Efficacy of topical versus oral 5-aminosalicylate for treatment of 2,4,6-trinitrobenzene sulfonic acid-induced ulcerative colitis in rats

Abstract

5-aminosalicylic acid (5-ASA) is drug of choice for the treatment of ulcerative colitis (UC). In this study, the efficacy of topical versus oral 5-ASA for the treatment of UC was examined as well as the action mechanism of this medication. A flexible tube was inserted into the rat cecum to establish a topical administration model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced UC. A total of 60 rats were divided into sham operation group (receiving an enema of 0.9% saline solution instead of the TNBS solution via the tube), model group, topical 5-ASA group, oral Etiasa group (a release agent of mesalazine used as positive control) and oral 5-ASA group (n=12 each). Different treatments were administered 1 day after UC induction. The normal saline (2 mL) was instilled twice a day through the tube in the sham operation group and model group. 5-ASA was given via the tube in the topical 5-ASA group (7.5 g/L, twice per day, 100 mg/kg), and rats in the oral Etiasa group and oral 5-ASA group intragastrically received Etiasa (7.5 g/L, twice per day, 100 mg/kg) and 5-ASA (7.5 g/L, twice per day, 100 mg/kg), respectively. The body weight was recorded every day. After 7 days of treatment, blood samples were drawn from the heart to harvest the sera. Colonic tissues were separated and prepared for pathological and related molecular biological examinations. The concentrations of 5-ASA were detected at different time points in the colonic tissues, feces and sera in different groups by using the high pressure liquid chromatography (HPLC). The results showed that the symptoms of acute UC, including bloody diarrhea and weight loss, were significantly improved in topical 5-ASA-treated rats. The colonic mucosal damage, both macroscopical and histological, was significantly relieved and the myeloperoxidase activity was markedly decreased in rats topically treated with 5-ASA compared with those treated with oral 5-ASA or Etiasa. The mRNA and protein expression of IL-1β, IL-6, and TNF-α was down-regulated in the colonic tissue of rats topically treated with 5-ASA, significantly lower than those from rats treated with oral 5-ASA or Etiasa. The concentrations of 5-ASA in the colonic tissue were significantly higher in the topical 5-ASA group than in the oral 5-ASA and oral Etiasa groups. It was concluded that the topical administration of 5-ASA can effectively increase the concentration of 5-ASA in the colonic tissue, decrease the expression of proinflammatory cytokines, alleviate the colonic pathological damage and improve the symptoms of TNBS-induced acute UC in rats.

Keywords

ulcerative colitis / 5- aminosalicylic acid / 2,4,6-trinitrobenzene sulfonic acid

References

[1] FamularoG, TrinchieriV, De SimoneC. Inflammatory bowel disease. N Engl J Med, 2002, 347(24): 1982-1984

[2] ShanahanF. Crohn’s disease. Lancet, 2002, 359(9300): 62-69

[3] FarrellRJ, PeppercornMA. Ulcerative colitis. Lancet, 2002, 359(9303): 331-340

[4] CohenRD, WosethDM, ThistedRA, et al.. A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis. Am J Gastroenterol, 2000, 95(5): 1263-1276

[5] RizzelloF, GionchettiP, VenturiA, et al.. Medical treatment of severe ulcerative colitis. Aliment Pharmacol Ther, 2003, 17(Suppl2): 7-10

[6] LöfbergR. Medical treatment of mild to moderately active Crohn’s disease. Aliment Pharmacol Ther, 2003, 17(Suppl2): 18-22

[7] ScribanoM, PranteraC. Medical treatment of moderate to severe Crohn’s disease. Aliment Pharmacol Ther, 2003, 17(Suppl2): 23-30

[8] BianconeL, TostiC, FinaD, et al.. Maintenance treatment of Crohn’s disease. Aliment Pharmacol Ther, 2003, 17(Suppl2): 31-37

[9] CottoneM, OrlandoA, ViscidoA, et al.. Prevention of postsurgical relapse and recurrence in Crohn’s disease. Aliment Pharmacol Ther, 2003, 17(Suppl2): 38-42

[10] CampieriM. New steroids and new salicylates in inflammatory bowel disease: a critical appraisal. Gut, 2002, 50(Suppl3): III43-III46

[11] VegterS, TolleyK, Wilson WaterworthT, et al.. Meta-analysis using individual patient data: efficacy and durability of topical alicaforsen for the treatment of active ulcerative colitis. Aliment Pharmacol Ther, 2013, 38(3): 284-293

[12] StobaughDJ, DeepakP, ThorpeM, et al.. Simulated comparison of topical and oral formulations of 5-aminosalicylate for the treatment of ulcerative colitis. Inflamm Bowel Dis, 2013, 19(2): 301-308

[13] HarrisMS, LichtensteinGR. Delivery and efficacy of topical 5-aminosalicylic acid (mesalazine) therapy in the treatment of ulcerative colitis. Aliment Pharmacol Ther, 2011, 33(9): 996-1009

[14] MarshallJK, ThabaneM, SteinhartAH, et al.. Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev, 2012, 11: CD004118

[15] MarshallJK, IrvineEJ. Putting rectal 5-aminosalicylic acid in its place: the role in distal ulcerative colitis. Am J Gastroenterol, 2000, 95(7): 1628-1636

[16] FeaganBG, MacdonaldJK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev, 2012, 17: CD000543

[17] KimYS, SonM, KoJI, et al.. Effect of DA-6034, a derivative of flavonoid, on experimental animal models of inflammatory bowel disease. Arch Pharm Res, 1999, 22(4): 354-360

[18] MorrisGP, BeckPL, HerridgeMS, et al.. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology, 1989, 96(3): 795-803

[19] PadolI, HuangJQ, HogaboamCM, et al.. Therapeutic effects of the endothelin receptor antagonist Ro 48-5695 in the TNBS/DNBS rat model of colitis. Eur J Gastroenterol Hepatol, 2000, 12(3): 257-265

[20] WallaceJL, MacNaughtonWK, MorrisGP, et al.. Inhibition of leukotriene synthesis markedly accelerates healing in a rat model of inflammatory bowel disease. Gastroenterology, 1989, 96(1): 29-36

[21] GrishamMB, BenoitJN, GrangerDN. Assessment of leukocyte involvement during ischemia and reperfusion of intestine. Methods Enzymol, 1990, 186: 729-742

[22] Sánchez-HidalgoM, MartínAR, VillegasI, et al.. Rosiglitazone, an agonist of peroxisome proliferator-activated receptor gamma, reduces chronic colonic inflammation in rats. Biochem Pharmacol, 2005, 69(12): 1733-1744

[23] HussainFN, AjjanRA, MoustafaM, et al.. Simple method for the determination of 5-aminosalicylic and N-acetyl-5-aminosalicylic acid in rectal tissue biopsies. J Chromatogr B Biomed Sci Appl, 1998, 716(1–2): 257-266

[24] HanauerSB. Medical therapy for ulcerative colitis 2004. Gastroenterology, 2004, 126(6): 1582-1592

[25] GisbertJP, GomollónF, MatéJ, et al.. Role of 5-aminosalicylic acid (5-ASA) in treatment of inflammatory bowel disease: a systematic review. Dig Dis Sci, 2002, 47(3): 471-488

[26] BellCJ, GallDG, WallaceJL. Disruption of colonic electrolyte transport in experimental colitis. Am J Physiol, 1995, 268(4Pt1): G622-G630

[27] StroberW, FussIJ, BlumbergRS. The immunology of mucosal models of inflammation. Annu Rev Immunol, 2002, 20: 495-549

[28] WirtzS, NeufertC, WeigmannB, et al.. Chemically induced mouse models of intestinal inflammation. Nat Protoc, 2007, 2(3): 541-546

[29] NeurathMF. IL-23: a master regulator in Crohn disease. Nat Med, 2007, 13(1): 26-28

[30] ElsonCO, CongY, WeaverCT, et al.. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology, 2007, 132(7): 2359-2370