Resveratrol inhibits inflammatory signaling implicated in ionizing radiation-induced premature ovarian failure through antagonistic crosstalk between silencing information regulator 1 (SIRT1) and poly(ADP-ribose) polymerase 1 (PARP-1)

Biochem Pharmacol. 2016 Mar 1:103:140-50. doi: 10.1016/j.bcp.2016.01.019. Epub 2016 Jan 28.

Abstract

This study hypothesized that resveratrol, a silencing information regulator 1 (SIRT1) activator, would counteract the inflammatory signaling associated with radiotherapy-induced premature ovarian failure (POF). Immature female Sprague-Dawley rats were subjected to a single dose of γ-radiation to induce POF and treated with resveratrol (25mg/kg) once daily for two weeks before and three days post irradiation. Resveratrol preserves the entire ovarian follicle pool manifested by increasing serum anti-Müllerian hormone (AMH) levels. Radiation triggered inflammatory process in the ovary through enhanced NF-κB and poly(ADP-ribose) polymerase (PARP)-1 expression which convinced the expression of inflammatory markers including IL-6, IL-8, and visfatin mRNA levels, as well as inducible nitric oxide synthase and cyclooxygenase-2 protein expression with a concomitant reduction in IL-10 mRNA levels. Resveratrol significantly counteracted the effect of radiation and upregulated the gene expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and SIRT1. Resveratrol-activated SIRT1 expression was associated with inhibition of PARP-1 and NF-κB expression-mediated inflammatory cytokines. Our findings suggest that resveratrol restored ovarian function through increasing AMH levels, and diminishing ovarian inflammation, predominantly via upregulation of PPAR-γ and SIRT1 expression leading to inhibition of NF-κB provoked inflammatory cytokines.

Keywords: Inflammation; Ovarian failure; Resveratrol; SIRT1; γ-Radiation.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Cyclooxygenase 2 / metabolism
  • Cytokines / metabolism
  • Female
  • Gamma Rays
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Ovarian Follicle / drug effects
  • Ovarian Follicle / physiology
  • Ovarian Reserve / drug effects
  • PPAR gamma / metabolism
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Primary Ovarian Insufficiency / metabolism
  • Primary Ovarian Insufficiency / pathology
  • Primary Ovarian Insufficiency / prevention & control*
  • Radiation Injuries, Experimental / metabolism
  • Radiation Injuries, Experimental / pathology
  • Radiation Injuries, Experimental / prevention & control*
  • Rats, Sprague-Dawley
  • Resveratrol
  • Signal Transduction
  • Sirtuin 1 / metabolism*
  • Stilbenes / pharmacology*
  • Stilbenes / therapeutic use
  • Transcription Factor RelA / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • PPAR gamma
  • Stilbenes
  • Transcription Factor RelA
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2
  • Parp1 protein, rat
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Sirt1 protein, rat
  • Sirtuin 1
  • Resveratrol