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Amlexanox Ameliorates Acetaminophen-Induced Acute Liver Injury by Reducing Oxidative Stress in Mice

Amlexanox Ameliorates Acetaminophen-Induced Acute Liver Injury by Reducing Oxidative Stress in Mice

Jing Qi, Zixiong Zhou, Chae Woong Lim, Jong-Won Kim, Bumseok Kim

Toxicol Appl Pharmacol. 2019 Dec 15;385:114767.

PMID: 31697998

Abstract:

Amlexanox, a clinically approved small-molecule therapeutic presently used to treat allergic rhinitis, ulcer, and asthma, is an inhibitor of the noncanonical IkB kinase-ε (IKKε) and TANK-binding kinase 1 (TBK1). This study was to investigate the protective mechanism of amlexanox in acetaminophen (APAP)-induced acute liver injury (ALI). Mice were intraperitoneally injected with APAP (300 mg/kg, 12 h) to induce ALI and were orally administrated with amlexanox (25, 50 and 100 mg/kg) one hour after APAP treatment. Inhibition of IKKε and TBK1 by treatment of amlexanox attenuated APAP-induced ALI as confirmed by decreased serum levels of aspartate aminotransferase and alanine aminotransferase. Furthermore, amlexanox significantly decreased hepatocellular apoptosis in injured livers of mice as evidenced by histopathologic observation. Consistently, reduced oxidative stress by amlexanox was observed by increased hepatic glutathione concomitant with decreased levels of malondialdehyde. Amlexanox also enhanced expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes including heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase in injured livers of mice. Mechanistic insights into the mode of action of amlexanox against APAP-induced hepatotoxicity were involved in increasing phosphorylation of AMP-activated protein kinase (AMPK) and nuclear translocation of Nrf2, both in vivo and in vitro. Furthermore, the protective effects of amlexanox on APAP-induced hepatotoxicity were abolished by compound C, an AMPK inhibitor. Taken together, our findings suggest that amlexanox exerts antioxidative activities against APAP-mediated hepatotoxicity via AMPK/Nrf2 pathway.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP68302578	Amlexanox		68302-57-8	Price

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