Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT1A receptor activation.

BACKGROUND AND PURPOSE: We aimed to demonstrate the involvement of 5-HT(1A) receptors in the therapeutic effect of cannabidiol, a non-psychoactive constituent of Cannabis sativa, in a model of hepatic encephalopathy induced by bile-duct ligation (BDL) in mice. EXPERIMENTAL APPROACH: Cannabidiol (5 mg x kg(-1); i.p.) was administered over 4 weeks to BDL mice. Cognition and locomotion were evaluated using the eight-arm maze and the open field tests respectively. Hippocampi were analysed by RT-PCR for expression of the genes for tumour necrosis factor-alpha receptor 1, brain-derived neurotrophic factor (BDNF) and 5-HT(1A) receptor. N-(2-(4-(2-methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), a 5-HT(1A) receptor antagonist (0.5 mg x kg(-1)), was co-administered with cannabidiol. Liver function was evaluated by measuring plasma liver enzymes and bilirubin. KEY RESULTS: Cannabidiol improved cognition and locomotion, which were impaired by BDL, and restored hippocampal expression of the tumour necrosis factor-alpha receptor 1 and the BDNF genes, which increased and decreased, respectively, following BDL. It did not affect reduced 5-HT(1A) expression in BDL mice. All the effects of cannabidiol, except for that on BDNF expression, were blocked by WAY-100635, indicating 5-HT(1A) receptor involvement in cannabidiol's effects. Cannabidiol did not affect the impaired liver function in BDL. CONCLUSIONS AND IMPLICATIONS: The behavioural outcomes of BDL result from both 5-HT(1A) receptor down-regulation and neuroinflammation. Cannabidiol reverses these effects through a combination of anti-inflammatory activity and activation of this receptor, leading to improvement of the neurological deficits without affecting 5-HT(1A) receptor expression or liver function. BDNF up-regulation by cannabidiol does not seem to account for the cognitive improvement.

Quality of life in patients stented for malignant biliary obstructions.

BACKGROUND/AIMS: Endoscopic stent placement is the standard treatment for patients with extrahepatic malignant biliary strictures (EMBS) who are too frail to undergo surgical resection. Stenting relieves jaundice and pruritus but the effects upon other systemic symptoms and quality of life (QOL) are not known. METHODS: Forty-seven patients (age: 46-89 years) with jaundice due to EMBS completed the European Organisation for Research and Treatment of Cancer QOL questionnaire, EORTC QLQ-C30, and two further questions assessing jaundice and pruritus, at the time of diagnosis and 1 month after endoscopic stenting. Thirty-eight patients successfully completed the study; nine patients succumbed to their illness within a month. RESULTS: No significant difference was found in the baseline QOL measurements and liver function tests between those patients who completed the study and those who were either too weak to answer the questionnaire or died within the first month of stenting. For patients who successfully completed follow-up, liver function tests (apart from serum albumin) improved after stenting. They also reported significant improvement in emotional, cognitive and global health scores (P < 0.01). In addition to the expected improvement in pruritus and jaundice (P < 0.01), anorexia, diarrhoea and sleep pattern were also reported to be improved (P < 0.01). CONCLUSION: Endoscopic stent insertion considerably improves a range of symptoms and enhances quality of life.

Altered preferences for sucrose, sodium chloride, urea and hydrochloric acid solutions in an animal model of cholestatic liver disease.

Preferences for sucrose, sodium chloride (NaCl), urea and hydrochloric acid (HCl) solutions (representing sweet, salty, bitter and sour stimuli) were examined in rats with bile duct ligation using 24-hr two-bottle choice tests. Preferences in bile duct ligated rats for sucrose and NaCl solutions were decreased relative to control animals in the initial stages following ligation (Days 1-5) and then increased in the later stages (Days 11-20). Preferences for both HCl and urea solutions were decreased briefly compared to control animals but showed no consistent pattern. The results provide the first demonstration for altered ingestive behavior in an animal model of liver disease and suggest that the bile duct ligated rat may be useful in studying mechanisms of chemosensory disturbances in human liver disease.