhao, Lifang Chu, Zhe Song, Bing Zhang & Xiaohui Su Shijiazhuang Key Laboratory of Oncology and Geriatric Diseases, Shijiazhuang, China The Key Laboratory of Neurology of Hebei Province, Shijiazhuang, China Yumei Xue, Yu Zhao, Lifang Chu, Zhe Song, Bing Zhang, Xiaohui Su & Xiaobing Li Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China Department of Neurology, The Third Hospital of Hebei Medical University, Shijiazhuang, China Clinical Trial Center for Drugs and Medical Devices, Shijiazhuang People’s Hospital, Shijiazhuang, China The authors declare no competing interests.

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