Early Physiological and Cellular Indicators of Cisplatin-Induced Ototoxicity
Early Physiological and Cellular Indicators of Cisplatin-Induced Ototoxicity
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DOI：
10.1007/s10162-020-00782-z
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发表时间：
2021-01-07
影响因子：
2.4
通讯作者：
Bao, Jianxin
中科院分区：
文献类型：
--
作者：
Chen, Yingying;Bielefeld, Eric C.;Bao, Jianxin
顺铂化疗通常会导致永久性听力损失，从而导致生活质量的多方面下降。早期发现顺铂致耳蜗损伤将大大提高临床诊断水平，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分析的改进，最近的一项重大发现表明，内毛细胞和螺旋神经节神经元之间的突触丧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目前的研究确定顺铂诱导的听力损失的早期功能、细胞和分子变化，部分是为了确定突触损伤是否由顺铂暴露引起。顺铂在一到三个治疗周期内给雄性和雌性小鼠。顺铂治疗3个周期后，阈值漂移在不同频率的测试中被观察到，与之前的研究一样。经过两个周期的治疗，除了外毛细胞的损失和高频听力阈值的增加外，还观察到听觉脑干反应波1的明显延迟，包括在听力阈值没有变化的频率区域。仅在一个治疗周期后，就检测到波1潜伏期延迟为早期顺铂诱导的耳毒性，未发现明显的阈值移位。在相同的小鼠中，观察到耳蜗底部的线粒体丢失和线粒体形态健康下降。因此，我们已经确定了顺铂治疗后早期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转移。
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.