Anti-inflammatory effects and changes in prostaglandin patterns induced by 7beta-hydroxy-epiandrosterone in rats with colitis.
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).
Hennebert
Olivier
O
Laboratoire de Biologie, E.A. 3199, Conservatoire National des Arts et Métiers, 2 rue Conté, Paris, France.
Pelissier
Marie-Agnès
MA
Le Mee
Sandrine
S
Wülfert
Ernst
E
Morfin
Robert
R
D000465:Algorithms; D000738:Androsterone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D016264:Dextran Sulfate; D004353:Drug Evaluation, Preclinical; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D008297:Male; D011453:Prostaglandins / Q000097:blood / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
C531236:7-hydroxyandrosterone; D000893:Anti-Inflammatory Agents; D054834:Lipocalins; D011453:Prostaglandins; D016264:Dextran Sulfate; D000738:Androsterone; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C495729:membrane-associated PGE synthase, rat; C022466:prostaglandin R2 D-isomerase