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The Endocannabinoid System In Inflammatory Bowel Diseases: From Pathophysiology To Therapeutic Opportunity

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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 [82]. 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 [56]. 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

[45]. 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 [62]. 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 [3] also showed

some beneficial effects in DSS- and TNBS-induced colitis [86].

Indeed, O-1602 reduced colon alterations and myeloperoxidase

activity, suggesting an influence on neutrophil recruitment, confirmed

with chemotactic assays [86]. O-1602 retained its efficacy in

CB1//CB2/ mice as well as in GPR55/ mice [86]. 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.



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