Translational Research Center, Department of Neurobiology and Anatomy, Northeast Ohio Medical University, Rootstown, OH, 44272, USA.
Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, NV, 95616, USA.
J Assoc Res Otolaryngol. 2021 Apr;22(2):107-126. doi: 10.1007/s10162-020-00782-z. Epub 2021 Jan 7.
Cisplatin chemotherapy often causes permanent hearing loss, which leads to a multifaceted decrease in quality of life. Identification of early cisplatin-induced cochlear damage would greatly improve clinical diagnosis and provide potential drug targets to prevent cisplatin's ototoxicity. With improved functional and immunocytochemical assays, a recent seminal discovery revealed that synaptic loss between inner hair cells and spiral ganglion neurons is a major form of early cochlear damage induced by noise exposure or aging. This breakthrough discovery prompted the current study to determine early functional, cellular, and molecular changes for cisplatin-induced hearing loss, in part to determine if synapse injury is caused by cisplatin exposure. Cisplatin was delivered in one to three treatment cycles to both male and female mice. After the cisplatin treatment of three cycles, threshold shift was observed across frequencies tested like previous studies. After the treatment of two cycles, beside loss of outer hair cells and an increase in high-frequency hearing thresholds, a significant latency delay of auditory brainstem response wave 1 was observed, including at a frequency region where there were no changes in hearing thresholds. The wave 1 latency delay was detected as early cisplatin-induced ototoxicity after only one cycle of treatment, in which no significant threshold shift was found. In the same mice, mitochondrial loss in the base of the cochlea and declining mitochondrial morphometric health were observed. Thus, we have identified early spiral ganglion-associated functional and cellular changes after cisplatin treatment that precede significant threshold shift.
顺铂化疗常导致永久性听力损失，从而导致生活质量多方面下降。鉴定顺铂引起的早期耳蜗损伤将极大地改善临床诊断，并为预防顺铂耳毒性提供潜在的药物靶点。随着功能和免疫细胞化学检测方法的改进，最近的一项重要发现揭示了内毛细胞和螺旋神经节神经元之间的突触丢失是噪声暴露或衰老引起的早期耳蜗损伤的主要形式。这一突破性发现促使本研究确定顺铂引起的听力损失的早期功能、细胞和分子变化，部分目的是确定突触损伤是否是由顺铂暴露引起的。顺铂在一个至三个治疗周期内输送给雄性和雌性小鼠。在三个周期的顺铂治疗后，像以前的研究一样，在测试的各个频率上都观察到了阈值变化。在两个周期的治疗后，除了外毛细胞丢失和高频听力阈值增加外，还观察到听觉脑干反应波 1 的潜伏期显著延迟，包括在听力阈值没有变化的频率区域。在仅一个周期的治疗后，就检测到了波 1 潜伏期的延迟，这是顺铂引起的早期耳毒性，在该周期中未发现显著的阈值变化。在相同的小鼠中，耳蜗底部的线粒体丢失和线粒体形态计量健康状况下降也被观察到。因此，我们已经鉴定出顺铂治疗后早期与螺旋神经节相关的功能和细胞变化，这些变化先于显著的阈值变化。
