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

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.

• Authors: Gabriella Varga, Melinda Ugocsai, Petra Hartmann, Norbert Lajkó, Réka Molnár, Szilárd Szűcs, Dávid Kurszán Jász, Dániel Érces, Miklós Ghyczy, Gábor Tóth, Mihály Boros
• Journal: Inflammopharmacology (Inflammopharmacology) Vol. 26 Issue 1 Pg. 261-271 (Feb 2018) ISSN: 1568-5608 [Electronic] Switzerland
• PMID: 28451776 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Methylamines
• Nitrates
• Nitrites
• Tumor Necrosis Factor-alpha
• Mesalamine
• Trinitrobenzenesulfonic Acid
• methylamine
• Peroxidase
• Aspirin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Aspirin (pharmacology)
• Colitis (drug therapy, metabolism)
• Colon (drug effects, metabolism)
• Disease Models, Animal
• Intestinal Mucosa (drug effects, metabolism)
• Male
• Mesalamine (pharmacology)
• Methylamines (pharmacology)
• Nitrates (metabolism)
• Nitrites (metabolism)
• Peroxidase (metabolism)
• Rats
• Rats, Sprague-Dawley
• Trinitrobenzenesulfonic Acid (pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)