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Inflammopharmacology

, Volume 26, Issue 1, pp 261–271 | Cite as

Acetylsalicylic acid-tris-hydroxymethyl-aminomethane reduces colon mucosal damage without causing gastric side effects in a rat model of colitis

  • Gabriella Varga
  • Melinda Ugocsai
  • Petra Hartmann
  • Norbert Lajkó
  • Réka Molnár
  • Szilárd Szűcs
  • Dávid Kurszán Jász
  • Dániel Érces
  • Miklós Ghyczy
  • Gábor Tóth
  • Mihály Boros
Original Article
  • 175 Downloads

Abstract

Background

We have developed a novel compound from acetylsalicylic acid (ASA) and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) precursors with ASA-like anti-inflammatory efficacy and reduced the mucosa-damaging side-effects. Our aim was to examine local and remote consequences of ASA-Tris administration in 2-,4-,6-trinitrobenzene-sulfonic acid (TNBS)-induced colitis as compared to ASA or mesalamine (5-aminosalicylate) treatment.

Methods

Sprague–Dawley rats were randomized to five groups (n = 6, each), and TNBS enemas were performed. Group 1 was the negative control; group 2 was the untreated colitis group. 12 hour after colitis induction repeated doses of ASA, ASA-Tris (both 0.55 mmol/kg) and mesalamine (0.77 mmol/kg) were given 3 times daily for 3 days to groups 3–5. On day 3 of colitis, the in vivo histology of the colon and stomach was investigated. Tissue xanthine-oxidoreductase, myeloperoxidase, nitrite/nitrate changes, and circulating TNF-alpha levels were measured. In addition, liver mitochondria were examined with high-resolution respirometry to analyze alterations in the electron transport chain.

Results

TNBS enema significantly elevated inflammatory enzyme activities, NO production, TNF-alpha concentration, and induced morphological damage in the colon. ASA-treatment reduced the inflammatory marker levels and mucosal injury in the colon, but gastric tissue damage was present. ASA-Tris- and mesalamine-treatments significantly reduced the cytokine levels, inflammatory enzyme activities, and colonic mucosal damage without inducing gastric injury. Also, ASA significantly reduced the Complex IV-linked respiration of liver mitochondria, which was not observed after ASA-Tris-treatment.

Conclusion

As compared to ASA, ASA-Tris conjugation provides significant protection against the colonic injury and cytokine-mediated progression of inflammatory events in experimental colitis without influencing the gastric epithelial structure.

Keywords

TNBS colitis Gastritis Non-steroidal anti-inflammatory drugs Acetylsalicylic-acid Mitochondria 

Notes

Acknowledgements

The authors are grateful to Ms. Ágnes Fekete, Csilla Mester, Nikolett Beretka and Lilla Kovács, Károly Tóth for their skilful assistance. We would like to also thank Ferenc Bogár (Department of Medical Chemistry) for determination of pKa and AlogP values. The study was supported by the Hungarian Science Research Funds OTKA K104656, NKFI-116861 and GINOP-2.3.2-15-2016-00015 I-KOM TEAMING. Miklós Ghyczy was (until 09.2016) applicant and proprietor of European patent application EP 2889286A1 and International patent application WO 2015/101501 (PCT/EP2014/078296) entitled “Pharmaceutically active compound for use as anti-inflammatory agent”.

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Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  • Gabriella Varga
    • 1
  • Melinda Ugocsai
    • 1
  • Petra Hartmann
    • 1
  • Norbert Lajkó
    • 1
  • Réka Molnár
    • 1
  • Szilárd Szűcs
    • 1
  • Dávid Kurszán Jász
    • 1
  • Dániel Érces
    • 1
  • Miklós Ghyczy
    • 1
  • Gábor Tóth
    • 2
  • Mihály Boros
    • 1
  1. 1.Institute of Surgical Research, Faculty of MedicineUniversity of SzegedSzegedHungary
  2. 2.Department of Medical Chemistry, Faculty of MedicineUniversity of SzegedSzegedHungary

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