Diacerein counteracts acetaminophen-induced hepatotoxicity in mice via targeting NLRP3/caspase-1/IL-1b and IL-4/MCP-1 signaling pathways

• Published in: Archives of pharmacal research pp. 142 - 158
• Main Authors: Mahmoud Elshal, Marwa E. Abdelmageed
• Format: Journal Article
• Language: English
• Published: 대한약학회 01.03.2022
• Subjects: 약학
• ISSN: 0253-6269; 1976-3786
• DOI: 10.1007/s12272-022-01373-7

The current study aims at repurposing the antiarthriticdrug diacerein (DCN) for the treatment of acetaminophenhepatotoxicity and investigating the potentialunderlying mechanisms. Mice were randomly divided intosix groups receiving either no treatment (control group),20 mg/kg DCN i.p , 400 mg/kg acetaminophen i.p , DCN 4 hbefore acetaminophen, DCN 2 h after acetaminophen, or400 mg/kg N-acetylcysteine (NAC) i.p , 2 h after acetaminophen. Biomarkers of liver dysfunction, oxidative stress,and apoptosis were assessed. Hepatic necroinfl ammatorychanges were evaluated along with hepatic expression ofNF-κB and caspase-1. The levels of NLRP3, IL-1β, IL-4,MCP-1, and TNF-α in the liver, as well as CYP2E1 mRNAexpression, were measured. Diacerein signifi cantly reducedbiomarkers of liver dysfunction, oxidative stress, hepatocytenecrosis, and infi ltration of neutrophils and macrophageswhether administered 4 h before or 2 h after acetaminophen. Further, the eff ects were comparable to those ofNAC. Diacerein also counteracted acetaminophen-inducedhepatocellular apoptosis by increasing Bcl-2 and decreasingBax and caspase-3 expression levels. Moreover, DCN normalizedhepatic TNF-α and signifi cantly decreased NF-κBp65 expression. Accordingly, DCN can prevent or reverseacetaminophen hepatotoxicity in mice, suggesting potentialutility as a repurposed drug for clinical treatment. KCI Citation Count: 0