Association between histone deacetylases and the loss of cochlear hair cells: Role of the former in noise-induced hearing loss

Abstract ELMOD3, an ARL2 GTPase-activating protein, is implicated in causing hearing impairment in humans. However, the specific role of ELMOD3 in auditory function is still far from being elucidated. In the present study, we used the CRISPR/Cas9 technology to establish an Elmod3 knockout mice line in the C57BL/6 background (hereinafter referred to as Elmod3−/− mice) and investigated the role of Elmod3 in the cochlea and auditory function. Elmod3−/− mice started to exhibit hearing loss from 2 months of age, and the deafness progressed with aging, while the vestibular function of Elmod3−/− mice was normal. We also observed that Elmod3−/− mice showed thinning and receding hair cells in the organ of Corti and much lower expression of F-actin cytoskeleton in the cochlea compared with wild-type mice. The deafness associated with the mutation may be caused by cochlear hair cells dysfunction, which manifests with shortening and fusion of inner hair cells stereocilia and progressive degeneration of outer hair cells stereocilia. Our finding associates Elmod3 deficiencies with stereocilia dysmorphologies and reveals that they might play roles in the actin cytoskeleton dynamics in cochlear hair cells, and thus relate to hearing impairment.

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Glucose Protects Cochlear Hair Cells Against Oxidative Stress and Attenuates Noise-Induced Hearing Loss in Mice

Neuroscience Bulletin ◽

10.1007/s12264-020-00624-1 ◽

2021 ◽

Author(s):

Hao Xiong ◽

Lan Lai ◽

Yongyi Ye ◽

Yiqing Zheng

Keyword(s):

Oxidative Stress ◽

Hearing Loss ◽

Hair Cells ◽

Noise Induced Hearing Loss ◽

Cochlear Hair Cells

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Outcomes of Peptide Vaccine GV1001 Treatment in a Murine Model of Acute Noise-Induced Hearing Loss

Antioxidants ◽

10.3390/antiox9020112 ◽

2020 ◽

Vol 9 (2) ◽

pp. 112

Author(s):

Sang-Yeon Lee ◽

Jae Joon Han ◽

Sang-Youp Lee ◽

Gaon Jung ◽

Hyun Jin Min ◽

...

Keyword(s):

Oxidative Stress ◽

Hearing Loss ◽

White Noise ◽

Hair Cells ◽

Murine Model ◽

Outer Hair Cells ◽

Saline Control ◽

Noise Induced Hearing Loss ◽

Cochlear Hair Cells ◽

Ribbon Synapses

Noise-induced hearing loss (NIHL) is primarily caused by damage to cochlear hair cells, associated with synaptopathy. The novel cell-penetrating peptide GV1001, an antitumor agent, also has antioxidant and anti-inflammatory effects, and is otoprotective in a murine model of kanamycin-induced ototoxicity. Here, we explored whether GV1001 attenuated NIHL, and the underlying mechanism at play. We established an NIHL model by exposing 4- to 6-week-old C57/BL6 mice to white noise at 120 dB SPL for 2 h, resulting in a significant permanent threshold shift (PTS). We then subcutaneously injected saline (control), GV1001, or dexamethasone immediately after cessation of PTS-noise exposure and evaluated the threshold shifts, structural damages to outer hair cells (OHCs), and ribbon synapses. We also verified whether GV1001 attenuates oxidative stress at the level of lipid peroxidation or protein nitration in OHCs 1 h after exposure to white noise at 120 dB SPL. GV1001-treated mice exhibited significantly less hearing threshold shifts over 2 weeks and preserved OHCs and ribbon synapses compared with controls. Similarly, dexamethasone-treated mice showed comparable protection against NIHL. Importantly, GV1001 markedly attenuated oxidative stress in OHCs. Our findings suggest that GV1001 may protect against NIHL by lowering oxidative stress and may serve as preventive or adjuvant treatment.

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Regeneration of Cochlear Hair Cells with Atoh1 Gene Therapy after Noise-Induced Hearing Loss

Journal of Regenerative Medicine ◽

10.4172/2325-9620.1000121 ◽

2015 ◽

Vol 04 (01) ◽

Author(s):

Andrew K Wise Brianna O Flynn ◽

Patrick J Atkinson ◽

James B Fallon ◽

Madeline Nicholson

Keyword(s):

Gene Therapy ◽

Hearing Loss ◽

Hair Cells ◽

Noise Induced Hearing Loss ◽

Cochlear Hair Cells

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Fluorocitrate Neural Dystrophy of the Guinea Pig Cochlea

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100115468 ◽

1975 ◽

Vol 33 ◽

pp. 368-369

Author(s):

G.J. Spector ◽

C.D. Carr ◽

I. Kaufman Arenberg ◽

R.H. Maisel

Keyword(s):

Hearing Loss ◽

Hair Cells ◽

Sodium Phosphate ◽

Sensory Cells ◽

Barium Salt ◽

Perfusion Medium ◽

Cochlear Hair Cells ◽

Neural Degeneration ◽

Sodium Phosphate Buffer ◽

Cochlear Neurons

All studies on primary neural degeneration in the cochlea have evaluated the end stages of degeneration or the indiscriminate destruction of both sensory cells and cochlear neurons. We have developed a model which selectively simulates the dystrophic changes denoting cochlear neural degeneration while sparing the cochlear hair cells. Such a model can be used to define more precisely the mechanism of presbycusis or the hearing loss in aging man.Twenty-two pigmented guinea pigs (200-250 gm) were perfused by the perilymphatic route as live preparations using fluorocitrate in various concentrations (15-250 ug/cc) and at different incubation times (5-150 minutes). The barium salt of DL fluorocitrate, (C6H4O7F)2Ba3, was reacted with 1.0N sulfuric acid to precipitate the barium as a sulfate. The perfusion medium was prepared, just prior to use, as follows: sodium phosphate buffer 0.2M, pH 7.4 = 9cc; fluorocitrate = 15-200 mg/cc; and sucrose = 0.2M.

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MicroRNAs in Noise-Induced Hearing Loss and their Regulation by Oxidative Stress and Inflammation

Current Drug Targets ◽

10.2174/1389450121666200615145552 ◽

2020 ◽

Vol 21 (12) ◽

pp. 1216-1224

Author(s):

Fatemeh Forouzanfar ◽

Samira Asgharzade

Keyword(s):

Oxidative Stress ◽

Hearing Loss ◽

Hair Cell ◽

Noise Exposure ◽

Cell Damage ◽

Sensory Cells ◽

Noise Induced Hearing Loss ◽

Irreversible Damage ◽

Open Access Journals

Noise exposure (NE) has been recognized as one of the causes of sensorineural hearing loss (SNHL), which can bring about irreversible damage to sensory hair cells in the cochlea, through the launch of oxidative stress pathways and inflammation. Accordingly, determining the molecular mechanism involved in regulating hair cell apoptosis via NE is essential to prevent hair cell damage. However, the role of microRNAs (miRNAs) in the degeneration of sensory cells of the cochlea during NE has not been so far uncovered. Thus, the main purpose of this study was to demonstrate the regulatory role of miRNAs in the oxidative stress pathway and inflammation induced by NE. In this respect, articles related to noise-induced hearing loss (NIHL), oxidative stress, inflammation, and miRNA from various databases of Directory of Open Access Journals (DOAJ), Google Scholar, PubMed; Library, Information Science & Technology Abstracts (LISTA), and Web of Science were searched and retrieved. The findings revealed that several studies had suggested that up-regulation of miR-1229-5p, miR-451a, 185-5p, 186 and down-regulation of miRNA-96/182/183 and miR-30b were involved in oxidative stress and inflammation which could be used as biomarkers for NIHL. There was also a close relationship between NIHL and miRNAs, but further research is required to prove a causal association between miRNA alterations and NE, and also to determine miRNAs as biomarkers indicating responses to NE.

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The role of middle ear muscles in the development of resistance to noise induced hearing loss

Hearing Research ◽

10.1016/0378-5955(94)90172-4 ◽

1994 ◽

Vol 74 (1-2) ◽

pp. 22-28 ◽

Cited By ~ 28

Author(s):

Donald Henderson ◽

Malini Subramaniam ◽

Martin Papazian ◽

Vlasta P. Spongr

Keyword(s):

Hearing Loss ◽

Middle Ear ◽

Noise Induced Hearing Loss ◽

Development Of Resistance

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Outer hair cells in the mammalian cochlea and noise-induced hearing loss

Nature ◽

10.1038/315662a0 ◽

1985 ◽

Vol 315 (6021) ◽

pp. 662-665 ◽

Cited By ~ 77

Author(s):

A. R. Cody ◽

I. J. Russell

Keyword(s):

Hearing Loss ◽

Hair Cells ◽

Outer Hair Cells ◽

Noise Induced Hearing Loss

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Effects of cochlear hair cell ablation on spatial learning/memory

Scientific Reports ◽

10.1038/s41598-020-77803-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Z. Jason Qian ◽

Anthony J. Ricci

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Spatial Learning ◽

Hair Cells ◽

Noise Exposure ◽

Memory Errors ◽

Cochlear Hair Cells ◽

Cochlear Hair Cell ◽

Cell Ablation ◽

Spatial Learning Memory

AbstractCurrent clinical interest lies in the relationship between hearing loss and cognitive impairment. Previous work demonstrated that noise exposure, a common cause of sensorineural hearing loss (SNHL), leads to cognitive impairments in mice. However, in noise-induced models, it is difficult to distinguish the effects of noise trauma from subsequent SNHL on central processes. Here, we use cochlear hair cell ablation to isolate the effects of SNHL. Cochlear hair cells were conditionally and selectively ablated in mature, transgenic mice where the human diphtheria toxin (DT) receptor was expressed behind the hair-cell specific Pou4f3 promoter. Due to higher Pou4f3 expression in cochlear hair cells than vestibular hair cells, administration of a low dose of DT caused profound SNHL without vestibular dysfunction and had no effect on wild-type (WT) littermates. Spatial learning/memory was assayed using an automated radial 8-arm maze (RAM), where mice were trained to find food rewards over a 14-day period. The number of working memory errors (WME) and reference memory errors (RME) per training day were recorded. All animals were injected with DT during P30–60 and underwent the RAM assay during P90–120. SNHL animals committed more WME and RME than WT animals, demonstrating that isolated SNHL affected cognitive function. Duration of SNHL (60 versus 90 days post DT injection) had no effect on RAM performance. However, younger age of acquired SNHL (DT on P30 versus P60) was associated with fewer WME. This describes the previously undocumented effect of isolated SNHL on cognitive processes that do not directly rely on auditory sensory input.

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Neurotrophin gene therapy may be able to treat individuals with noise-induced hearing loss or neural presbyacusis

10.31219/osf.io/spkxh ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Gene Therapy ◽

Hearing Loss ◽

Hair Cell ◽

Hair Cells ◽

Cell Loss ◽

Cell Populations ◽

Noise Induced Hearing Loss ◽

Hair Cell Loss ◽

Functional Impairments ◽

Peripheral Axon

Neurotrophin (NT) cochlear gene therapy might perhaps give a single treatment that might greatly enhance neuronal survival, resulting in CI patients, provided the many challenges described above can be adequately addressed and safety concerns allayed by more animal model investigations. This is particularly crucial for juvenile CI patients, who have to rely on electrical hearing for the remainder of their lives, and whose outcomes are quite different. In addition, NT gene therapy may have the potential to treat patients with noise-induced hearing loss or neural presbyacusis (e.g., age-related cochlear synaptopathy), where primary neuronal loss is a key cause of hearing loss. Animal research into noise-induced hearing loss has shown that even exposures that generate only reversible threshold alterations and no hair cell loss can lead to permanent loss of SGN synapses on hair cells, resulting in functional impairments and ultimately SGN degeneration. Cochlear synapses frequently precede both hair cell loss and threshold increases in human ears, according to current studies. Cochlear synaptopathy is characterized by ears with intact hair cell populations and normal audiograms as "hidden" hearing loss. Many frequent perceptual abnormalities, including speech-in-noise difficulties, tinnitus, and hyperacusis, are likely produced by suppressing affected neurons, which radically alters information processing. Thus, in the future, NT gene therapy may be successful in inducing SGN peripheral axon resprouting and synaptic regeneration into residual (or even regenerated) hair cell populations. We have demonstrated compelling evidence that, in this investigation, BDNF gene therapy can boost SGN survival and enhance peripheral axon maintenance or rerouting. NT-3 has been found in adult animals exposed to acoustic damage to induce synaptic regeneration of these fibers, reconnecting them to hair cells and their ribbon synapses, and restoring hearing function. Combining BDNF and NT-3 gene therapy may be the most effective way to maintain/restore a more normal cochlear neuronal substrate.

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