Back to Search
Start Over
The MAP2K4/JNK/c-Jun Signaling Pathway Plays A Key Role In Dexmedetomidine Protection Against Acetaminophen-Induced Liver Toxicity.
- Source :
-
Drug design, development and therapy [Drug Des Devel Ther] 2019 Nov 14; Vol. 13, pp. 3887-3898. Date of Electronic Publication: 2019 Nov 14 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- Purpose: Dexmedetomidine [DEX; (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole] is a selective α <subscript>2</subscript> -adrenergic receptor (α <subscript>2</subscript> -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).<br />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.<br />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.<br />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.<br />Competing Interests: The authors declare no conflicts of interest in this work.<br /> (© 2019 Chou et al.)
- Subjects :
- Acetaminophen pharmacology
Animals
Chemical and Drug Induced Liver Injury metabolism
Dose-Response Relationship, Drug
JNK Mitogen-Activated Protein Kinases antagonists & inhibitors
JNK Mitogen-Activated Protein Kinases metabolism
Liver metabolism
MAP Kinase Kinase 4 antagonists & inhibitors
MAP Kinase Kinase 4 metabolism
Male
Mice
Mice, Inbred C57BL
Proto-Oncogene Proteins c-jun antagonists & inhibitors
Proto-Oncogene Proteins c-jun metabolism
Signal Transduction drug effects
Structure-Activity Relationship
Acetaminophen antagonists & inhibitors
Adrenergic alpha-2 Receptor Agonists pharmacology
Chemical and Drug Induced Liver Injury prevention & control
Dexmedetomidine pharmacology
Liver drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1177-8881
- Volume :
- 13
- Database :
- MEDLINE
- Journal :
- Drug design, development and therapy
- Publication Type :
- Academic Journal
- Accession number :
- 31814709
- Full Text :
- https://doi.org/10.2147/DDDT.S215473