The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice.
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.
Elia
E
E
Laboratorio de Fisio-patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Facultad de Medicina (UBA), Consejo de Investigaciones Científicas y Tecnológicas (CONICET), Paraguay 2155, 1121 Buenos Aires, Argentina.
Sander
V
V
Luchetti
C G
CG
Solano
M E
ME
Di Girolamo
G
G
Gonzalez
C
C
Motta
A B
AB
D055372:AMP-Activated Protein Kinases; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D002374:Catalase / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism; D017588:Hyperandrogenism / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D011085:Polycystic Ovary Syndrome / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D011458:Prostaglandins E / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
D000276:Adjuvants, Immunologic; D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; D011458:Prostaglandins E; D003687:Dehydroepiandrosterone; D008687:Metformin; D002374:Catalase; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005978:Glutathione