ENT Institute and Otorhinolaryngology Department, Affiliated Eye and ENT Hospital, Fudan University and Key Laboratory of Hearing Medicine of National Health and Family Planning Commission (NHFPC), Shanghai 200031, China.
ENT Institute and Otorhinolaryngology Department, Affiliated Eye and ENT Hospital, Fudan University and Key Laboratory of Hearing Medicine of National Health and Family Planning Commission (NHFPC), Shanghai 200031, China.
Toxicol Appl Pharmacol. 2021 Mar 15;415:115447. doi: 10.1016/j.taap.2021.115447. Epub 2021 Feb 9.
Deafness is the most common sensory disorder in the world. Ototoxic drugs are common inducing factors of sensorineural hearing loss, and cochlear hair cell (HC) damage is the main concern of the present studies. Cisplatin is a widely used, highly effective antitumor drug, but some patients have experienced irreversible hearing loss as a result of its application. This hearing loss is closely related to HC apoptosis and autophagy. U0126 is a specific inhibitor of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) signaling pathway and has neuroprotective effects. For example, the neuroprotective effect of U0126 on ischemic stroke has been widely recognized. In neural cells, U0126 can prevent death due to excess glutamate, dopamine, or zinc ions. However, no studies of U0126 and ototoxic drug-induced injury have been reported to date. In the present study, we found that U0126 pretreatment significantly reduced the apoptosis and autophagy of HCs in auditory House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and cochlear HCs. In addition, U0126 reduced the cisplatin-induced production of reactive oxygen species as well as the cisplatin-induced decrease in the mitochondrial membrane potential. These findings suggest that U0126 may be a potential therapeutic candidate for the prevention of cisplatin-induced ototoxicity.
耳聋是世界上最常见的感觉障碍。耳毒性药物是导致感音神经性听力损失的常见诱发因素，耳蜗毛细胞（HC）损伤是目前研究的主要关注点。顺铂是一种广泛应用的高效抗肿瘤药物，但由于其应用，一些患者出现了不可逆转的听力损失。这种听力损失与 HC 凋亡和自噬密切相关。U0126 是细胞外信号调节蛋白激酶 1 和 2（ERK1/2）信号通路的特异性抑制剂，具有神经保护作用。例如，U0126 对缺血性中风的神经保护作用已得到广泛认可。在神经细胞中，U0126 可以防止因过量谷氨酸、多巴胺或锌离子引起的死亡。然而，迄今为止，尚无关于 U0126 和耳毒性药物诱导损伤的研究报道。在本研究中，我们发现 U0126 预处理可显著减少听觉 House Ear Institute-Organ of Corti 1（HEI-OC1）细胞和耳蜗 HC 中的 HC 凋亡和自噬。此外，U0126 降低了顺铂诱导的活性氧产生以及顺铂诱导的线粒体膜电位下降。这些发现表明，U0126 可能是预防顺铂耳毒性的潜在治疗候选药物。
