Cannabidiol ameliorates cognitive and motor impairments in mice with bile duct ligation☆

Background/Aims

The endocannabinoid system in mice plays a role in models of human cirrhosis and hepatic encephalopathy (HE), induced by a hepatotoxin. We report now the therapeutic effects of cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa, on HE caused by bile duct ligation (BDL), a model of chronic liver disease.

Methods

CBD (5mg/kg; i.p.) was administered over 4weeks to mice that had undergone BDL.

Results

Cognitive function in the eight arm maze and the T-maze tests, as well as locomotor function in the open field test were impaired by the ligation and were improved by CBD. BDL raised hippocampal expression of the TNF-α-receptor 1 gene, which was reduced by CBD. However, BDL reduced expression of the brain-derived neurotrophic factor (BDNF) gene, which was increased by CBD. The effects of CBD on cognition, locomotion and on TNF-α receptor 1 expression were blocked by ZM241385, an A₂A adenosine receptor antagonist. BDL lowers the expression of this receptor.

Conclusions

The effects of BDL apparently result in part from down-regulation of A₂A adenosine receptor. CBD reverses these effects through activation of this receptor, leading to compensation of the ligation effect.

Abbreviations: HE, human cirrhosis and Hepatic Encephalopathy, CBD, cannabidiol, BDL, bile duct ligation, BDNF, brain-derived neurotrophic factor, LPS, lipopolysaccharide, ECs, endocannabinoids, CBr, cannabinoid receptors, Anandamide, arachidonoyl ethanolamide, 2-AG, 2-arachidonoylglycerol, TAA, hepatotoxin thioacetamide, A_2aArs, adenosine receptors, i.p., intraperitoneally, Ct, threshold cycle, BSF, Binational Science Foundation

Keywords: Cognition, Activity, Inflammation, Bile duct ligation, Gene expression