Abstract
Cannabidiol (CBD) is a non-psychoactive component of marijuana, which has anti-inflammatory effects. It has also been approved by FDA for various orphan diseases for exploratory trials. Herein, we investigated the effects of CBD on liver injury induced by chronic plus binge alcohol feeding in mice. CBD or vehicle was administered daily throughout the alcohol feeding study. At the conclusion of the feeding protocol, serums samples, livers or isolated neutrophils were utilized for molecular biology, biochemistry and pathology analysis. CBD significantly attenuated the alcohol feeding-induced serum transaminase elevations, hepatic inflammation (mRNA expressions of TNFα, MCP1, IL1β, MIP2 and E-Selectin, and neutrophil accumulation), oxidative/nitrative stress (lipid peroxidation, 3-nitrotyrosine formation, and expression of reactive oxygen species generating enzyme NOX2). CBD treatment also attenuated the respiratory burst of neutrophils isolated from chronic plus binge alcohol fed mice or from human blood, and decreased the alcohol-induced increased liver triglyceride and fat droplet accumulation. Furthermore, CBD improved alcohol-induced hepatic metabolic dysregulation and steatosis by restoring changes in hepatic mRNA or protein expression of ACC-1, FASN, PPARα, MCAD, ADIPOR-1, and mCPT-1. Thus, CBD may have therapeutic potential in the treatment of alcoholic liver diseases associated with inflammation, oxidative stress and steatosis, which deserves exploration in human trials.
Highlights
Chronic alcohol consumption is a leading cause of alcoholic liver disease in the USA and worldwide, which eventually may progress to cirrhosis or hepatocellular carcinoma in susceptible subjects[1,2]
Since hepatic steatosis and neutrophil infiltration[1,22,23] are critical pathological features of alcohol-induced liver injury, and the previously discussed studies suggested that CBD had beneficial effect on these processes, we investigated the effects of CBD on alcohol-induced liver steatosis, metabolic changes, inflammation and neutrophil-mediated oxidative injury, using a well-established model of chronic ethanol feeding plus binge alcohol gavage (NIAAA model)[24,25], which closely relates to human drinking behavior[26]
Chronic alcohol consumption is a major cause of alcoholic liver disease characterized by metabolic dysregulation, enhanced oxidative stress, inflammation and steatosis in the liver, which may eventually culminate in cirrhosis or hepatocellular carcinoma in susceptible subjects[1,2]
Summary
Chronic alcohol consumption is a leading cause of alcoholic liver disease in the USA and worldwide, which eventually may progress to cirrhosis or hepatocellular carcinoma in susceptible subjects[1,2]. CBD improved brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice[15], decreased hepatic ischemia-reperfusion induced injury both in mice[16] and rats[17], attenuated alcohol-binge-induced injury in mice[18] and hepatotoxicity of cadmium[19] and cocaine[20] Some of these studies have not explored the detailed mechanisms behind the protective effects of CBD against liver injury, but others proposed attenuation of the pro-inflammatory response and signaling (e.g. neutrophil infiltration, TNF-α, macrophage inflammatory protein-1α/2, cyclooxygenase 2, nuclear factor kappa B (NF-κB), oxidative/nitrative stress, stress signaling (p38MAPK and JNK) and cell death (apoptotic/necrotic), as well as promotion of autophagy[16,17,18]. Our results may have important implication for treatment of liver steatosis in alcoholic liver disease
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