Prevention of acetic acid-induced colitis by desferrithiocin analogs in a rat model.

Abstract

Iron contributes significantly to the formation of reactive oxygen species via the Fenton reaction. Therefore, we assessed whether a series of desferrithiocin analogs, both carboxylic acids and hydroxamates, could (1) either promote or diminish the iron-mediated oxidation of ascorbate, (2) quench a model radical species, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), and (3) when applied topically, prevent acetic acid-induced colitis in rats. Surprisingly, most of the desferrithiocin analogs inhibited the Fenton reaction to an approximately equivalent degree; however, substantial differences were observed in the capacity of the analogs to scavenge the model radical cation. Four carboxylic acid desferrithiocin analogs and their respective N-methylhydroxamates were tested along with desferrioxamine and Rowasa, a currently accepted topical therapeutic agent for inflammatory bowel disease (IBD), in a rodent model of acetic acid-induced colitis. The colonic damage was quantitated by two independent measurements. Although neither radical scavenging nor prevention of Fenton chemistry was a definitive predictor of in vivo efficacy, the overall trend is that desferrithiocin analogs substituted with an N-methylhydroxamate in the place of the carboxylic acid are both better free radical scavengers and more active against acetic acid-induced colitis. These results represent an intriguing alternative avenue to the development of improved IBD therapeutic agents.

• Authors: Raymond J Bergeron, Jan Wiegand, William R Weimar, John Nhut Nguyen, Charles A Sninsky
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 48 Issue 2 Pg. 399-407 (Feb 2003) ISSN: 0163-2116 [Print] United States
• PMID: 12643622 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Dihydropyridines
• Thiazoles
• Acetic Acid
• desferrithiocin

Topics

• Acetic Acid
• Animals
• Colitis (pathology, prevention & control)
• Dihydropyridines (pharmacology)
• Disease Models, Animal
• Drug Interactions
• Intestinal Mucosa (drug effects, pathology)
• Male
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Reference Values
• Sensitivity and Specificity
• Thiazoles (pharmacology)