Anti-inflammatory effects and changes in prostaglandin patterns induced by 7beta-hydroxy-epiandrosterone in rats with colitis.

Abstract

High dose levels of dehydroepiandrosterone and its 7-hydroxylated derivatives have been shown to reduce oxidative stress and inflammatory responses in dextran sodium sulfate (DSS)-induced colitis in rats. Another endogenous steroid, 7beta-hydroxy-epiandrosterone (7beta-hydroxy-EpiA) has been shown to exert neuroprotective effects at much smaller doses. Our aims were to evaluate whether 7beta-hydroxy-EpiA pre-treatment prevents DSS-induced colitis and to determine whether the effects involve changes in anti-inflammatory prostaglandin (PG) D(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) levels. Rats were administered 0.01, 0.1 and 1mg/kg 7beta-hydroxy-EpiA i.p. once a day for 7 days. Thereafter, colitis was induced by administration of 5% DSS in drinking water for 7 days. Levels of the PGs and the expression of cyclooxygenase (COX-2) and PG synthases were assessed during the course of the experiment. Administration of 7beta-hydroxy-EpiA caused a transient increase in COX-2 and PGE synthase expression within 6-15h and augmented colonic tissue levels of 15d-PGJ(2) levels starting at day 2. Treatment with DSS resulted in shortened colon length, depleted mucus in goblet cells and induced oxidative stress. COX-2 and mPGES-1 synthase expression were enhanced and accompanied by increased PGE(2), D(2) and 15d-PGJ(2) production. Although all dose levels of 7beta-hydroxy-EpiA reduced PGE(2) production, only the lowest dose (0.01mg/kg) of the steroid completely prevented colitis damage and tissue inflammation. 7beta-Hydroxy-EpiA pre-treatment prevents the occurrence of DSS-induced colitis through a shift from PGE(2) to PGD(2) production, associated with an early but transient increase in COX-2 expression and a sustained increase in the production of the anti-inflammatory prostaglandin 15d-PGJ(2).

• Authors: Olivier Hennebert, Marie-Agnès Pelissier, Sandrine Le Mee, Ernst Wülfert, Robert Morfin
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 110 Issue 3-5 Pg. 255-62 (Jun 2008) ISSN: 0960-0760 [Print] England
• PMID: 18502118 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 7-hydroxyandrosterone
• Anti-Inflammatory Agents
• Lipocalins
• Prostaglandins
• Dextran Sulfate
• Androsterone
• Cyclooxygenase 2
• Intramolecular Oxidoreductases
• membrane-associated PGE synthase, rat
• prostaglandin R2 D-isomerase

Topics

• Algorithms
• Androsterone (analogs & derivatives, pharmacology, therapeutic use)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Colitis (chemically induced, drug therapy, metabolism, prevention & control)
• Cyclooxygenase 2 (genetics, metabolism)
• Cytoprotection (drug effects)
• Dextran Sulfate
• Drug Evaluation, Preclinical
• Intramolecular Oxidoreductases (genetics, metabolism)
• Lipocalins (genetics, metabolism)
• Male
• Prostaglandins (blood, metabolism)
• Rats
• Rats, Wistar