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Bolus injection of newly synthesized vitamin E derivative ETS-GS for the treatment of acute severe ulcerative colitis in a mouse model

New vitamin E derivative for acute severe UC

International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

Vitamin E with its antioxidant action has therapeutic effects on ulcerative colitis (UC), but use of vitamin E is limited because of its insolubility in water. We developed ETS-GS (γ-l-glutamyl-S-[2-[[[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltri-decyl)-2 H-1-benzopyran-6-yl]oxy]carbonyl]-3-oxo-3-[(2-sulfoethyl)amino]propyl]-l-cysteinylglycine sodium salt), a newly synthesized soluble vitamin E derivative with strong antioxidant action. We evaluated the therapeutic effects of bolus injection of ETS-GS on acute severe UC in a mouse model.

Methods

An animal model of acute severe UC was induced by feeding mice 5 % dextran sulfate sodium (DSS) for 5 days, followed by 1 % DSS on days 5–8, the experimental period. ETS-GS or saline was administered by subcutaneous bolus injection during the experimental period. We examined disease activity index (DAI) score, histological score, colon length, colon weight, and serum cytokines in the mice.

Results

The following results at day 8 in the DSS + ETS-GS group were significantly lower than those in the DSS + Saline group: DAI score, 2.6 ± 0.6 vs. 3.1 ± 0.5; histological score, 2.1 ± 1.0 vs. 3.1 ± 0.8; serum interleukin (IL)-6, 15 ± 9.4 vs. 39 ± 23 pg/ml; and keratinocyte-derived chemokine (KC), 122 ± 61 vs. 228 ± 66 pg/ml (P < 0.05). Colon length, colon weight, and serum IL-10 in the DSS + ETS-GS group were significantly higher than those in the DSS + Saline group (88 ± 12 vs. 75 ± 5.7 mm, 0.48 ± 0.09 vs. 0.38 ± 0.05 g, and 55 ± 18 vs. 31 ± 10 pg/ml, respectively; P < 0.05).

Conclusions

Bolus injection of ETS-GS may be one therapeutic modality for acute severe UC. Its effects are associated with suppression of serum IL-6 and serum KC and promotion of serum IL-10.

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References

  1. Molodecky NA, Soon IS, Rabi DM et al (2012) Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142:46–54

    Article  PubMed  Google Scholar 

  2. Katz JA (2000) Medical and surgical management of severe colitis. Semin Gastrointest Dis 11:18–32

    PubMed  CAS  Google Scholar 

  3. Van Assche G, Vermeire S, Rutgeerts P (2011) Management of acute severe ulcerative colitis. Gut 60:130–133

    Article  PubMed  Google Scholar 

  4. Ahmed L, Nazrul Islam S, Khan MN, Huque S, Ahsan M (2004) Antioxidant micronutrient profile (vitamin E, C, A, copper, zinc, iron) of colostrum: association with maternal characteristics. J Trop Pediatr 50:357–358

    Article  PubMed  CAS  Google Scholar 

  5. Mirbagheri SA, Nezami BG, Assa S, Hajimahmoodi M (2008) Rectal administration of d-alpha tocopherol for active ulcerative colitis: a preliminary report. World J Gastroenterol 14:5990–5995

    Article  PubMed  CAS  Google Scholar 

  6. Stuyvesant VW, Jolley WB (1967) Anti-inflammatory activity of d-alpha-tocopherol (vitamin E) and linoleic acid. Nature 216:585–586

    Article  PubMed  CAS  Google Scholar 

  7. Cid L, Pararajasegaram G, Sevanian A et al (1992) Anti-inflammatory effects of vitamin E on experimental lens-induced uveitis. Int Ophthalmol 16:27–32

    Article  PubMed  CAS  Google Scholar 

  8. Rezk BM, van der Vijgh WJ, Bast A, Haenen GR (2007) Alpha-tocopheryl phosphate is a novel apoptotic agent. Front Biosci 12:2013–2019

    Article  PubMed  CAS  Google Scholar 

  9. Koonsvitsky BP, Berry DA, Jones MB et al (1997) Olestra affects serum concentrations of alpha-tocopherol and carotenoids but not vitamin D or vitamin K status in free-living subjects. J Nutr 127:1636S–1645S

    PubMed  CAS  Google Scholar 

  10. Zhao Z, Satsu H, Fujisawa M et al (2008) Attenuation by dietary taurine of dextran sulfate sodium-induced colitis in mice and of THP-1-induced damage to intestinal Caco-2 cell monolayers. Amino Acids 35:217–224

    Article  PubMed  CAS  Google Scholar 

  11. Giris M, Depboylu B, Dogru-Abbasoglu S et al (2008) Effect of taurine on oxidative stress and apoptosis-related protein expression in trinitrobenzene sulphonic acid-induced colitis. Clin Exp Immunol 152:102–110

    Article  PubMed  CAS  Google Scholar 

  12. Oz HS, Chen TS, McClain CJ, de Villiers WJ (2005) Antioxidants as novel therapy in a murine model of colitis. J Nutr Biochem 16:297–304

    Article  PubMed  CAS  Google Scholar 

  13. Carrier JC, Aghdassi E, Jeejeebhoy K, Allard JP (2006) Exacerbation of dextran sulfate sodium-induced colitis by dietary iron supplementation: role of NF-kappaB. Int J Colorectal Dis 21:381–387

    Article  PubMed  Google Scholar 

  14. Hagiwara S, Koga H, Iwasaka H et al (2011) ETS-GS, a new antioxidant, ameliorates renal ischemia–reperfusion injury in a rodent model. J Surg Res 171:226–233

    Article  PubMed  CAS  Google Scholar 

  15. Hagiwara S, Koga H, Iwasaka H et al (2011) ETS-GS, a new anti-oxidative drug, protects against lipopolysaccharide-induced acute lung and liver injury. J Surg Res 171:734–741

    Article  PubMed  CAS  Google Scholar 

  16. Murai R, Kanbe T, Mukoyama T et al (2007) Effect of rectal administration of rebamipide on dextran sulfate sodium-induced colitis: role of hepatocyte growth factor. Inflamm Res 56:240–245

    Article  PubMed  CAS  Google Scholar 

  17. Cooper HS, Murthy SN, Shah RS, Sedergran DJ (1993) Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest 69:238–249

    PubMed  CAS  Google Scholar 

  18. Yao J, Wang JY, Liu L et al (2010) Anti-oxidant effects of resveratrol on mice with DSS-induced ulcerative colitis. Arch Med Res 41:288–294

    Article  PubMed  CAS  Google Scholar 

  19. Alex P, Zachos NC, Nguyen T et al (2009) Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBS-induced colitis. Inflamm Bowel Dis 15:341–352

    Article  PubMed  Google Scholar 

  20. Kostadinova FI, Baba T, Ishida Y et al (2010) Crucial involvement of the CX3CR1–CX3CL1 axis in dextran sulfate sodium-mediated acute colitis in mice. J Leukoc Biol 88:133–143

    Article  PubMed  CAS  Google Scholar 

  21. Holtkamp W, Stollberg T, Reis HE (1995) Serum interleukin-6 is related to disease activity but not disease specificity in inflammatory bowel disease. J Clin Gastroenterol 20:123–126

    Article  PubMed  CAS  Google Scholar 

  22. Joshi R, Kumar S, Unnikrishnan M, Mukherjee T (2005) Free radical scavenging reactions of sulfasalazine, 5-aminosalicylic acid and sulfapyridine: mechanistic aspects and antioxidant activity. Free Radic Res 39:1163–1172

    Article  PubMed  CAS  Google Scholar 

  23. Suzuki Y, Matsumoto T, Okamoto S, Hibi T (2008) A lecithinized superoxide dismutase (PC-SOD) improves ulcerative colitis. Colorectal Dis 10:931–934

    PubMed  CAS  Google Scholar 

  24. Broeyer FJ, van Aken BE, Suzuki J et al (2008) The pharmacokinetics and effects of a long-acting preparation of superoxide dismutase (PC-SOD) in man. Br J Clin Pharmacol 65:22–29

    Article  PubMed  CAS  Google Scholar 

  25. Suzuki J, Broeyer F, Cohen A, Takebe M, Burggraaf J, Mizushima Y (2008) Pharmacokinetics of PC-SOD, a lecithinized recombinant superoxide dismutase, after single- and multiple-dose administration to healthy Japanese and Caucasian volunteers. J Clin Pharmacol 48:184–192

    Article  PubMed  CAS  Google Scholar 

  26. Rezaie A, Parker RD, Abdollahi M (2007) Oxidative stress and pathogenesis of inflammatory bowel disease: an epiphenomenon or the cause? Dig Dis Sci 52:2015–2021

    Article  PubMed  Google Scholar 

  27. Tamaki H, Nakamura H, Nishio A et al (2006) Human thioredoxin-1 ameliorates experimental murine colitis in association with suppressed macrophage inhibitory factor production. Gastroenterology 131:1110–1121

    Article  PubMed  CAS  Google Scholar 

  28. Seo JY, Kim H, Seo JT, Kim KH (2002) Oxidative stress induced cytokine production in isolated rat pancreatic acinar cells: effects of small-molecule antioxidants. Pharmacology 64:63–70

    Article  PubMed  CAS  Google Scholar 

  29. Strober W, Fuss IJ (2011) Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 140:1756–1767

    Article  PubMed  CAS  Google Scholar 

  30. Sanchez-Munoz F, Dominguez-Lopez A, Yamamoto-Furusho JK (2008) Role of cytokines in inflammatory bowel disease. World J Gastroenterol 14:4280–4288

    Article  PubMed  CAS  Google Scholar 

  31. Song F, Ito K, Denning TL et al (1999) Expression of the neutrophil chemokine KC in the colon of mice with enterocolitis and by intestinal epithelial cell lines: effects of flora and proinflammatory cytokines. J Immunol 162:2275–2280

    PubMed  CAS  Google Scholar 

  32. Aleksandra Nielsen A, Nederby Nielsen J, Schmedes A, Brandslund I, Hey H (2005) Saliva interleukin-6 in patients with inflammatory bowel disease. Scand J Gastroenterol 40:1444–1448

    Article  PubMed  Google Scholar 

  33. Egesten A, Eliasson M, Olin AI et al (2007) The proinflammatory CXC-chemokines GRO-alpha/CXCL1 and MIG/CXCL9 are concomitantly expressed in ulcerative colitis and decrease during treatment with topical corticosteroids. Int J Colorectal Dis 22:1421–1427

    Article  PubMed  Google Scholar 

  34. Lindsay JO, Sandison A, Cohen P, Brennan FM, Hodgson HJ (2004) IL-10 gene therapy is therapeutic for dextran sodium sulfate-induced murine colitis. Dig Dis Sci 49:1327–1334

    Article  PubMed  CAS  Google Scholar 

  35. Yao J, Wang JY, Lai MG et al (2011) Treatment of mice with dextran sulfate sodium-induced colitis with human interleukin 10 secreted by transformed Bifidobacterium longum. Mol Pharm 8:488–497

    Article  PubMed  CAS  Google Scholar 

  36. King MR, Ismail AS, Davis LS, Karp DR (2006) Oxidative stress promotes polarization of human T cell differentiation toward a T helper 2 phenotype. J Immunol 176:2765–2772

    PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to express our gratitude to Dr. Kazumi Ogata, who synthesized and provided the agents used in this study, and to Dr. Satoshi Hagiwara, and Dr. Takayuki Noguchi for the scientific assistance, and to Ms. Yuiko Aso, Mr. Kazune Komiya, and Ms. Kaori Sakai for their technical assistance. This work was supported in part by Grants-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (ASPS) (No. 23591967).

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Correspondence to Takahiro Hiratsuka.

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Hiratsuka, T., Inomata, M., Hagiwara, S. et al. Bolus injection of newly synthesized vitamin E derivative ETS-GS for the treatment of acute severe ulcerative colitis in a mouse model. Int J Colorectal Dis 28, 305–311 (2013). https://doi.org/10.1007/s00384-012-1502-y

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