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Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1 and CB2 receptors

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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 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.

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Abbreviations

TNBS:

trinitrobenzene sulfonic acid

FAAH:

fatty acid amide hydrolase

2-AG:

2-arachidonyl glycerol

GI:

gastrointestinal

MAGL:

monoacyl-glycerol lipase

DSS:

dextran sodium sulfate

MPO:

myeloperoxidase

HTAB:

hexadecyl-trimethyl-ammonium-bromide

PBS:

phosphate-buffered saline

CD:

Crohn’s disease

IBD:

inflammatory bowel disease

CB1 :

cannabinoid-1

TRPV1:

transient receptor potential vanilloid-1

EC:

endocannabinoid

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Acknowledgments

We thank Winnie Ho for genotyping of the CB1- and CB2-receptor-gene-deficient mice used in this study and the CIHR Group grant molecular core facility. This work contains parts of the unpublished degree thesis of D. Emmerdinger. This work was supported by grants from the Canadian Institutes of Health Research (to KAS and KDP), the Crohn’s and Colitis Foundation of Canada (CCFC, to KAS and MAS), and a Deutsche Forschungsgemeinschaft (DFG) grant (to B.L.). Martin Storr is supported by a CCFC and Alberta Heritage Foundation for Medical Research (AHFMR) Visiting Scientist Awards, the Werner-Creutzfeldt Award of Gastrointestinal Pathophysiology of the German Society of Digestive Diseases (DGVS) and the DFG (STO645/2-1). Keith Sharkey is an AHFMR Medical Scientist and holds the Crohn’s and Colitis Foundation of Canada Chair in IBD Research at University of Calgary. Kamala Patel is an AHFMR Senior Scholar and Canada Research Chair. Stephan Brandt is supported by grants of the DFG (BR1912/5-1) and Else-Kröner-Fresenius-Stiftung (P60/05//EKMS05/62).

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, University of Calgary, 3280 Hospital Dr. N.W., Calgary, Alberta, T2N 4N1, Canada

    Martin A. Storr

  2. Institute of Infection, Immunity and Inflammation and Hotchkiss Brain Institute, Department of Physiology & Biophysics, University of Calgary, 3280 Hospital Dr. N.W., Calgary, Alberta, T2N 4N1, Canada

    Martin A. Storr, Catherine M. Keenan, Hong Zhang, Kamala D. Patel & Keith A. Sharkey

  3. Department of Internal Medicine II, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany

    Martin A. Storr, Dominik Emmerdinger, Birol Yüce, Andrei Sibaev, Burkhard Göke & Stephan Brand

  4. INSERM, Inst. F. Magendi, Avenir 146 Rue Leo Saignat, 33077, Bordeaux, France

    Federico Massa

  5. Institute of Experimental Surgery, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany

    Birol Yüce & Andrei Sibaev

  6. Department of Physiological Chemistry, Johannes Gutenberg-University, 55099, Mainz, Germany

    Federico Massa & Beat Lutz

  7. Department of Biological Sciences, California State Polytechnic University, Pomona, CA, 91768, USA

    Nancy E. Buckley

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  1. Martin A. Storr
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Correspondence to Martin A. Storr.

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Storr, M.A., Keenan, C.M., Emmerdinger, D. et al. Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1 and CB2 receptors. J Mol Med 86, 925–936 (2008). https://doi.org/10.1007/s00109-008-0359-6

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  • DOI: https://doi.org/10.1007/s00109-008-0359-6

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