Melatonin Attenuates Cisplatin-Induced Ototoxicity via Regulating the Cell Apoptosis of the Inner Ear.

Objective: The mechanism of ototoxicity caused by cisplatin is currently unclear, and the induced apoptosis may play an important role in inner ear injury. Melatonin has high antioxidant and antiapoptotic effects. This study is aimed at clarifying the protective effect on the inner ear and the underlying mechanism of melatonin.

Design: The mice and HEI-OC1 cells were randomly separated into four groups: control group, cisplatin group, melatonin group, and cisplatin exposure after melatonin pretreatment group. From September 2018 to September 2021, all experiments were completed at the Second Hospital of Shandong University. And the study was approved by the Ethics Committee of the Second Hospital of Shandong University (KYLL-2020 (KJ) A-0191). Mice were pretreated with peritoneal injection of melatonin prior to the application of cisplatin. Auditory Brainstem Response (ABR) test was performed before and after treatment, then the temporal bones were collected for histology investigation. HEI-OC1 cells were pretreated with melatonin before adding cisplatin. The apoptosis of HEI-OC1 cells was observed by MTS, TUNEL, and flow cytometry, respectively. Moreover, the mRNA expression of apoptosis-related factors was detected by qRT-PCR.

Results: ABR and morphological analysis showed that cisplatin caused damage to the function and structure of the inner ear. MTS, TUNEL, and flow cytometry showed that the application of cisplatin caused a significant increase in the apoptosis level of HEI-OC1 cells, and melatonin pretreatment reduced this damage. Moreover, melatonin pretreatment reversed the mRNA expression changes of apoptosis-related factors induced by cisplatin.

Conclusions: Apoptosis is involved in the inner ear dysfunction caused by cisplatin. Melatonin reduces the ototoxicity of cisplatin by regulating the induced apoptosis response.