A novel cannabinoid 2 (CB2) receptor agonists, LEI-102 protects against alcohol-induced liver injury

Authors

• Y Wang
• K Erdelyi
• E Holovac
• G Szanda
• R Cinar
• B Gao
• G Kunos
• MVD Stelt
• P Pacher

Abstract

Cannabinoid 2 receptor (CB2) is emerging as an attractive therapeutic target for various forms of tissue injury and inflammatory diseases. CB2 receptors are predominantly expressed by immune or immune-derived cells, therefore targeting these receptors is not associated with undesirable consequences of cannabinoid 1 receptor (CB1) stimulation in the CNS or cardiovascular system. We recently identified a potent and selective CB2 agonist LEI-102. Herein, we investigated the effects of LEI-102 on liver injury induced by chronic plus binge alcohol feeding, as well as in an established nephropathy model induced by cisplatin in mice. Chronic treatment with LEI-102 markedly attenuated the alcohol feeding-induced liver transaminases elevations, hepatic inflammation (mRNA expressions of TNFα, MCP1, IL1β, MIP2 and E-Selectin, and neutrophil accumulation), oxidative/nitrative stress (lipid peroxidation, 3-nitrotyrosin formation, and expression of reactive oxygen species generating enzyme NADPH oxidase NOX2 and p67phox isoforms). LEI-102 treatment also decreased the alcohol-induced increased liver triglyceride and fat droplet accumulation (measured by oil-O-Red staining). At 3 or 10 mg/kg (p.o. or i.p.) the drug dose-dependently prevented kidney inflammation, oxidative stress, histopathological injury and renal dysfunction induced by cisplatin in mice. Furthermore, LEI-102 had excellent oral bioavailability in mice reaching high concentrations in kidney and liver. Taken together, these results show that CB2 agonist LEI-102 protects against alcohol-induced liver or cisplatin-induced kidney injury by attenuating inflammation, oxidative stress and parenchymal damage. Thus, targeting CB2 may be a promising treatment in diseases of the liver and kidney that are associated with enhanced inflammation and/or oxidative stress.

Scientific Focus Area: Molecular Pharmacology

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