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Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1 and CB2
Martin A Storr1, Catherine M Keenan, Dominik Emmerdinger
1Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada. mstorr@ucalgary.ca
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.
Insights
Blocking the degradation or reuptake of endocannabinoids (ECs) significantly reduced intestinal inflammation in mice with colitis. Targeting EC degradation pathways shows therapeutic potential for inflammatory bowel diseases.
Area of Science:
- Gastroenterology
- Immunology
- Pharmacology
Background:
- The endocannabinoid (EC) system plays a crucial role in protecting the gastrointestinal tract from inflammation.
- Understanding the EC system's mechanisms in inflammatory conditions is vital for developing new therapies.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting endocannabinoid degradation or reuptake in experimental colitis.
- To explore the role of fatty acid amide hydrolase (FAAH) and EC transporters in inflammatory bowel disease (IBD).
Main Methods:
- Experimental colitis was induced in mice using trinitrobenzene-sulfonic acid.
- Mice were treated with URB597 (FAAH blocker) and VDM11 (EC membrane transport inhibitor), alone and in combination.
- Inflammation was assessed via macroscopic damage, myeloperoxidase levels, and colon length.
- Gene expression analysis (FAAH mRNA) and genetic analysis of the FAAH C385A polymorphism in Crohn's disease patients were performed.
Main Results:
- Treatment with URB597, VDM11, or both significantly reduced colitis severity in mice.
- These protective effects were dependent on cannabinoid receptors (CB1 and CB2).
- FAAH mRNA expression was downregulated early in colitis models but returned to normal levels as the disease resolved.
- The FAAH C385A polymorphism showed no significant association with Crohn's disease in the studied cohort.
Conclusions:
- Inhibiting EC degradation pathways presents a promising therapeutic strategy for inflammatory bowel diseases.
- Reduced FAAH mRNA expression is implicated in the pathophysiology of colitis.
- Targeting the endocannabinoid system offers a novel approach for managing intestinal inflammation.
