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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
Volume 15 - 2024 |
doi: 10.3389/fphar.2024.1387409
Feasibility exploration of GSH in the treatment of acute hepatic encephalopathy from the aspects of pharmacokinetics, pharmacodynamics, and mechanism
Provisionally accepted- 1 China Pharmaceutical University, Nanjing, Jiangsu Province, China
- 2 Hebei Chemical and Pharmaceutical College, Shijiazhuang, Hebei Province, China
- 3 Hebei Zhitong Biopharmaceutical Co Ltd, Shijiazhuang, China
Our previous study highlighted the therapeutic potential of glutathione (GSH), an intracellular thiol tripeptide ubiquitous in mammalian tissues, in mitigating hepatic and cerebral damage. Building on this premise, we posited the hypothesis that GSH could be a promising candidate for treating acute hepatic encephalopathy (AHE). To verify this conjecture, we systematically investigated the feasibility of GSH as a therapeutic agent for AHE through comprehensive pharmacokinetic, pharmacodynamic, and mechanistic studies using a thioacetamide-induced AHE rat model. Our pharmacodynamic data demonstrated that oral GSH could significantly improve behavioral scores and reduce hepatic damage of AHE rats by regulating intrahepatic ALT, AST, inflammatory factors, and homeostasis of amino acids. Additionally, oral GSH demonstrated neuroprotective effects by alleviating the accumulation of intracerebral glutamine, down-regulating glutamine synthetase, and reducing taurine exposure. Pharmacokinetic studies suggested that AHE modeling led to significant decrease in hepatic and cerebral exposure of GSH and cysteine. However, oral GSH greatly enhanced the intrahepatic and intracortical GSH and CYS in AHE rats. Given the pivotal roles of CYS and GSH in maintaining redox homeostasis, we investigated the interplay between oxidative stress and pathogenesis/treatment of AHE. Our data revealed that GSH administration significantly relieved oxidative stress levels caused by AHE modeling via down-regulating the expression of NADPH oxidase 4 (NOX4) and NF-κB P65. Importantly, our findings further suggested that GSH administration significantly regulated the excessive endoplasmic reticulum (ER) stress caused by AHE modeling through the iNOS/ATF4/Ddit3 pathway. In summary, our study uncovered that exogenous GSH could stabilize intracerebral GSH and CYS levels to act on brain oxidative and ER stress, which have great significance for revealing the therapeutic effect of GSH on AHE and promoting its further development and clinical application.
Keywords: Glutathione, Acute hepatic encephalopathy, Oxidative Stress, Endoplasmic Reticulum Stress, iNOS/ATF4/Ddit3
Received: 17 Feb 2024; Accepted: 06 May 2024.
Copyright: © 2024 Hu, Xu, Fan, Liu, Di, Xu, Wu, Ding, Zhang, Wang, Ai, Xie, Wang and Liang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Kangrui Hu, China Pharmaceutical University, Nanjing, 210009, Jiangsu Province, China
Yexin Xu, China Pharmaceutical University, Nanjing, 210009, Jiangsu Province, China
Jiye Fan, Hebei Chemical and Pharmaceutical College, Shijiazhuang, 050026, Hebei Province, China
Huafang Liu, China Pharmaceutical University, Nanjing, 210009, Jiangsu Province, China
Chanjuan Di, Hebei Zhitong Biopharmaceutical Co Ltd, Shijiazhuang, China
Feng Xu, Hebei Zhitong Biopharmaceutical Co Ltd, Shijiazhuang, China
Linlin Wu, China Pharmaceutical University, Nanjing, 210009, Jiangsu Province, China
Ke Ding, China Pharmaceutical University, Nanjing, 210009, Jiangsu Province, China
Tingting Zhang, China Pharmaceutical University, Nanjing, 210009, Jiangsu Province, China
Leyi Wang, China Pharmaceutical University, Nanjing, 210009, Jiangsu Province, China
Haoyu Ai, China Pharmaceutical University, Nanjing, 210009, Jiangsu Province, China
Lin Xie, China Pharmaceutical University, Nanjing, 210009, Jiangsu Province, China
Guangji Wang, China Pharmaceutical University, Nanjing, 210009, Jiangsu Province, China
Yan Liang, China Pharmaceutical University, Nanjing, 210009, Jiangsu Province, China
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