Carvacrol and Thymol Modulate the Cross-Talk between TNF-α and IGF-1 Signaling in Radiotherapy-Induced Ovarian Failure.

Yasmen F Mahran,Raghad Bin-Zaid,Alhanouf Aldosari,Amira M Badr,Hind N Alotaibi,Francisco J Romero

doi:10.1155/2019/3173745

Abstract

Premature ovarian failure (POF) is a common cause of infertility in premenopausal women who are unavoidably exposed to cytotoxic therapy. Radiotherapy is one of the most effective cytotoxic treatments. However, the radiosensitivity of ovarian tissues limits its therapeutic outcome and results in the depletion of the primordial follicle and loss of fertility. Therefore, the need for an effective radioprotective therapy is evident especially when none of the current clinically used modalities for radioprotection succeeds efficiently. The present study investigated the potential radioprotective effect of carvacrol (CAR) (80 mg) or thymol (80 mg) on gamma- (γ-) irradiation-induced ovarian damage as well as their role in the cross-talk between IGF-1 and TNF-α signaling and antioxidative activity. In immature female Wister rats, a single dose of whole-body irradiation (3.2 Gy, LD20) produced considerable ovarian damage, which was evident by histopathological findings and hormonal changes. Interestingly, pretreatment with CAR or thymol significantly enhanced the follicular development and restored the anti-Mullerian hormone (AMH), E2, and FSH levels. Both essential oils improved the irradiation-mediated oxidative stress and reduction in proliferating cell nuclear antigen (PCNA) expression. Moreover, irradiated rats exhibited an inverse relationship between IGF-1 and TNF-α levels two days post irradiation, which was further inverted by the pretreatment with CAR and thymol and ought to contribute in their radioprotective mechanisms. In conclusion, CAR and thymol showed a radioprotective effect and rescued the ovarian reserve mainly through counteracting oxidative stress and the dysregulated cross-talk between IGF-1 and TNF-α.

Highlights

Radiotherapy is one of the most important therapies for cancer that relies on DNA damage to eradicate tumors [1]
Concurrent treatment with CAR or thymol increased the weight gained by ovaries as well as their relative ovary weight when compared with the irradiated group (Table 1)
Our current study showed a correlated inverse relationship between TNF-α and insulin-like growth factor 1 (IGF-1) in irradiated rats; this was in accordance with a previous study which found that Zymosan increased TNF-α, and this was associated with a 40% decrease in the IGF-I concentration in plasma, liver, heart, and brain [64]

Summary

Introduction

Radiotherapy is one of the most important therapies for cancer that relies on DNA damage to eradicate tumors [1] This process has the unintended off-target effect of permanently damaging normal tissues that are within the treatment field [2, 3] during or shortly after the completion of irradiation and limiting its therapeutic outcome [4]. Any factor that damages the follicle pool—such as radiation—can accelerate reproductive aging and lead to premature amenorrhea, subfertility, or even infertility [9]. In this context, radiotherapy has an array of serious effects on ovarian functions [3], such as the depletion of the nonrenewable primordial follicle reserve [10]. The ideal mitigation paradigm has not been discovered yet

Objectives

Results

Discussion

Conclusion