Abstract
This study aims to investigate the effect of irisin on ethanol-induced behavioral deficits and explore the underlying mechanisms. A mouse model of ethanol addiction/withdrawal was constructed through chronic ethanol administration. Depressive-like behaviors were evaluated by the tail suspension test and forced swimming test, and anxiety-like behaviors were evaluated by the marble-burying test and elevated plus maze test. The expression of Nrf2 was measured by western blotting. Levels of inflammatory mediators (NF-κB, TNF-α, IL-1β and IL-6) and oxidative stress factors (ROS, MDA, GSH and SOD) were detected by ELISA. The ethanol-induced PC12/BV2 cell injury model was used to elucidate whether the effect of irisin on ethanol-induced neurological injury was related to anti-inflammatory and antioxidant mechanisms. Ethanol-induced ethanol preference and emotional deficits were improved by chronic irisin treatment; however, these improvements were partly reversed by cotreatment with the Nrf2 inhibitor ML385. Further results implied that the improvement effect of irisin on behavioral abnormalities may be related to its anti-inflammatory and antioxidant effects. In detail, irisin inhibited ethanol-induced abnormal expression of ROS and MDA and upregulated the expression of GSH and SOD. Meanwhile, irisin treatment inhibited ethanol-induced overexpression of NF-κB, TNF-α, IL-1β and IL-6 in the hippocampus and cerebral cortex. The regulation of oxidative stress factors by irisin was reversed after ML385 treatment. In the in vitro study, overexpression of oxidative stress factors in ethanol-treated PC12 cells was inhibited by irisin treatment; however, the prevention was reversed after the knockdown of Nrf2 siRNA. Moreover, ethanol-induced overexpression of inflammatory mediators in BV2 cells was also inhibited by irisin treatment. Irisin improved depressive and anxiety-like behaviors induced by ethanol addiction/withdrawal in mice, and this protection was greatly associated with the NF-κB-mediated anti-inflammatory signaling pathway and Nrf2-mediated antioxidative stress signaling pathway.
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References
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Acknowledgements
The authors thank Dr Ying Hu, Dean of Pharmacology Department, Manipal Zhejiang Pharmaceutical University, for providing facilities to carry out this project, and Mr Yingzheng Zhao Head of Department of Pharmacy, Wenzhou Medical College, for facilitating the animal experiments and providing necessary support to carry out this project.
Funding
This work was funded by Zhejiang Province Public Welfare Technology Application Research Project of China (LGF18H090014), Public science and technology project of Ningbo (202002N3151) for Xuefeng Yu. The Science and Technology Project of Zhejiang Medical and Health Department (2020KY289), Ningbo Natural Science Foundation (2019A610300), the Science and Technology Project of Ningbo Yinzhou District (2022AS036) for Xi Jiang. The Science and Technology Project of Zhejiang Medical and Health Department (2023KY1254) for Qizhi Yan.
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Conceptualization, Xi Jiang and Xuefeng Yu; Data curation, Qizhi Yan, Qian Lin and Xuefeng Yu; Formal analysis, Xi Jiang, Lei Chen and Jin Chen; Methodology, Qizhi Yan, Wendie Lao and Fuhe Liu; Project administration, Qian Lin and Haoran Cao.
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This study and included experimental procedures were approved by the institutional animal care and use committee of Wenzhou Medical University (approval no. wydw2021-01913). All animal housing and experiments were conducted in strict accordance with the institutional guidelines for care and use of laboratory animals.
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The expression of nuclear Nrf2 in control and siRNA-treated PC12 cells. Values are expressed as the mean ± S.E.M. n = 6. ***p < 0.001 compared with the control group. (JPG 186 KB)
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Jiang, X., Yan, Q., Lao, W. et al. Irisin attenuates ethanol-induced behavioral deficits in mice through activation of Nrf2 and inhibition of NF-κB pathways. Metab Brain Dis 38, 1643–1656 (2023). https://doi.org/10.1007/s11011-023-01202-w
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DOI: https://doi.org/10.1007/s11011-023-01202-w