Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice

Yunhu Bai, Kenan Li, Xiaodong Li, Xiyu Chen, Jie Zheng, Feifei Wu, Jinghao Chen, Ze Li, Shuai Zhang, Kun Wu, Yong Chen (), Yayun Wang () and Yanling Yang ()
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Yunhu Bai: The Fourth Military Medical University
Kenan Li: The Fourth Military Medical University
Xiaodong Li: The Fourth Military Medical University
Xiyu Chen: The Fourth Military Medical University
Jie Zheng: The Fourth Military Medical University
Feifei Wu: The Fourth Military Medical University
Jinghao Chen: The Fourth Military Medical University
Ze Li: The Fourth Military Medical University
Shuai Zhang: The Fourth Military Medical University
Kun Wu: 518 Hospital
Yong Chen: The Fourth Military Medical University
Yayun Wang: The Fourth Military Medical University
Yanling Yang: The Fourth Military Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE), but the mechanism remains unclear. GABAergic neurons in substantia nigra pars reticulata (SNr) contribute to the motor deficit of HE. The present study aims to investigate the effects of oxidative stress on HE in male mice. The results validate the existence of oxidative stress in both liver and SNr across two murine models of HE induced by thioacetamide (TAA) and bile duct ligation (BDL). Systemic mitochondria-targeted antioxidative drug mitoquinone (Mito-Q) rescues mitochondrial dysfunction and oxidative injury in SNr, so as to restore the locomotor impairment in TAA and BDL mice. Furthermore, the GAD2-expressing SNr population (SNrGAD2) is activated by HE. Both overexpression of mitochondrial uncoupling protein 2 (UCP2) targeted to SNrGAD2 and SNrGAD2-targeted chemogenetic inhibition targeted to SNrGAD2 rescue mitochondrial dysfunction in TAA-induced HE. These results define the key role of oxidative stress in the pathogenesis of HE.

Date: 2023
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DOI: 10.1038/s41467-023-40081-8

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