The Potential Therapeutic Effects of Insulin Sensitizer in Ovarian Failure Induced by either Chemotherapy or Gamma-Radiation Therapy

Abstract

The present study aimed to investigate the radioprotective effect of RSV against γ-radiation induced POF, in particular, its impact on inflammatory cytokines, proinflammatory enzymes iNOS and COX-2, the transcription factors NF-κB p65, PARP-1, SIRT1, and PPAR-γ expressions, as well as AMPK activity. The study was designed as follows: immature female Sprague-Dawely rats were subjected to a single dose of γ-radiation (3.2 Gy) to induce POF and/or treated with RSV (25 mg/kg, P.O., once daily for two weeks before and three days post irradiation). The following parameters were investigated: A. Assessment of serum AMH levels. B. Ovarian histopathological examination. C. Morphometric analysis of ovarian follicles. D. Assessment of ovarian inflammatory markers: TNF-α level, NF-κB expression and IL-6, IL-8, IL-10 mRNA levels as well as iNOS and COX-2 expression. E. PARP-1 expression. F. Visfatin mRNA levels. G. SIRT1 mRNA levels. H. PPAR-γ mRNA levels. I. AMPK-α [pT172] levels. The results of the present study can be summarized as follows: 1. Histopathological examination of irradiated ovaries showed that stromal tissue occupied most of the ovarian structure, which was characterized by interstitial hyperplasia with marked fibrosis and severe hemorrhage in between. Irradiation resulted also in a marked reduction in overall ovarian size with appearance of atypical follicles. Interestingly, RSV treatment reversed the POF pathology observed following radiation exposure and maintained the follicular stock. 2. The percentage of healthy resting follicles was suppressed by more than 40% in irradiated ovaries. Moreover, severe depletion of primordial follicles induced by whole-body irradiation of female rats provokes POF. It is noticeable that the number of preantral follicles decreased significantly in irradiated ovaries; in contrast antral follicle's population remained unaffected as compared to control ovaries. Interestingly, RSVtreatment preserves remaining healthy follicles particularly primordial follicles’ stock, and minimizes the percentage of follicular depletion induced by irradiation, suggesting the ovarian radioprotective effect of RSV. 3. The current study demonstrated that endocrine environment was affected by radiation as shown by a significant reduction in serum AMH concentration, which may be as a consequence of decreased ovarian preantral follicle'