title: Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1 and CB2 receptors.
abstract: 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 CB(1)- and CB(2)-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.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada. mstorr@ucalgary.ca
authors.forename: Martin A
authors.initials: MA
authors.lastname: Storr
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Keenan
authors.forename: Dominik
authors.initials: D
authors.lastname: Emmerdinger
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Birol
authors.initials: B
authors.lastname: Yüce
authors.forename: Andrei
authors.initials: A
authors.lastname: Sibaev
authors.forename: Federico
authors.initials: F
authors.lastname: Massa
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Buckley
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
authors.forename: Kamala D
authors.initials: KD
authors.lastname: Patel
authors.forename: Keith A
authors.initials: KA
authors.lastname: Sharkey
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002219:Carbamates / Q000627:therapeutic use; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D063388:Endocannabinoids; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid / Q000627:therapeutic use; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D063388:Endocannabinoids; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D014302:Trinitrobenzenesulfonic Acid; D000099252:Fatty Acid Amide Hydrolases; C462953:N-(2-methyl-3-hydroxyphenyl)-5,8,11,14-eicosatetraenamide; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester