title: Dual targeting of TNF-α and free radical toxic stress as a promising strategy to manage experimental polycystic ovary.
abstract: BACKGROUND
  It is now clear that oxidative stress (OS) and chronic low-grade inflammation are two main pathways involved in polycystic ovary syndrome (PCOS) pathogenesis. Therefore, simultaneous targeting of these pathways by means of carvedilol and Semelil (ANGIPARS™), as established medicines with dual anti-cytokine and anti-oxidant potential may be a therapeutic alternative approach to the current treatments.
  
  
  OBJECTIVE
  The objective of this study is to study the protective effects of carvedilol and ANGIPARS™ on inflammatory and oxidative response in hyperandrogenism-induced polycystic ovary (PCO).
  
  
  METHODS
  The murine model of PCO was induced by letrozole (1 mg/kg/d; orally) and effective doses of carvedilol (10 mg/kg/d; orally) and ANGIPARS™ (2.1 mg/kg/d; orally) were administrated for 21 d in PCO and non-PCO healthy rats. Ovarian folliculogenesis, sex hormones concentrations, OS, inflammatory, and metabolic biomarkers were assessed in serum and ovaries.
  
  
  RESULTS
  PCO rats exhibited ovarian cystogenesis which was preserved by the application of carvedilol and ANGIPARS™. In comparison with controls, decreased level of the total antioxidant power (TAP) and higher levels of reactive oxygen species (ROS) and lipid peroxidation (LPO) in serum and ovaries (2.41 ± 0.67 versus 0.72 ± 0.11; and 0.17 ± 0.04 versus 0.05 ± 0.01; 5.48 ± 1.30 versus 10.56 ± 0.77; and 7.06 ± 1.94 versus 17.98 ± 0.98; p < 0.05, respectively) were detected in PCO rats. Moreover, the PCO rats exhibited hyperandrogenism due to a 3.7-fold increase in serum testosterone concentration (35.04 ± 3.17 versus 131.09 ± 13.24; p < 0.05) along with a 2.98-fold decrease in serum progesterone (6.19 ± 0.40 versus 18.50 ± 1.03; p < 0.05) and 5.2-fold decrease in serum estradiol (9.30 ± 0.61 versus 48.3 ± 2.10; p < 0.05) when compared with those of the control group. However, similar to the control group, normal levels of OS markers and sex hormones were detected in ANGIPARS™ and carvedilol co-treated PCO rats. Besides, when compared with controls, increased levels of TNF-α (770.75 ± 42.06 versus 477.14 ± 28.77; p < 0.05) and insulin (1.27 ± 0.10 versus 0.36 ± 0.05; p < 0.05) in PCO rats were significantly inhibited by carvedilol and ANGIPARS™ co-treatment.
  
  
  CONCLUSIONS
  We evidenced the beneficial effects of carvedilol and ANGIPARS™ in PCO, which underpin the new alternative approach in using these kinds of medicines in female reproductive disorders.
authors.affiliation: a Division of Toxicology, Department of Toxicology and Pharmacology, Faculty of Pharmacy , Tehran University of Medical Sciences , Tehran , Iran .|b Pharmaceutical Sciences Research Center , Tehran University of Medical Sciences , Tehran , Iran .
authors.forename: Mohammad Amin
authors.initials: MA
authors.lastname: Rezvanfar
authors.affiliation: c Pharmaceutical Sciences Branch , Azad University , Tehran , Iran .
authors.forename: Sarah
authors.initials: S
authors.lastname: Saeedi
authors.affiliation: c Pharmaceutical Sciences Branch , Azad University , Tehran , Iran .
authors.forename: Parisa
authors.initials: P
authors.lastname: Mansoori
authors.affiliation: c Pharmaceutical Sciences Branch , Azad University , Tehran , Iran .
authors.forename: Sepideh
authors.initials: S
authors.lastname: Saadat
authors.affiliation: d Faculty of Medicine , Tehran University of Medical Sciences , Tehran , Iran , and.
authors.forename: Maziar
authors.initials: M
authors.lastname: Goosheh
authors.affiliation: e Centre de Recherche en Biologie de la Reproduction , UniversitéLaval , Québec City , QC , Canada.
authors.forename: Habib A
authors.initials: HA
authors.lastname: Shojaei Saadi
authors.affiliation: b Pharmaceutical Sciences Research Center , Tehran University of Medical Sciences , Tehran , Iran .
authors.forename: Maryam
authors.initials: M
authors.lastname: Baeeri
authors.affiliation: a Division of Toxicology, Department of Toxicology and Pharmacology, Faculty of Pharmacy , Tehran University of Medical Sciences , Tehran , Iran .|b Pharmaceutical Sciences Research Center , Tehran University of Medical Sciences , Tehran , Iran .
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abdollahi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D012739:Gonadal Steroid Hormones / Q000097:blood; D017588:Hyperandrogenism / Q000139:chemically induced; D018836:Inflammation Mediators / Q000097:blood; D000077289:Letrozole; D015227:Lipid Peroxidation / Q000187:drug effects; D009570:Nitriles; D010053:Ovary / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology*; D011085:Polycystic Ovary Syndrome / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D015415:Biomarkers; D012739:Gonadal Steroid Hormones; D018836:Inflammation Mediators; D009570:Nitriles; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C000610751:Semelil; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D000077289:Letrozole
keywords: Beta-blockers; herbal medicine; hyperandrogenism; oxidative stress