Beneficial effects of minocycline on the ovary of polycystic ovary syndrome mouse model: Molecular docking analysis and evaluation of TNF-α, TNFR2, TLR-4 gene expression

J Reprod Immunol. 2021 Apr:144:103289. doi: 10.1016/j.jri.2021.103289. Epub 2021 Feb 15.

Abstract

Polycystic ovary syndrome (PCOS) is the most common cause of ovulatory infertility. Inflammation may be involved in the pathogenesis and development of PCOS. We investigated the anti-inflammatory effect of minocycline on TNF-α, TNFR2, and TLR4 expression levels and the key features of PCOS in a mouse model. Molecular docking was performed by Molecular Operating Environment software. PCOS was induced by estradiol valerate injection (EV) (2 mg/kg/day) in 40 mice. After 28 days, the mice were divided into five groups, including control, PCOS, minocycline control, minocycline PCOS model (50 mg/kg), and letrozole PCOS (0.5 mg/kg). The Levels of FSH, LH, E2, and testosterone were determined by ELISA. H&E staining was used for histological analysis in the ovarian tissues. Docking scores were -10.35, -10.57, and -12.45 kcal/mol for TNFα, TLR-4, and TNFR2, respectively. The expression levels of TNF-α, TNFR2, and TLR4 were detected by Real-Time PCR. PCOS models exhibited acyclicity, a significant increase in E2 levels (P < 0.01), and no difference in FSH, LH, and testosterone. The expression levels of TNF-α, TNFR2, and TLR-4 significantly increased in PCOS (2.70, 7.90, and 14.83-fold, respectively). EV treatment significantly increased graafian follicles (P < 0.001) and decreased corpus luteum (CL) (P < 0.01). Minocycline treatment in PCOS led to a significant decrease in E2 (P < 0.01) and graafian follicles (P < 0.001) and a significant increase in the CL numbers (P < 0.05). Our findings showed the positive effects of minocycline on estradiol level, CL and graafian follicles counts, suggesting that minocycline might inhibit these proteins and improve ovulation in our mouse model of PCOS.

Keywords: Minocycline; PCOS; TLR-4; TNF-α; TNFR2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Estradiol / administration & dosage
  • Estradiol / toxicity
  • Female
  • Humans
  • Letrozole / pharmacology
  • Letrozole / therapeutic use
  • Mice
  • Minocycline / pharmacology*
  • Minocycline / therapeutic use
  • Molecular Docking Simulation
  • Ovary / immunology
  • Ovary / pathology
  • Ovulation / drug effects*
  • Ovulation / immunology
  • Polycystic Ovary Syndrome / chemically induced
  • Polycystic Ovary Syndrome / drug therapy*
  • Polycystic Ovary Syndrome / immunology
  • Polycystic Ovary Syndrome / pathology
  • Receptors, Tumor Necrosis Factor, Type II / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Receptors, Tumor Necrosis Factor, Type II
  • Tlr4 protein, mouse
  • Tnf protein, mouse
  • Tnfrsf1b protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Estradiol
  • Letrozole
  • Minocycline