Synergistic effect of melatonin and ghrelin in preventing cisplatin‐induced ovarian damage via regulation of FOXO 3a phosphorylation and binding to the p27 Kip1 promoter in primordial follicles

作者：Hoon Jang, Younghwa Na, Kwonho Hong, Sang Ho Lee, Sohyeon Moon, Minha Cho, Miseon Park, Ok‐Hee Lee, Eun Mi Chang, Dong Ryul Lee, Jung Jae Ko, Woo Sik Lee, Youngsok Choi · 发表于：Journal of Pineal Research · 年份：2017 · DOI：10.1111/jpi.12432 · 被引用次数：89 · 研究领域：Reproductive Biology and Fertility、Ovarian function and disorders、FOXO transcription factor regulation

Abstract Premature ovarian failure during chemotherapy is a serious problem for young women with cancer. To preserve the fertility of these patients, approaches to prevent chemotherapy‐induced ovarian failure are needed. In a previous study, we reported that melatonin treatment prevents the depletion of the dormant follicle pool via repression of the simultaneous activation of dormant primordial follicles by cisplatin. However, melatonin's protective effect was only partial and thus insufficient. In this study, we found that the hormone ghrelin enhances the protective effect of melatonin against cisplatin‐induced ovarian failure in mouse model. Co‐administration of melatonin and ghrelin more effectively prevented cisplatin‐induced follicle disruption. Simultaneous treatment with melatonin and ghrelin almost restored the number of primordial follicles and the corpus luteum in cisplatin‐treated ovaries, compared with single administration. We found melatonin and ghrelin receptors on the cell membrane of premature oocytes of primordial follicles. In addition, melatonin and ghrelin co‐administration inhibited the cisplatin‐induced phosphorylation of PTEN and FOXO 3a that induces cytoplasmic translocation of FOXO 3a. Inhibition of FOXO 3a phosphorylation by melatonin and ghrelin increased the binding affinity of FOXO 3a for the p27 Kip1 promoter in primordial follicles. Co‐administration of melatonin and ghrelin in cisplatin‐treated ovaries restored the expression of p27 Kip1 , wh...