Department of Human Nutrition and Metabolism, Braun School of Public Health, Hebrew University Medical Faculty, Jerusalem, Israel.
Br J Pharmacol. 2010 Feb;159(4):950-7. doi: 10.1111/j.1476-5381.2009.00589.x. Epub 2010 Jan 29.
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.
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.
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.
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.
我们旨在证明大麻素（Cannabis sativa 的非精神活性成分）的一种成分——大麻二酚在胆管结扎（BDL）诱导的肝性脑病模型中发挥治疗作用与 5-羟色胺（1A）受体有关。
BDL 小鼠腹腔内给予大麻二酚（5mg·kg-1）4 周。通过八臂迷宫和旷场试验分别评估认知和运动能力。通过 RT-PCR 分析海马肿瘤坏死因子-α受体 1、脑源性神经营养因子（BDNF）和 5-羟色胺（1A）受体的基因表达。同时，与大麻二酚共给药 N-（2-（4-（2-甲氧基-苯基）-1-哌嗪-1-基）乙基）-N-（2-吡啶基）环己烷甲酰胺（WAY-100635），一种 5-羟色胺（1A）受体拮抗剂（0.5mg·kg-1）。
大麻二酚改善了 BDL 引起的认知和运动障碍，恢复了海马肿瘤坏死因子-α受体 1 和 BDNF 基因的表达，BDL 后这两个基因的表达分别增加和减少。它对 BDL 小鼠中减少的 5-羟色胺（1A）表达没有影响。大麻二酚的所有作用，除了 BDNF 表达的作用外，均被 WAY-100635 阻断，表明 5-羟色胺（1A）受体参与了大麻二酚的作用。大麻二酚对 BDL 引起的肝功能损害没有影响。
BDL 的行为结果既来自 5-羟色胺（1A）受体下调，也来自神经炎症。大麻二酚通过抗炎活性和激活该受体的联合作用逆转这些作用，从而改善神经功能缺陷，而不影响 5-羟色胺（1A）受体表达或肝功能。大麻二酚引起的 BDNF 上调似乎不是认知改善的原因。
