title: 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.
authors.affiliation: Gastroenterologia, Università di Napoli Federico II, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Argenio
authors.forename: Marta
authors.initials: M
authors.lastname: Valenti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Scaglione
authors.forename: Vittorio
authors.initials: V
authors.lastname: Cosenza
authors.forename: Italo
authors.initials: I
authors.lastname: Sorrentini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000328:Adult; D000368:Aged; D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D001095:Arachidonic Acids / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000633:toxicity; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003093:Colitis, Ulcerative / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000737:chemistry / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D063388:Endocannabinoids; D005260:Female; D005989:Glycerides / Q000032:analysis; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000737:chemistry / Q000473:pathology; D008297:Male; D019804:Mesalamine / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009195:Peroxidase / Q000032:analysis; D053284:Polyunsaturated Alkamides; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000502:physiology*; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D001557:Benzenesulfonates; D063388:Endocannabinoids; D005989:Glycerides; D019804:Mesalamine; D009195:Peroxidase; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D012701:Serotonin; D014302:Trinitrobenzenesulfonic Acid; D000099252:Fatty Acid Amide Hydrolases; C462953:N-(2-methyl-3-hydroxyphenyl)-5,8,11,14-eicosatetraenamide; C114007:arachidonoylserotonin; C001073:2,4-dinitrobenzenesulfonic acid; C094503:glyceryl 2-arachidonate; C078814:anandamide