Abstract
In our previous study, we concluded that sirtuin 5 (SIRT5) was highly expressed in microglia following ischaemic stroke, which induced excessive neuroinflammation and neuronal injury. Therefore, SIRT5-targeting interventions should reduce neuroinflammation and protect against ischaemic brain injury. Here, we showed that treatment with a specific SIRT5 inhibitor, MC3482, alleviated microglia-induced neuroinflammation and improved long-term neurological function in a mouse model of stroke. The mice were administrated with either vehicle or 2 mg/kg MC3482 daily for 7 days via lateral ventricular injection following the onset of middle cerebral artery occlusion. The outcome was assessed by a panel of tests, including a neurological outcome score, declarative memory, sensorimotor tests, anxiety-like behavior and a series of inflammatory factors. We observed a significant reduction of infarct size and inflammatory factors, and the improvement of long-term neurological function in the early stages during ischaemic stroke when the mice were treated with MC3482. Mechanistically, the administration of MC3482 suppressed the desuccinylation of annexin-A1, thereby promoting its membrane recruitment and extracellular secretion, which in turn alleviated neuroinflammation during ischaemic stroke. Based on our findings, MC3482 offers promise as an anti-ischaemic stroke treatment that targets directly the disease's underlying factors.
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The datasets used during the current study are available from the corresponding author on reasonable request.
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Funding
This study was supported by funding from the National Natural Science Foundation of China (No. 32271037 to XL, 82201472 to QX), Tongji Hospital (HUST) Foundation for Excellent Young Scientist (No. 2020YQ17 to XL), Shanxi Provincial Department of Science and Technology General projects in natural science research (No. 202203021221241 to YHW) and Scientific Research Foundation for the Returned Overseas Chinese Scholars, Tongji Hospital (No. 2021hgry011 to YLZ).
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Qian Xia and Yongbo Yu conceived the ideas and designed and conducted the experiments; Gaofeng Zhan, Xue Zhang, Shuai Gao and Tangrui Han conducted the data analysis; Yilin Zhao, Xing Li and Yonghong Wang conceived the ideas, designed the experiments, supervised the entire project, and wrote the manuscript. All authors contributed to manuscript revision and approved the submitted version.
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Xia, Q., Yu, Y., Zhan, G. et al. The Sirtuin 5 Inhibitor MC3482 Ameliorates Microglia‑induced Neuroinflammation Following Ischaemic Stroke by Upregulating the Succinylation Level of Annexin-A1. J Neuroimmune Pharmacol 19, 17 (2024). https://doi.org/10.1007/s11481-024-10117-x
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DOI: https://doi.org/10.1007/s11481-024-10117-x