The DNA methylation inhibitor RG108 protects against noise-induced hearing loss,Cell Biology and Toxicology

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The DNA methylation inhibitor RG108 protects against noise-induced hearing loss
Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2021-03-15 , DOI: 10.1007/s10565-021-09596-y
Zhiwei Zheng _{1,

2} , Shan Zeng _{1,

2} , Chang Liu _{1,

2} , Wen Li _{1,

2} , Liping Zhao _{1,

2} , Chengfu Cai ₃ , Guohui Nie ₄ , Yingzi He _{1,

2}

Affiliation

Background

Noise-induced hearing loss represents a commonly diagnosed type of hearing disability, severely impacting the quality of life of individuals. The current work is aimed at assessing the effects of DNA methylation on noise-induced hearing loss.

Methods

Blocking DNA methyltransferase 1 (DNMT1) activity with a selective inhibitor RG108 or silencing DNMT1 with siRNA was used in this study. Auditory brainstem responses were measured at baseline and 2 days after trauma in mice to assess auditory functions. Whole-mount immunofluorescent staining and confocal microcopy of mouse inner ear specimens were performed to analyze noise-induced damage in cochleae and the auditory nerve at 2 days after noise exposure.

Results

The results showed that noise exposure caused threshold elevation of auditory brainstem responses and cochlear hair cell loss. Whole-mount cochlea staining revealed a reduction in the density of auditory ribbon synapses between inner hair cells and spiral ganglion neurons. Inhibition of DNA methyltransferase activity via a non-nucleoside specific pharmacological inhibitor, RG108, or silencing of DNA methyltransferase-1 with siRNA significantly attenuated ABR threshold elevation, hair cell damage, and the loss of auditory synapses.

Conclusions

This study suggests that inhibition of DNMT1 ameliorates noise-induced hearing loss and indicates that DNMT1 may be a promising therapeutic target.

Graphical abstract

中文翻译：

DNA 甲基化抑制剂 RG108 可防止噪音引起的听力损失

背景

噪声性听力损失是一种常见的听力障碍类型，严重影响个人的生活质量。目前的工作旨在评估 DNA 甲基化对噪声性听力损失的影响。

方法

本研究使用选择性抑制剂 RG108 阻断 DNA 甲基转移酶 1 (DNMT1) 活性或用 siRNA 沉默 DNMT1。在小鼠的基线和创伤后 2 天测量听觉脑干反应以评估听觉功能。对小鼠内耳标本进行整体免疫荧光染色和共聚焦显微镜检查，以分析噪声暴露后 2 天耳蜗和听神经中的噪声引起的损伤。

结果

结果表明，噪声暴露导致听觉脑干反应阈值升高和耳蜗毛细胞损失。整体耳蜗染色显示内毛细胞和螺旋神经节神经元之间的听觉带状突触密度降低。通过非核苷特异性药理学抑制剂 RG108 抑制 DNA 甲基转移酶活性或使用 siRNA 沉默 DNA 甲基转移酶-1 可显着减轻 ABR 阈值升高、毛细胞损伤和听觉突触的丧失。