The MAP2K4/JNK/c-Jun Signaling Pathway Plays a Key Role in Dexmedetomidine Protection Against Acetaminophen-Induced Liver Injury

Abstract

Background: 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 hepatoprotective effects against acetaminophen (APAP)-induced liver injury. Methods: APAP-induced hepatotoxic mice were established by intraperitoneal administration of a hepatotoxic dose of APAP (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. Findings: DEX treatment significantly attenuated APAP-induced liver injury in mice, with the strongest beneficial effects at a dose of 25 μg/kg. The levels of hepatic cytokines (TNF-α and 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 4 (MAP2K4), c-jun N-terminal kinase (JNK), and c-Jun expression induced by APAP overdose. Interpretation: The data suggests 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 APAP-induced hepatotoxicity. Funding: The present study was supported by a grant from the Chang Gung Medical Research Project (BMRPC19, CMRPG3D1471, CMRPG3D1472, CMRPG3D1473), Chang Gung Memorial Hospital, Linkou, Taiwan, and the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-182A- 061- MY2). Declaration of Interest: The authors have declared that no conflict of interest exists. Ethical Approval: All animal study protocols were reviewed and approved by the Institutional Animal Care and Use Committee of Chang Gung University. All experiments were performed according to the guidelines of the Animal Welfare Act and the Guide for Care and Use of Laboratory Animals from the National Institutes of Health.