A novel reactive aldehyde species inhibitor prevents the deleterious effects of ethanol in an animal model of alcoholic liver disease

• Published in: International immunopharmacology Vol. 113; p. 109400
• Main Authors: Duryee, Michael J., Aripova, Nozima, Hunter, Carlos D., Ruskamp, Ryan J., Tessin, Mariah R., Works, Duncan R., Mikuls, Ted R., Thiele, Geoffrey M.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.12.2022
• Subjects: Alcoholic liver disease; Aldehydes; Inflamation; Malondialdehyde acetaldehyde adducts; Reactive aldehyde species (RASP) inhibitors; Triglycerides; Reactive aldehyde species (RASP) inhibitors; Triglycerides; Aldehydes; Inflamation; Malondialdehyde acetaldehyde adducts; Alcoholic liver disease
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2022.109400

•Reactive aldehyde species inhibitors trap aldehydes produced from ethanol metabolism.•Triglycerides generated from ethanol metabolism are reduced by reactive aldehyde species inhibitors.•Reactive aldehyde species inhibitors reduce inflammation.•Reactive aldehyde species inhibitors may be used as a potential treatment for alcoholic liver disease. Current treatment strategies for alcoholic liver disease (ALD) are limited by the lack of agents specifically targeting the metabolic breakdown products of ethanol. Reactive aldehyde species (RASP) inhibitors have been developed that have the capability to sequester these aldehyde byproducts, potentially limiting toxicity. The purpose of this study was to determine if the RASP inhibitor ADX-629 could target these metabolic breakdown products in a mouse model of ALD. A chronic/binge mouse model of ALD was used to determine the efficacy of ADX-629 treatment. Mice were fed an alcohol-containing (5 %) liquid or control diet for 10 days and treated by oral gavage with ADX-629 30 min prior to administering a bolus gavage of 31.5 % ethanol. Test groups included: Control - no ADX, Control + ADX, Ethanol – no ADX and Ethanol + ADX. Compared to ethanol-fed mice receiving sham treatment, ethanol mice treated with ADX-629 demonstrated significant decreases (p < 0.05) in liver acetaldehyde (AA), liver malondialdehyde-acetaldehyde (MAA), circulating anti-MAA antibody, liver/serum triglycerides (p < 0.01) levels, and overall fat accumulation in the liver as determined by Oil Red O and bodipy staining (p < 0.0001). Serum levels of pro-inflammatory cytokines IFN-γ and MCP-1 levels were decreased following ADX-629 treatment (p < 0.01). These findings demonstrate that the use of this unique RASP inhibitor (ADX-629) is effective in the treatment of ALD. Given the ubiquitous nature of aldehydes in the context of tissue inflammation and damage, ADX-629 and other RASP inhibitors may have additional applications in disease states.