The DNA methylation inhibitor RG108 protects against noise-induced hearing loss

Abstract

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

Resveratrol prevents hearing loss and a subregion specific- reduction of serotonin reuptake transporter induced by noise exposure in the central auditory system

“…Some previous studies have reported that noise exposure can increase the hearing threshold and cause the loss of hair cells in the cochlea (Shi et al, 2014;Wen et al, 2015;Zhang et al, 2017;Seist et al, 2021;Zheng et al, 2021;Han et al, 2022). Consistently, we also found that noise exposure can cause an increase of hearing threshold in mice.…”

Dnmt1 is required for the development of auditory organs via cell cycle arrest and Fgf signalling

“…Our previous study explored that using Dnmt1 inhibitor RG108, or specific siRNA target Dnmt1, could provide protective function against noise‐induced hearing loss in C57BL/6J mice, indicating a potential therapeutic effect of DNA hypomethylation on hearing impairment 34 . However, the role of Dnmt1 in the development of auditory organ is unclear.…”

“…Our previous study explored that using Dnmt1 inhibitor RG108, or specific siRNA target Dnmt1, could provide protective function against noise-induced hearing loss in C57BL/6J mice, indicating a potential therapeutic effect of DNA hypomethylation on hearing impairment. 34 However, the role of Dnmt1 in the development of auditory organ is unclear. In this study, we demonstrated that Dnmt1 was required for the development of zebrafish through a loss-offunction strategy using special antisense morpholino targeting Dnmt1.…”

Deciphering the potential ability of RG108 in cisplatin-induced HEI-OC1 ototoxicity: a research based on RNA-seq and molecular biology experiment

“…RG108 as DNMT1 plays a vital character in many biological behaviour [ 15 ]. Previous researches have shown that RG108 reduces oxidative DNA damage and apoptosis of auditory cells after noise exposure, and RG108 has a rescue effect on noise-induced hearing loss [ 16 ]. This study mainly focused on the mechanism of action of RG 108 on drug-induced deafness.…”