Up‐regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation

Abstract

Direct stimulation of cannabinoid CB1 receptors exerts a protective function in animal models of inflammatory bowel diseases (IBDs). However, it is not known whether endocannabinoids are up-regulated during IBDs in animals or humans, nor whether pharmacological elevation of endocannabinoid levels can be exploited therapeutically in these disorders. In this study we addressed these questions. Colon inflammation was induced in mice and rats with 2,4-dinitrobenzene- and 2,4,6-trinitrobenzene sulfonic acids (DNBS and TNBS), respectively. DNBS-treated mice were treated chronically (for 3 or 7 days) with inhibitors of anandamide enzymatic hydrolysis (N-arachidonoyl-serotonin, AA-5-HT) or reuptake (VDM11), 10 or 5 mg/kg, s.c., or with 5-amino-salicilic acid (5-ASA, 1.4 mg/kg, i.r.). Endocannabinoids (anandamide and 2-arachidonoylglycerol, 2-AG) were quantified in mouse colon, or in rat colon mucosa and submucosa, and in bioptic samples from the colon of patients with untreated ulcerative colitis, by liquid chromatography-mass spectrometry. A strong elevation of anandamide, but not 2-AG, levels was found in the colon of DNBS-treated mice, in the colon submucosa of TNBS-treated rats, and in the biopsies of patients with ulcerative colitis. VDM-11 significantly elevated anandamide levels in the colon of DNBS-treated mice and concomitantly abolished inflammation, whereas AA-5-HT did not affect endocannabinoid levels and was significantly less efficacious at attenuating colitis. 5-ASA also increased anandamide levels and abolished colitis. Thus, anandamide is elevated in the inflamed colon of patients with ulcerative colitis, as well as in animal models of IBDs, to control inflammation, and elevation of its levels with inhibitors of its cellular reuptake might be used in the treatment of IBDs.

The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease

“…FAAH can also degrade 2-AG in vitro , 7,13 yet variations of its activity observed in IBD mucosa did not exert any effect on 2-AG levels. Our results are in agreement with the observation of Marquez et al , 21 who found lower NAPE-PLD expression and high AEA levels in inflamed ulcerative colitis when compared with control mucosa, but they diverge from those by D ' Argenio et al 22 Moreover, the findings of Marquez et al , 21 who showed the lack of difference in the diacylglycerol lipase / monoacylglycerol lipase ratio between ulcerative colitis patient and healthy control epithelium, support our data on mucosal 2-AG levels.…”

The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity

“…Indeed, anandamide and N-palmitoylethanolamine levels are altered in colon mucosal biopsies of patients with ulcerative colitis (UC) or Crohn's disease (CD), especially during acute flares, with no change in 2-arachidonoylglycerol levels [35,52,53] (changes in the ECS in human IBD are summarized in Table 1). NAE levels were reported to be either increased or decreased depending on the study.…”

β-Caryophyllene Inhibits Dextran Sulfate Sodium-Induced Colitis in Mice through CB2 Receptor Activation and PPARγ Pathway

“…3 Recent evidence suggests a role for the cannabinoid system in IBD regulation. Cannabinoid receptors 1 and 2 (CB1 and CB2) are expressed in normal human colon 4,5 and are up-regulated in IBD colonic tissue. In addition, an enhanced level of endocannabinoids was found in biopsy specimens from patients with ulcerative colitis.…”

“…In addition, an enhanced level of endocannabinoids was found in biopsy specimens from patients with ulcerative colitis. 5 It is thought that CB1 activation results in a decrease of intestinal hypermotility and hypersecretion, whereas the activation of CB2 results in the inhibition of proinflammatory mediators. In addition, both CB2 and CB1 knockout mice are more susceptible to the development of experimental colitis, and the activation of these receptors is extremely important for the abrogation of intestinal inflammation.…”