Rapamycin has been proven to effectively inhibit the activation of primordial follicles while cisplatin-induced the loss of primordial follicles due to the over-activation of the primordial follicle stockpile. Whether rapamycin could inhibit the loss of primordial follicles induced by cisplatin is still unknown. The ovaries of neonatal Sprague Dawley rats were cultured in vitro in different doses of rapamycin (0.08, 0.16, and 0.32 μg/ml) and cisplatin (0.1, 0.4, and 0.8 μg/ml). The immature BALB/c mice were administered cisplatin with or without rapamycin by intraperitoneal injection. Ovaries were collected to analyze the histomorphology, the messenger RNA (mRNA) expression of anti-Mullerian hormone (AMH), growth differentiation factor 9 (GDF9), and bone morphogenetic protein 15 (BMP15) and the expression of key proteins of mammalian target of rapamycin (mTOR) pathway. Growing follicle counts of ovaries cultured in vitro in the R0.16 and R0.32 groups were decreased and the ratio of growing to primordial follicles was also decreased in a dose-dependent manner. In the C0.8 group, growing follicles were decreased compared with the other groups while the ratio was substantially increased in the C0.4 and C0.8 group. Co-treatment attenuated primordial follicle loss and reduced the upregulated ratio induced by cisplatin. Ovarian follicle dynamics in vivo was consistent with the in vitro results. Primordial follicles counts were statistically increased and the ratio was reduced in the rapamycin group compared with the control group. Primordial follicle counts were dramatically reduced in the cisplatin group whereas co-treatment with rapamycin slightly recovered its counts. There was no obvious difference in the number of growing follicles between the cisplatin group and other groups. The ratio was significantly increased in cisplatin-treated mice whereas decreased in the co-treatment group. The apoptosis rate of antral follicles in cisplatin-treated mice was higher than the other groups while the apoptosis rate was decreased in the co-treatment group in vivo. Compared with the control and rapamycin group, the mRNA expression of AMH, GDF9, and BMP15 were downregulated in the cisplatin group. The co-treatment group recovered the mRNA expression of BMP15. In addition, the expression of key protein of mTOR pathway rpS6 and its phosphorylated forms were increased in the cisplatin-treated group while co-treatment decreased their expression. Rapamycin attenuated the loss of primordial follicles induced by cisplatin through the inhibitory effect of rapamycin on the mTOR pathway. These results suggest that rapamycin may be an effective drug for the protection of ovarian function during chemotherapy.

中文翻译：

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雷帕霉素在体外和体内顺铂治疗期间均保留了原始卵泡池。

已证明雷帕霉素可有效抑制原始卵泡的活化，而顺铂则由于原始卵泡储备的过度活化而诱导原始卵泡的损失。雷帕霉素是否可以抑制顺铂诱导的原始卵泡的丢失尚不清楚。在不同剂量的雷帕霉素（0.08、0.16和0.32μg/ ml）和顺铂（0.1、0.4和0.8μg/ ml）中体外培养新生Sprague Dawley大鼠的卵巢。给未成熟的BALB / c小鼠腹膜内注射顺铂和雷帕霉素，或不加雷帕霉素。收集卵巢以分析组织形态，抗穆勒激素（AMH）的信使RNA（mRNA）表达，生长分化因子9（GDF9），和骨形态发生蛋白15（BMP15）以及雷帕霉素（mTOR）途径的哺乳动物靶标关键蛋白的表达。在R0.16和R0.32组中，体外培养的卵巢的卵泡生长数量减少，并且与原始卵泡的生长比例也呈剂量依赖性降低。在C0.8组中，与其他组相比，生长中的卵泡减少，而在C0.4和C0.8组中，卵泡的比率显着增加。联合治疗减弱了原始卵泡的损失并降低了顺铂诱导的上调比例。体内卵泡动力学与体外结果一致。与对照组相比，雷帕霉素组的原始卵泡计数在统计学上有所增加，且比率降低。顺铂组的原始卵泡计数显着降低，而与雷帕霉素联合治疗则略有恢复。顺铂组与其他组之间的卵泡生长数量没有明显差异。该比例在顺铂治疗的小鼠中显着增加，而在联合治疗组中则降低。顺铂治疗组小鼠体内卵泡的凋亡率高于其他组，而联合治疗组在体内凋亡率则降低。与对照组和雷帕霉素组相比，顺铂组AMH，GDF9和BMP15的mRNA表达下调。联合治疗组恢复了BMP15的mRNA表达。此外，顺铂治疗组mTOR途径rpS6关键蛋白及其磷酸化形式的表达增加，而联合治疗则降低了其表达。雷帕霉素通过雷帕霉素对mTOR途径的抑制作用来减轻顺铂诱导的原始卵泡的损失。这些结果表明雷帕霉素可能是化学疗法中保护卵巢功能的有效药物。