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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.
AuthorsMireille Alhouayek, Didier M Lambert, Nathalie M Delzenne, Patrice D Cani, Giulio G Muccioli
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 25 Issue 8 Pg. 2711-21 (Aug 2011) ISSN: 1530-6860 [Electronic] United States
PMID21551239 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Arachidonic Acids
  • Benzodioxoles
  • Endocannabinoids
  • Enzyme Inhibitors
  • Glycerides
  • Indoles
  • Inflammation Mediators
  • JZL 184
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • iodopravadoline
  • rimonabant
  • 2-arachidonylglycerol
  • Trinitrobenzenesulfonic Acid
  • Monoacylglycerol Lipases
Topics
  • Animals
  • Arachidonic Acids (metabolism)
  • Benzodioxoles (pharmacology)
  • Colitis (chemically induced, metabolism, pathology, prevention & control)
  • Disease Models, Animal
  • Endocannabinoids
  • Endotoxemia (prevention & control)
  • Enzyme Inhibitors (pharmacology)
  • Glycerides (metabolism)
  • Humans
  • Indoles (pharmacology)
  • Inflammation (metabolism, pathology, prevention & control)
  • Inflammation Mediators (blood)
  • Inflammatory Bowel Diseases (drug therapy)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monoacylglycerol Lipases (antagonists & inhibitors)
  • Piperidines (pharmacology)
  • Pyrazoles (pharmacology)
  • Receptor, Cannabinoid, CB1 (antagonists & inhibitors, metabolism)
  • Receptor, Cannabinoid, CB2 (antagonists & inhibitors, metabolism)
  • Trinitrobenzenesulfonic Acid (toxicity)

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