2. Academic Validation
  3. Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice

Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice

  • Nat Commun. 2023 Jul 24;14(1):4456. doi: 10.1038/s41467-023-40081-8.
Yunhu Bai # 1 2,  Kenan Li # 3,  Xiaodong Li 1,  Xiyu Chen 1,  Jie Zheng 3,  Feifei Wu 3,  Jinghao Chen 1,  Ze Li 3,  Shuai Zhang 3,  Kun Wu 4,  Yong Chen 5,  Yayun Wang 6,  Yanling Yang 7
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
  • 2 Department of General Surgery, 988 Hospital of Joint Logistic Support Force, Zheng Zhou, 450000, China.
  • 3 Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, 710032, China.
  • 4 Department of pharmacy, 518 Hospital, Xi'an, 710032, China.
  • 5 Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China. gdwkcy@163.com.
  • 6 Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, 710032, China. wangyy@fmmu.edu.cn.
  • 7 Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China. yangyanl@fmmu.edu.cn.
  • # Contributed equally.
PMID: 37488119 DOI: 10.1038/s41467-023-40081-8
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.

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