Targeting endocannabinoid degradation protects against experimental colitis in mice:: involvement of CB1 and CB2 receptors
Targeting endocannabinoid degradation protects against experimental colitis in mice:: involvement of CB1 and CB2 receptors
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DOI：
10.1007/s00109-008-0359-6
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发表时间：
2008-08-01
影响因子：
4.7
通讯作者：
Sharkey, Keith A.
中科院分区：
文献类型：
--
作者：
Storr, Martin A.;Keenan, Catherine M.;Sharkey, Keith A.
内源性大麻素(EC)系统介导对肠道炎症的保护作用。在本研究中，我们研究了阻断EC降解或细胞重摄取在小鼠实验性结肠炎中的作用。在存在和不存在脂肪酸酰胺水解酶(FAAH)阻断剂URB597、EC膜运输抑制剂VDM11以及两者组合的情况下，用三硝基苯磺酸治疗小鼠。根据肉眼损伤评分、髓过氧化物酶水平和结肠长度的评估，在URB597和/或VDM11存在的情况下，炎症显著减轻。这些效应在CB1和CB2受体基因缺陷小鼠中被取消。通过不同途径诱导实验性结肠炎后的定量逆转录聚合酶链式反应显示，在不同的炎症模型中，FAAH信使RNA(MRNA)的表达在结肠炎早期显著降低，并随着疾病的进展而恢复到对照水平。对202例克罗恩病(CD)患者和206例健康对照的基因组DNA进行了FAAH基因C385A多态性分析，以探讨FAAH基因在人类中的可能作用。在本组中，C385A基因多态性在CD患者和健康对照组中分布均匀。总之，针对EC降解的药物在治疗炎症性肠病方面提供了治疗潜力。此外，FAAH基因表达的减少也参与了结肠炎的病理生理反应。
The endocannabinoid (EC) system mediates protection against intestinal inflammation. In this study, we investigated the effects of blocking EC degradation or cellular reuptake in experimental colitis in mice. Mice were treated with trinitrobenzene-sulfonic acid in presence and absence of the fatty acid amide hydrolase (FAAH) blocker URB597, the EC membrane transport inhibitor VDM11, and combinations of both. Inflammation was significantly reduced in the presence of URB597, VDM11, or both as evaluated by macroscopic damage score, myeloperoxidase levels, and colon length. These effects were abolished in CB1- and CB2-receptor-gene-deficient mice. Quantitative reverse transcription polymerase chain reaction after induction of experimental colitis by different pathways showed that expression of FAAH messenger RNA (mRNA) is significantly reduced in different models of inflammation early in the expression of colitis, and these return to control levels as the disease progresses. Genomic DNA from 202 patients with Crohn's disease (CD) and 206 healthy controls was analyzed for the C385A polymorphism in the FAAH gene to address a possible role in humans. In our groups, the C385A polymorphism was equally distributed in patients with CD and healthy controls. In conclusion, drugs targeting EC degradation offer therapeutic potential in the treatment of inflammatory bowel diseases. Furthermore, reduction of FAAH mRNA expression is involved in the pathophysiological response to colitis.