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

Abstract

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

Funding

The study was supported by a grant from the Chang Gung Medical Research Project (BMRPC19, CMRPG3D1471, CMRPG3D1472, CMRPG3D1473) and the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-182A-061-MY2).

Abbreviations

ALF, acute liver failure; ALT, alanine transaminase; ANOVA, one-way analysis of variance; AP-1, activator protein 1; α₂-AR, α₂-adrenergic receptor; BAX, BCL2-associated X protein; BCL2, B-cell lymphoma 2; CRP, C-reactive protein; DEX, dexmedetomidine; DNA, deoxyribonucleic acid; DTT, 1,4-dithiothreitol; ECL, enhanced chemiluminescence; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular-signal-regulated kinase; GSH, glutathione; H&E, haematoxylin and eosin; HEPES, 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid; HRP, horseradish peroxidase; IL-1β, interleukin-1 β; IL-6, interleukin-6; IL-8, interleukin-8; I/R, ischemia and reperfusion; JNK, C-jun N-terminal kinase; KPO₄, potassium phosphate buffers; MAPK, mitogen-activated protein kinase; MAP2K4, mitogen-activated protein kinase kinase 4; MPO, myeloperoxidase; NAC, N-acetyl cysteine; NAPQI, N-acetyl-p-benzoquinone imine; NRf2, nuclear factor erythroid 2-related factor 2; PARA, acetaminophen; PBS, phosphate-buffered saline; PCNA, proliferating cell nuclear antigen; p-c-Jun, phospho-c-Jun; p-ERK, phospho-extracellular-signal-regulated kinase; p-JNK, phospho-c-jun N-terminal kinase; p-MAP2K4: phospho-mitogen-activated protein kinase kinase 4; PMSF, phenylmethane sulphonyl fluoride; ROS, reactive oxygen species; SEM, standard error of the mean; TNF-α, tumor necrosis factor-alpha.

Disclosure

The authors declare no conflicts of interest in this work.