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

J Hepatol. 2009 Sep;51(3):528-34. doi: 10.1016/j.jhep.2009.04.021. Epub 2009 May 27.

Abstract

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-alpha-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-alpha receptor 1 expression were blocked by ZM241385, an A(2)A adenosine receptor antagonist. BDL lowers the expression of this receptor.

Conclusions: The effects of BDL apparently result in part from down-regulation of A(2)A adenosine receptor. CBD reverses these effects through activation of this receptor, leading to compensation of the ligation effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Antagonists
  • Animals
  • Bile Ducts / physiopathology
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cannabidiol / pharmacology
  • Cannabidiol / therapeutic use*
  • Chronic Disease
  • Cognition / drug effects
  • Cognition / physiology
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / etiology*
  • Cognition Disorders / metabolism
  • Cyclooxygenase 2 / metabolism
  • Disease Models, Animal
  • Female
  • Gait Disorders, Neurologic / drug therapy*
  • Gait Disorders, Neurologic / etiology*
  • Gait Disorders, Neurologic / metabolism
  • Hepatic Encephalopathy / complications*
  • Hepatic Encephalopathy / etiology
  • Ligation / adverse effects
  • Liver Diseases / complications*
  • Liver Diseases / etiology
  • Mice
  • Mice, Inbred Strains
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • RNA, Messenger / metabolism
  • Receptor, Adenosine A2A / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Treatment Outcome
  • Triazines / pharmacology
  • Triazoles / pharmacology

Substances

  • Adenosine A2 Receptor Antagonists
  • Brain-Derived Neurotrophic Factor
  • RNA, Messenger
  • Receptor, Adenosine A2A
  • Receptors, Tumor Necrosis Factor, Type I
  • Triazines
  • Triazoles
  • ZM 241385
  • Cannabidiol
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2