Drug Design, Development and Therapy (Nov 2019)
The MAP2K4/JNK/c-Jun Signaling Pathway Plays A Key Role In Dexmedetomidine Protection Against Acetaminophen-Induced Liver Toxicity
Abstract
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, TaiwanCorrespondence: Fu-Chao LiuDepartment of Anesthesiology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 5, Fusing Street, Gueishan District, Taoyuan City 33305, TaiwanTel +886-3-3281200 (ext. 3624)Fax +886-3-3281200 (ext. 2787)Email [email protected]: 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
