Inflammation Research

, Volume 67, Issue 2, pp 147–155 | Cite as

Effect of roxithromycin on mucosal damage, oxidative stress and pro-inflammatory markers in experimental model of colitis

Original Research Paper


Objective and design

Roxithromycin, a macrolide antibiotic, exhibits anti-inflammatory property. The present study was designed to evaluate its protective effect in a rat model of colitis.


The anti-inflammatory property of roxithromycin was first validated in rat paw edema model at 5 and 20 mg/kg doses where it produced 19 and 51% inhibition of paw swelling induced by carrageenan. The efficacy of roxithromycin was evaluated at these doses in a rat model where colitis was induced by intra-colonic instillation of acetic acid. Rats were divided into six groups viz. normal control, experimental control and drug-treated groups: roxithromycin 5 and 20 mg/kg, diclofenac 10 mg/kg and mesalazine 300 mg/kg. All drugs were given orally 1 h before induction of colitis. The macro and microscopic changes, mean ulcer score, mucus content and markers of oxidative stress and inflammation were evaluated in all the groups after 24 h.


Pretreatment with roxithromycin markedly decreased hyperemia, ulceration, edema and restored histological architecture. The protection afforded by roxithromycin was substantiated by dose-dependent increase in mucus content, normalization of markers of oxidative stress (GSH and TBARS) and levels of TNF-α, PGE2 and nitrite along with marked decrease in expression of NFκB (p65), IL-1β and COX-2. The protective effect of roxithromycin was found to be comparable to mesalazine while diclofenac was found ineffective.


Our study demonstrates that roxithromycin ameliorates experimental colitis by maintaining redox homeostasis, preserving mucosal integrity and downregulating NFκB-mediated pro-inflammatory signaling and suggests that it has a therapeutic potential in inflammatory conditions of the colon.


Inflammation Oxidative stress Roxithromycin Ulcerative colitis 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American college of gastroenterology, practice parameters committee. Am J Gastroenterol. 2010;105:501–23.CrossRefPubMedGoogle Scholar
  2. 2.
    Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;365:1713–25.CrossRefPubMedGoogle Scholar
  3. 3.
    Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627–40.CrossRefPubMedGoogle Scholar
  4. 4.
    Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006;3:390–407.CrossRefPubMedGoogle Scholar
  5. 5.
    Xavier RJ, Podolsky DK. Unraveling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–34.CrossRefPubMedGoogle Scholar
  6. 6.
    Harris DW, Smith PR, Swan CH. Determination of prostaglandin synthetase activity in rectal biopsy material and its significance in colonic disease. Gut. 1978;19:875–7.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Sharon P, Ligumsky M, Rachmilewitz D, Zor U. Role of prostaglandins in ulcerative colitis. Enhanced production during active disease and inhibition by sulfasalazine. Gastroenterology. 1978;75:638–40.PubMedGoogle Scholar
  8. 8.
    Vong L, Ferraz JGP, Panaccione R, Beck PL, Wallace JL. A pro-resolution mediator, prostaglandin D2, is specifically up-regulated in individuals in long-term remission from ulcerative colitis. PNAS. 2010;107:12023–7.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Keshavarzian A, Haydek J, Zabihi R, Doria M, D′Astice M, Sorensen JRJ. Agents capable of eliminating reactive oxygen species: catalase, WR-2721 or Cu(II)2(3,5-DIPS)4 decrease experimental colitis. Dig Dis Sci. 1992;37:1866–73.CrossRefPubMedGoogle Scholar
  10. 10.
    Keshavarzian A, Morgan G, Sedghi S, Gordon JH, Doria M. Role of reactive oxygen metabolites in experimental colitis. Gut. 1990;31:786–90.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ordás I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 2012;91:635–46.CrossRefPubMedGoogle Scholar
  12. 12.
    Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel JF, Allez M, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis. 2012;6:991–1030.CrossRefPubMedGoogle Scholar
  13. 13.
    Mowat C, Cole A, Windsor A, Ahmad T, Arnott I, Driscoll R, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2011;60:571–607.CrossRefPubMedGoogle Scholar
  14. 14.
    Scaglione F, Rossoni G. Comparative anti-inflammatory effects of roxithromycin, azithromycin and clarithromycin. J Antimicrob Chemother. 1998;41:47–50.CrossRefPubMedGoogle Scholar
  15. 15.
    Kwiatkowska B, Maślińska M. Macrolide therapy in chronic inflammatory diseases. Mediators Inflamm. 2012;2012:636157.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Tamaoki J, Kadota J, Takizawa H. Clinical implications of the immunomodulatory effects of macrolides. Am J Med. 2004;117:5S–11S.Google Scholar
  17. 17.
    Choi Y, Koh SJ, Lee HS, Kim JW, Kim GB, Lee KL, et al. Roxithromycin inhibits nuclear factor kappaB signaling and endoplasmic reticulum stress in intestinal epithelial cells and ameliorates experimental colitis in mice. Exp Biol Med (Maywood). 2015;240:1664–71.CrossRefGoogle Scholar
  18. 18.
    Winter CA, Risley EA, Nuss GW. Carrageenin-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs. Proc Soc Exp Biol Med. 1962;111:544–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Pandey A, Kumar VL. Protective effect of metformin against acute inflammation and oxidative stress in rat. Drug Dev Res. 2016;77:278–84.CrossRefPubMedGoogle Scholar
  20. 20.
    Kumar VL, Chaudhary P, Ramos MV, Mohan M, Matos MPV. Protective effect of proteins derived from the latex of Calotropis procera against inflammatory hyperalgesia in monoarthritic rats. Phytother Res. 2011;25:1336–41.PubMedGoogle Scholar
  21. 21.
    Myers BS, Martin JS, Dempsey DT, Parkman HP, Thomas RM, Ryan JP. Acute experimental colitis decreases colonic circular smooth muscle contractility in rats. Am J Physiol. 1997;273:G928–36.Google Scholar
  22. 22.
    Al-Rejaie SS, Abuohashish HM, Al-Enazi MM, Al-Assaf AH, Parmar MY, Ahmed MM. Protective effect of naringenin on acetic acid-induced ulcerative colitis in rats. World J Gastroenterol. 2013;19:5633–44.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Moriss GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology. 1989;96:795–803.CrossRefGoogle Scholar
  24. 24.
    Hamiza OO, Rehman MU, Tahir M, Khan R, Khan AQ, Lateef A, et al. Amelioration of 1,2 dimethylhydrazine (DMH) induced colon oxidative stress, inflammation and tumor promotion response by tannic acid in wistar rats. Asian Pac J Cancer Prev. 2012;13:4393–402.CrossRefPubMedGoogle Scholar
  25. 25.
    Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959;82:70–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Okhawa H, Ohishi N. Assay of lipid peroxide in animal tissue by thio-barbituric acid reaction. Anal Biochem. 1979;95:351–8.CrossRefGoogle Scholar
  27. 27.
    Sasaki S, Miurat T, Nishikawa S, Yamada K, Hirasue M, Nakane A. Protective role of nitric oxide in Staphylococcus aureus infection in mice. Infect Immun. 1998;66:1017–22.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Popov SV, Markov PA, Nikitina IR, Petrishev S, Smirnov V, Ovodov YS. Preventive effect of a pectic polysaccharide of the common cranberry Vaccinium oxycoccos L. on acetic acid-induced colitis in mice. World J Gastroenterol. 2006;12:6646–51.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Fedchenko N, Reifenrath J. Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue—a review. Diagn Pathol. 2014;9:221.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Bryskier A. Roxithromycin: review of its antimicrobial activity. J Antimicrob Chemother. 1998;41:1–21.CrossRefPubMedGoogle Scholar
  31. 31.
    Otsuki N, Iwata S, Yamada T, Hosono O, Dang NH, Hatano R, et al. Modulation of immunological responses and amelioration of collagen-induced arthritis by the novel roxithromycin derivative 5-I. Mod Rheumatol. 2015;25:562–70.CrossRefPubMedGoogle Scholar
  32. 32.
    Chernomortseva ES, Pokrovskii MV, Pokrovskaia TG, Artiushkova EB, Gureev VV. Experimental study of cardioprotective and endothelioprotective action of macrolides and azalides. Eksp Klin Farmakol. 2009;72:29–31.PubMedGoogle Scholar
  33. 33.
    Aoki D, Ueno S, Kubo F, Oyama T, Sakuta T, Matsushita K, et al. Roxithromycin inhibits angiogenesis of human hepatoma cell in vivo by suppressing VEGF production. Anticancer Res. 2005;25:133–8.PubMedGoogle Scholar
  34. 34.
    Randhawa PK, Singh K, Singh N, Jaggi AS. A review on chemical-induced inflammatory bowel disease models in rodents. Korean J Physiol Pharmacol. 2014;18:279–88.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kawada M, Arihiro A, Mizoguchi E. Insights from advances in research of chemically induced experimental models of human inflammatory bowel disease. World J Gastroenterol. 2007;13:5581–93.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Johansson ME, Hansson GC. Mucus and the goblet cell. Dig Dis. 2013;31:305–9.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Jarry A, Muzeau F, Laboisse C. Cytokine effects in a human colonic goblet cell line. Cellular damage and its partial prevention by 5 aminosalicylic acid. Dig Dis Sci. 1992;37:1170–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Baert F, Hart J, Blackstone MO. A case of diclofenac-induced colitis with focal granulomatous change. Am J Gastroenterol. 1995;90:1871–3.PubMedGoogle Scholar
  39. 39.
    Piechota-Polanczyk A, Fichna J. Review article: the role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases. Naunyn-Schmiedeberg’s Arch Pharmacol. 2014;387:605–20.CrossRefGoogle Scholar
  40. 40.
    Rana SV, Sharma S, Prasad KK, Sinha SK, Singh K. Role of oxidative stress and antioxidant defence in ulcerative colitis patients from north India. Indian J Med Res. 2014;139:568–71.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Kolios G, Valatas V, Ward SG. Nitric oxide in inflammatory bowel disease: a universal messenger in an unsolved puzzle. Immunology. 2004;113:427–37.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Rachmilewitz D, Karmeli F, Okon E, Bursztyn M. Experimental colitis is ameliorated by inhibition of nitric oxide synthase activity. Gut. 1995;37:247–55.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Nieto N, Torres MI, Fernández MI, Giron MD, Ríos A, Suárez MD, et al. Experimental ulcerative colitis impairs antioxidant defense system in rat intestine. Dig Dis Sci. 2000;45:1820–7.CrossRefPubMedGoogle Scholar
  44. 44.
    Wang S, Liu Z, Wang L, Zhang X. NF-κB signaling pathway, inflammation and colorectal cancer. Cell Mol Immunol. 2009;6:327–34.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Sands BE, Kaplan GG. The role of TNF-alpha in ulcerative colitis. J Clin Pharmacol. 2007;47:930–41.CrossRefPubMedGoogle Scholar
  46. 46.
    Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011;31:986–1000.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Singer II, Kawka DW, Schloemann S, Tessner T, Riehl T, Stenson WF. Cyclooxygenase 2 is induced in colonic epithelial cells in inflammatory bowel disease. Gastroenterology. 1998;115:297–306.CrossRefPubMedGoogle Scholar
  48. 48.
    Andersen L, Jorgensen VL, Perner A, Hansen A, Eugen-Olsen J, Rask-Madsen J. Activation of nuclear factor κB in colonic mucosa from patients with collagenous and ulcerative colitis. Gut. 2005;54:503–9.CrossRefGoogle Scholar
  49. 49.
    Verma S, Kumar VL. Attenuation of gastric mucosal damage by artesunate in rat: modulation of oxidative stress and NFκB mediated signaling. Chem Biol Interact. 2016;257:46–53.CrossRefPubMedGoogle Scholar
  50. 50.
    Park SC, Jeen YT. Current and emerging biologics for ulcerative colitis. Gut Liver. 2015;9:18–27.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of PharmacologyAll India Institute of Medical SciencesNew DelhiIndia

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