1. The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice.
- Author
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Elia E, Sander V, Luchetti CG, Solano ME, Di Girolamo G, Gonzalez C, and Motta AB
- Subjects
- AMP-Activated Protein Kinases, Adjuvants, Immunologic pharmacology, Administration, Oral, Animals, Catalase metabolism, Cyclooxygenase 2 metabolism, Dehydroepiandrosterone pharmacology, Enzyme Activation drug effects, Female, Glutathione metabolism, Hyperandrogenism chemically induced, Hyperandrogenism metabolism, Hypoglycemic Agents administration & dosage, Hypoglycemic Agents pharmacology, Lipid Peroxidation drug effects, Metformin administration & dosage, Mice, Mice, Inbred C57BL, Multienzyme Complexes metabolism, Nitric Oxide Synthase metabolism, Ovary metabolism, Ovary physiopathology, Phosphorylation drug effects, Polycystic Ovary Syndrome chemically induced, Polycystic Ovary Syndrome metabolism, Polycystic Ovary Syndrome physiopathology, Prostaglandins E metabolism, Protein Serine-Threonine Kinases metabolism, Hyperandrogenism physiopathology, Metformin pharmacology, Ovary drug effects
- Abstract
The aim of this study was to investigate the mechanisms by which N,N'-dimethylbiguanide metformin (50 mg/100 g body weight (BW) in 0.05 ml of water, given orally with a cannula) prevents the ovarian disorders provoked by the hyperandrogenization with dehydroepiandrosterone (DHEA) in prepuberal BALB/c mice. The injection of DHEA (6 mg/100 g BW in 0.1 ml of oil) for 20 consecutive days re-creates a mouse model that resembles some aspects of the human polycystic ovary syndrome (PCOS). The treatment with DHEA increased ovarian oxidative stress because it enhanced lipid peroxidation (LPO) and diminished both catalase (CAT) activity and glutathione (GSH) content. Therefore, the treatment with DHEA diminished both ovarian nitric oxide synthase (NOS) activity and prostaglandin E (PGE) production. When metformin was administered together with DHEA, the ovarian GSH content, NOS activity and PGE production did not differ when compared with controls. However, metformin was not able to prevent the effect of DHEA on ovarian LPO or CAT activity. Finally, DHEA increased the ovarian protein expressions of inducible NOS (iNOS), inducible cyclooxygenase (COX2) and the phosphorylated AMP-dependent kinase alpha (AMPK-alpha) (Thr172). Metformin administered together with DHEA was able to prevent the increase of ovarian iNOS and COX2 expressions and to enhance the activation of phosphorylated AMPK-alpha expression.
- Published
- 2006
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