ABSTRACT

Cisplatin-induced ototoxicity is caused by reactive oxygen species. It has been recognized that estradiol (E2) regulates redox balance. However, little is known about the protective mechanisms of E2 against cisplatin-induced ototoxicity. In this study, we investigated the effect of E2 on nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated hair cell protection using the organ of Corti isolated from mice. The organ of Corti collected from C57BL/6 mice at 3–5 postnatal days was used in all experiments. The organ of Corti was exposed to 20 μM cisplatin with/without 100 nM E2 to examine the effect of E2 on cisplatin-induced hair cell loss. The mRNA expression of Nrf2 and the phase II detoxification gene after E2 and cisplatin treatment was analyzed using quantitative real-time PCR. E2 significantly reduces cisplatin-induced cochlear hair cell death. In addition, 100 nM E2 increased the mRNA expression of Nrf2 and phase II detoxification genes in the organ of Corti under cisplatin treatment. Our results suggest that E2 activates Nrf2, phase II detoxification enzymes and exerts a protective effect against cisplatin-induced ototoxicity.

摘要

顺铂诱导的耳毒性是由活性氧引起的。已经认识到雌二醇 (E2) 调节氧化还原平衡。然而，关于 E2 对顺铂诱导的耳毒性的保护机制知之甚少。在这项研究中，我们使用从小鼠身上分离的 Corti 器官研究了 E2 对核因子红细胞 2 相关因子 2 (Nrf2) 介导的毛细胞保护的影响。所有实验都使用了在出生后 3-5 天从 C57BL/6 小鼠身上收集的 Corti 器官。Corti 器官暴露于含/不含 100 nM E2 的 20 μM 顺铂，以检查 E2 对顺铂诱导的毛细胞丢失的影响。使用定量实时 PCR 分析 E2 和顺铂治疗后 Nrf2 和 II 期解毒基因的 mRNA 表达。E2 显着减少顺铂诱导的耳蜗毛细胞死亡。此外，100 nM E2 在顺铂治疗下增加了 Corti 器官中 Nrf2 和 II 期解毒基因的 mRNA 表达。我们的结果表明 E2 激活 Nrf2，II 期解毒酶并对顺铂诱导的耳毒性发挥保护作用。