Back to Journals » Drug Design, Development and Therapy » Volume 13

The MAP2K4/JNK/c-Jun Signaling Pathway Plays A Key Role In Dexmedetomidine Protection Against Acetaminophen-Induced Liver Toxicity

Authors Chou A-H, Liao CC, Lee HC, Liou J-T, Liu FC

Received 12 May 2019

Accepted for publication 2 October 2019

Published 14 November 2019 Volume 2019:13 Pages 3887—3898


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4

Editor who approved publication: Professor Manfred Ogris

An-Hsun Chou,1–3 Chia-Chih Liao,1,2 Hung-Chen Lee,1,4 Jiin-Tarng Liou,1,2 Fu-Chao Liu1,2

1Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Anesthesiology, Xiamen Chang Gung Hospital, Taoyuan, Taiwan; 4Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan

Correspondence: Fu-Chao Liu
Department of Anesthesiology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 5, Fusing Street, Gueishan District, Taoyuan City 33305, Taiwan
Tel +886-3-3281200 (ext. 3624)
Fax +886-3-3281200 (ext. 2787)

Purpose: Dexmedetomidine [DEX; (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole] is a selective α2-adrenergic receptor (α2-AR) agonist that attenuates the liver damage associated with local or systemic inflammation. However, it remains unclear whether DEX has protective effects against acetaminophen (Paracetamol, PARA)-induced liver toxicity (PILT).
Methods: PILT mice were established by intraperitoneal administration of a hepatotoxic dose of acetaminophen (300 mg/kg). Thirty minutes later, the mice were treated with DEX at a concentration of 0, 5, 25, or 50 μg/kg. Blood and liver samples were obtained for further analysis.
Results: DEX treatment significantly attenuated PILT in mice, with the strongest beneficial effects at a dose of 25 μg/kg. The levels of hepatic cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), in addition to myeloperoxidase (MPO) activity, were significantly decreased following DEX treatment. Moreover, DEX treatment reduced macrophage recruitment around the area of hepatotoxicity and the expression levels of hepatic phosphorylated mitogen-activated protein kinase kinase 4 (MAP2K4), c-jun N-terminal kinase (JNK), and c-Jun expression induced by acetaminophen overdose.
Conclusion: The data suggest that DEX likely downregulates the JNK signaling pathway and its downstream effectors to promote its hepatoprotective effect, providing a clinical application of DEX for the attenuation of PILT.

Keywords: dexmedetomidine, acetaminophen-induced liver toxicity, MAP2K4/JNK/c-Jun

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]