in vivo Posted March 3, 2014 Report Share Posted March 3, 2014 Crohn's disease and ulcerative colitis are two major forms of inflammatory bowel diseases (IBD), which are chronic inflammatory disorders of the gastrointestinal tract. These pathologies are currently under investigation to both unravel their etiology and find novel treatments. Anandamide and 2-arachidonoylglycerol are endogenous bioactive lipids that bind to and activate the cannabinoid receptors, and together with the enzymes responsible for their biosynthesis and degradation [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)] constitute the endocannabinoid system (ECS). The ECS is implicated in gut homeostasis, modulating gastrointestinal motility, visceral sensation, and inflammation, as well as being recently implicated in IBD pathogenesis. Numerous subsequent studies investigating the effects of cannabinoid agonists and endocannabinoid degradation inhibitors in rodent models of IBD have identified a potential therapeutic role for the ECS. Box 4. Non-psychotropic cannabinoids in IBD Although anecdotal reports of Cannabis sativa preparations being used to treat IBD offer a potential therapeutic pathway for investigation, the psychoactive side-effects of D9-THC constitute a major obstacle to widespread use. Thus, components of the cannabis plant that do not bind and activate classical cannabinoid receptors, or synthetic analogues, have been tested as treatments for IBD. Cannabidiol (CBD), present in Cannabis sativa, has antioxidant, anti-inflammatory, and immunomodulatory effects and is devoid of psychoactive properties . It has very low affinity for CB1 and CB2 receptors and could exert part of its actions through a PPARg pathway [3,83]. CBD effectively reduces colon alterations in TNBS- and DNBS-induced colitis [56,84]. Moreover, in DNBSinduced colitis, CBD counteracted colitis-induced alterations in cytokine and endocannabinoid levels in the colon; CBD reduced IL- 1b and increased IL-10, thus regulating the aberrant immune response, and diminished the colitis-induced increase in endocannabinoid levels . Beneficial effects of CBD in IBD could extend further than its immunomodulatory properties. Indeed, CBD was shown not to affect colonic motility in vivo in normal mice, while inhibiting inflammation-induced hypermotility [62,85]. Furthermore, on Caco-2 cells, a model of the intestinal epithelial barrier, CBD reduced the inflammation-induced increase in epithelial permeability . Moreover, CBD reduced nitrite production in vivo and oxidative stress in vitro in Caco-2 cells and in human colonic cultures derived from UC patients. This could be beneficial in this setting because oxidative stress is a tissue-destructive factor playing a role in IBD pathogenesis [56,83]. In another experiment, CBD potentiated the beneficial effects of D9-THC on colitis, significantly improving the effect of the same dose of D9-THC alone . This could prove interesting if it holds true with other cannabinoids. Thus, further studies are warranted to determine if CBD could potentiate the effects of low doses of CB1/CB2 agonists (i.e., devoid of CNS effects) in order to have beneficial effects in IBD. Finally, O- 1602, a synthetic atypical cannabinoid that binds to and activates GPR55 and lacks significant affinity for CB1 and CB2  also showed some beneficial effects in DSS- and TNBS-induced colitis . Indeed, O-1602 reduced colon alterations and myeloperoxidase activity, suggesting an influence on neutrophil recruitment, confirmed with chemotactic assays . O-1602 retained its efficacy in CB1//CB2/ mice as well as in GPR55/ mice . In summary, this ‘class’ of non-CB1/non-CB2 cannabinoid-like drugs with antiinflammatory actions in the colon deserves further investigation to make use of their potential as well as identify additional targets involved in IBD pathogenesis. http://www.uclouvain.be/cps/ucl/doc/ir-ldri/images/alyouayek2012.pdf Quote Link to comment Share on other sites More sharing options...
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