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Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation.

Abstract

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions for which new therapeutic approaches are needed. Genetic and pharmacological data point to a protective role of CB(1) and CB(2) cannabinoid receptor activation in IBD experimental models. Therefore, increasing the endogenous levels of 2-arachidonoylglycerol, the main full agonist of these receptors, should have beneficial effects on colitis. 2-Arachidonoylglycerol levels were raised in the trinitrobenzene sulfonic acid (TNBS)-induced colitis mouse model by inhibiting monoacylglycerol lipase (MAGL), the primary enzyme responsible for hydrolysis of 2-arachidonoylglycerol, using the selective inhibitor JZL184. MAGL inhibition in diseased mice increased 2-arachidonoylglycerol levels, leading to a reduction of macroscopic and histological colon alterations, as well as of colonic expression of proinflammatory cytokines. The restored integrity of the intestinal barrier function after MAGL inhibition resulted in reduced endotoxemia as well as reduced peripheral and brain inflammation. Coadministration of either CB(1) (SR141716A) or CB(2) (AM630) selective antagonists with JZL184 completely abolished the protective effect of MAGL inhibition on TNBS-induced colon alterations, thus demonstrating the involvement of both cannabinoid receptors. In conclusion, increasing 2-arachidonoylglycerol levels resulted in a dramatic reduction of colitis and of the related systemic and central inflammation. This could offer a novel pharmacological approach for the treatment of IBD based on the new protective role of 2-arachidonoylglycerol described here.

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  • Authors+Show Affiliations

    ,

    Université Catholique de Louvain, Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids Research Group, CHAM7230, Av. E. Mounier 72, 1200 Bruxelles, Belgium.

    , , ,

    Source

    MeSH

    Animals
    Arachidonic Acids
    Benzodioxoles
    Colitis
    Disease Models, Animal
    Endocannabinoids
    Endotoxemia
    Enzyme Inhibitors
    Glycerides
    Humans
    Indoles
    Inflammation
    Inflammation Mediators
    Inflammatory Bowel Diseases
    Male
    Mice
    Mice, Inbred C57BL
    Monoacylglycerol Lipases
    Piperidines
    Pyrazoles
    Receptor, Cannabinoid, CB1
    Receptor, Cannabinoid, CB2
    Rimonabant
    Trinitrobenzenesulfonic Acid

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21551239

    Citation

    TY - JOUR T1 - Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation. AU - Alhouayek,Mireille, AU - Lambert,Didier M, AU - Delzenne,Nathalie M, AU - Cani,Patrice D, AU - Muccioli,Giulio G, Y1 - 2011/05/06/ PY - 2011/5/10/entrez PY - 2011/5/10/pubmed PY - 2011/10/15/medline SP - 2711 EP - 21 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J. VL - 25 IS - 8 N2 - Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions for which new therapeutic approaches are needed. Genetic and pharmacological data point to a protective role of CB(1) and CB(2) cannabinoid receptor activation in IBD experimental models. Therefore, increasing the endogenous levels of 2-arachidonoylglycerol, the main full agonist of these receptors, should have beneficial effects on colitis. 2-Arachidonoylglycerol levels were raised in the trinitrobenzene sulfonic acid (TNBS)-induced colitis mouse model by inhibiting monoacylglycerol lipase (MAGL), the primary enzyme responsible for hydrolysis of 2-arachidonoylglycerol, using the selective inhibitor JZL184. MAGL inhibition in diseased mice increased 2-arachidonoylglycerol levels, leading to a reduction of macroscopic and histological colon alterations, as well as of colonic expression of proinflammatory cytokines. The restored integrity of the intestinal barrier function after MAGL inhibition resulted in reduced endotoxemia as well as reduced peripheral and brain inflammation. Coadministration of either CB(1) (SR141716A) or CB(2) (AM630) selective antagonists with JZL184 completely abolished the protective effect of MAGL inhibition on TNBS-induced colon alterations, thus demonstrating the involvement of both cannabinoid receptors. In conclusion, increasing 2-arachidonoylglycerol levels resulted in a dramatic reduction of colitis and of the related systemic and central inflammation. This could offer a novel pharmacological approach for the treatment of IBD based on the new protective role of 2-arachidonoylglycerol described here. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/21551239/abstract/Increasing_endogenous_2_arac`hidonoylglycerol_levels_counteracts_colitis_and_related_systemic_inflammation_ L2 - http://www.fasebj.org/doi/full/10.1096/fj.10-176602?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed ER -