scholarly journals miR-153/KCNQ4 axis contributes to noise-induced hearing loss in a mouse model

2021 ◽  
Vol 71 (1) ◽  
Author(s):  
Qin Wang ◽  
Wei Li ◽  
Cuiyun Cai ◽  
Peng Hu ◽  
Ruosha Lai
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Noise Exposure ◽  
Auditory Brainstem ◽  
Sensory Epithelium ◽  
Outer Hair Cells ◽  
Broadband Noise ◽  
Hek293 Cells ◽  
Auditory Brainstem Responses ◽  
Luciferase Reporter

AbstractDamage to the cochlear sensory epithelium is a key contributor to noise-induced sensorineural hearing loss (SNHL). KCNQ4 plays an important role in the cochlear potassium circulation and outer hair cells survival. As miR-153 can target and regulate KCNQ4, we sought to study the role of miR-153 in SNHL. 12-week-old male CBA/J mice were exposed to 2–20 kHz broadband noise at 96 dB SPL to induce temporary threshold shifts and 101 dB SPL to induce permanent threshold shifts. Hearing loss was determined by auditory brainstem responses (ABR). Relative expression of miR-153 and KCNQ4 in mice cochlea were determined by Real-Time quantitative PCR. miR-153 mimics were co-transfected with wild type or mutated KCNQ4 into HEK293 cells. Luciferase reporter assay was used to validate the binding between miR-153 and KCNQ4. AAV-sp-153 was constructed and administrated intra-peritoneally 24- and 2-h prior and immediately after noise exposure to knockdown miR-153. The KCNQ4 is mainly expressed in outer hair cells (OHCs). We showed that the expression of KCNQ4 in mice cochlea was reduced and miR-153 expression was significantly increased after noise exposure compared to control. miR-153 bound to 3′UTR of KNCQ4, and the knockdown of miR-153 with the AAV-sp-153 administration restored KCNQ4 mRNA and protein expression. In addition, the knockdown of miR-153 reduced ABR threshold shifts at 8, 16, and 32 kHz after permanent threshold shifts (PTS) noise exposure. Correspondingly, OHC losses were attenuated with inhibition of miR-153. This study demonstrates that miR-153 inhibition significantly restores KNCQ4 in cochlea after noise exposure, which attenuates SNHL. Our study provides a new potential therapeutic target in the prevention and treatment of SNHL.

scholarly journals Inhalation of Molecular Hydrogen, a Rescue Treatment for Noise-Induced Hearing Loss

2021 ◽  
Vol 15 ◽  
Author(s):  
Anette Elisabeth Fransson ◽  
Pernilla Videhult Pierre ◽  
Mårten Risling ◽  
Göran Frans Emanuel Laurell
Keyword(s):  
Hearing Loss ◽  
Molecular Hydrogen ◽  
Noise Exposure ◽  
Real Life ◽  
Outer Hair Cells ◽  
Broadband Noise ◽  
Hydrogen Gas ◽  
Rescue Treatment ◽  
Brainstem Response ◽  
Antioxidant Effects

Noise exposure is the most important external factor causing acquired hearing loss in humans, and it is strongly associated with the production of reactive oxygen species (ROS) in the cochlea. Several studies reported that the administration of various compounds with antioxidant effects can treat oxidative stress-induced hearing loss. However, traditional systemic drug administration to the human inner ear is problematic and has not been successful in a clinical setting. Thus, there is an urgent need to develop rescue treatment for patients with acute acoustic injuries. Hydrogen gas has antioxidant effects, rapid distribution, and distributes systemically after inhalation.The purpose of this study was to determine the protective efficacy of a single dose of molecular hydrogen (H2) on cochlear structures. Guinea pigs were divided into six groups and sacrificed immediately after or at 1 or 2 weeks. The animals were exposed to broadband noise for 2 h directly followed by 1-h inhalation of 2% H2 or room air. Electrophysiological hearing thresholds using frequency-specific auditory brainstem response (ABR) were measured prior to noise exposure and before sacrifice. ABR thresholds were significantly lower in H2-treated animals at 2 weeks after exposure, with significant preservation of outer hair cells in the entire cochlea. Quantification of synaptophysin immunoreactivity revealed that H2 inhalation protected the cochlear inner hair cell synaptic structures containing synaptophysin. The inflammatory response was greater in the stria vascularis, showing increased Iba1 due to H2 inhalation.Repeated administration of H2 inhalation may further improve the therapeutic effect. This animal model does not reproduce conditions in humans, highlighting the need for additional real-life studies in humans.

scholarly journals Treatment With Calcineurin Inhibitor FK506 Attenuates Noise-Induced Hearing Loss

2021 ◽  
Vol 9 ◽  
Author(s):  
Zu-Hong He ◽  
Song Pan ◽  
Hong-Wei Zheng ◽  
Qiao-Jun Fang ◽  
Kayla Hill ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Calcineurin Inhibitor ◽  
Noise Exposure ◽  
Cell Loss ◽  
Outer Hair Cells ◽  
Oxygen Species ◽  
Noise Induced Hearing Loss ◽  
Activated T Cells ◽  
Interfering Rna

Attenuation of noise-induced hair cell loss and noise-induced hearing loss (NIHL) by treatment with FK506 (tacrolimus), a calcineurin (CaN/PP2B) inhibitor used clinically as an immunosuppressant, has been previously reported, but the downstream mechanisms of FK506-attenuated NIHL remain unknown. Here we showed that CaN immunolabeling in outer hair cells (OHCs) and nuclear factor of activated T-cells isoform c4 (NFATc4/NFAT3) in OHC nuclei are significantly increased after moderate noise exposure in adult CBA/J mice. Consequently, treatment with FK506 significantly reduces moderate-noise-induced loss of OHCs and NIHL. Furthermore, induction of reactive oxygen species (ROS) by moderate noise was significantly diminished by treatment with FK506. In agreement with our previous finding that autophagy marker microtubule-associated protein light chain 3B (LC3B) does not change in OHCs under conditions of moderate-noise-induced permanent threshold shifts, treatment with FK506 increases LC3B immunolabeling in OHCs after exposure to moderate noise. Additionally, prevention of NIHL by treatment with FK506 was partially abolished by pretreatment with LC3B small interfering RNA. Taken together, these results indicate that attenuation of moderate-noise-induced OHC loss and hearing loss by FK506 treatment occurs not only via inhibition of CaN activity but also through inhibition of ROS and activation of autophagy.

scholarly journals Neuroprotective Effect of Near-Infrared Light in an Animal Model of CI Surgery

2020 ◽  
pp. 1-7
Author(s):  
Ira Strübing ◽  
Moritz Gröschel ◽  
Susanne Schwitzer ◽  
Arne Ernst ◽  
Felix Fröhlich ◽  
...  
Keyword(s):  
Animal Model ◽  
Hearing Loss ◽  
Hair Cells ◽  
Cochlear Implantation ◽  
Near Infrared ◽  
Outer Hair Cells ◽  
Auditory Brainstem Responses ◽  
Infrared Light ◽  
Residual Hearing ◽  
Significant Difference

<b><i>Introduction:</i></b> The preservation of residual hearing has become an important consideration in cochlear implant (CI) recipients in recent years. It was the aim of the present animal experimental study to investigate the influence of a pretreatment with near-infrared (NIR) light on preservation of sensory hair cells and residual hearing after cochlear implantation. <b><i>Methods:</i></b> NIR was applied unilaterally (15 min, 808 nm, 120 mW) to 8 guinea pigs, immediately before a bilateral scala tympani CI electrode insertion was performed. The nonirradiated (contralateral) side served as control. Twenty-eight days postoperatively, auditory brainstem responses (ABRs) were registered from both ears to screen for hearing loss. Thereafter, the animals were sacrificed and inner hair cells (IHCs) and outer hair cells (OHCs) were counted and compared between NIR-pretreated and control (contralateral) cochleae. <b><i>Results:</i></b> There was no IHC loss upon cochlear implantation. OHC loss was most prominent on both sides at the apical part of the cochlea. NIR pretreatment led to a statistically significant reduction in OHC loss (by 39.8%). ABR recordings (across the frequencies 4–32 kHz) showed a statistically significant difference between the 2 groups and corresponds well with the apical structural damage. Hearing loss was reduced by about 20 dB on average for the NIR-pretreated group (<i>p</i> ≤ 0.05). <b><i>Discussion/Conclusion:</i></b> A single NIR pretreatment in this animal model of CI surgery appears to be neuroprotective for residual hearing. This is in line with other studies where several NIR posttreatments have protected cochlear and other neural tissues. NIR pretreatment is an inexpensive, effective, and noninvasive approach that can complement other ways of preserving residual hearing and, hence, should deserve further clinical evaluation in CI patients.

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

2021 ◽  
Author(s):  
Zhiwei Zheng ◽  
Shan Zeng ◽  
Chang Liu ◽  
Wen Li ◽  
Liping Zhao ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Hearing Loss ◽  
Dna Methyltransferase ◽  
Noise Exposure ◽  
Auditory Brainstem ◽  
Auditory Brainstem Responses ◽  
Dna Methyltransferase 1 ◽  
Noise Induced Hearing Loss ◽  
Threshold Elevation ◽  
Whole Mount

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

scholarly journals Impulse Noise Induced Hidden Hearing Loss, Hair Cell Ciliary Changes and Oxidative Stress in Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1880
Author(s):  
Paul Gratias ◽  
Jamal Nasr ◽  
Corentin Affortit ◽  
Jean-Charles Ceccato ◽  
Florence François ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hearing Loss ◽  
Hair Cells ◽  
Impulse Noise ◽  
Noise Exposure ◽  
Morphological Changes ◽  
Nerve Fibers ◽  
Outer Hair Cells ◽  
Hidden Hearing Loss ◽  
The Impact

Recent studies demonstrated that reversible continuous noise exposure may induce a temporary threshold shift (TTS) with a permanent degeneration of auditory nerve fibers, although hair cells remain intact. To probe the impact of TTS-inducing impulse noise exposure on hearing, CBA/J Mice were exposed to noise impulses with peak pressures of 145 dB SPL. We found that 30 min after exposure, the noise caused a mean elevation of ABR thresholds of ~30 dB and a reduction in DPOAE amplitude. Four weeks later, ABR thresholds and DPOAE amplitude were back to normal in the higher frequency region (8–32 kHz). At lower frequencies, a small degree of PTS remained. Morphological evaluations revealed a disturbance of the stereociliary bundle of outer hair cells, mainly located in the apical regions. On the other hand, the reduced suprathreshold ABR amplitudes remained until 4 weeks later. A loss of synapse numbers was observed 24 h after exposure, with full recovery two weeks later. Transmission electron microscopy revealed morphological changes at the ribbon synapses by two weeks post exposure. In addition, increased levels of oxidative stress were observed immediately after exposure, and maintained for a further 2 weeks. These results clarify the pathology underlying impulse noise-induced sensory dysfunction, and suggest possible links between impulse-noise injury, cochlear cell morphology, metabolic changes, and hidden hearing loss.

scholarly journals Research Progress on Flat Epithelium of the Inner Ear

2020 ◽  
pp. 775-785
Author(s):  
L HE ◽  
J-Y GUO ◽  
K LIU ◽  
G-P WANG ◽  
S-S GONG
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Inner Ear ◽  
Hair Cells ◽  
Noise Exposure ◽  
Sensory Epithelium ◽  
Sensorineural Hearing ◽  
Research Progress ◽  
Supporting Cells ◽  
Mesenchymal Transition

Sensorineural hearing loss and vertigo, resulting from lesions in the sensory epithelium of the inner ear, have a high incidence worldwide. The sensory epithelium of the inner ear may exhibit extreme degeneration and is transformed to flat epithelium (FE) in humans and mice with profound sensorineural hearing loss and/or vertigo. Various factors, including ototoxic drugs, noise exposure, aging, and genetic defects, can induce FE. Both hair cells and supporting cells are severely damaged in FE, and the normal cytoarchitecture of the sensory epithelium is replaced by a monolayer of very thin, flat cells of irregular contour. The pathophysiologic mechanism of FE is unclear but involves robust cell division. The cellular origin of flat cells in FE is heterogeneous; they may be transformed from supporting cells that have lost some features of supporting cells (dedifferentiation) or may have migrated from the flanking region. The epithelial-mesenchymal transition may play an important role in this process. The treatment of FE is challenging given the severe degeneration and loss of both hair cells and supporting cells. Cochlear implant or vestibular prosthesis implantation, gene therapy, and stem cell therapy show promise for the treatment of FE, although many challenges remain to be overcome.

scholarly journals Preventing presbycusis in mice with enhanced medial olivocochlear feedback

2020 ◽  
Vol 117 (21) ◽  
pp. 11811-11819 ◽  
Author(s):  
Luis E. Boero ◽  
Valeria C. Castagna ◽  
Gonzalo Terreros ◽  
Marcelo J. Moglie ◽  
Sebastián Silva ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Outer Hair Cells ◽  
Auditory Brainstem Responses ◽  
Cochlear Function ◽  
Gain Of Function ◽  
Distortion Product ◽  
Age Related ◽  
Medial Olivocochlear ◽  
Age Related Hearing Loss

“Growing old” is the most common cause of hearing loss. Age-related hearing loss (ARHL) (presbycusis) first affects the ability to understand speech in background noise, even when auditory thresholds in quiet are normal. It has been suggested that cochlear denervation (“synaptopathy”) is an early contributor to age-related auditory decline. In the present work, we characterized age-related cochlear synaptic degeneration and hair cell loss in mice with enhanced α9α10 cholinergic nicotinic receptors gating kinetics (“gain of function” nAChRs). These mediate inhibitory olivocochlear feedback through the activation of associated calcium-gated potassium channels. Cochlear function was assessed via distortion product otoacoustic emissions and auditory brainstem responses. Cochlear structure was characterized in immunolabeled organ of Corti whole mounts using confocal microscopy to quantify hair cells, auditory neurons, presynaptic ribbons, and postsynaptic glutamate receptors. Aged wild-type mice had elevated acoustic thresholds and synaptic loss. Afferent synapses were lost from inner hair cells throughout the aged cochlea, together with some loss of outer hair cells. In contrast, cochlear structure and function were preserved in aged mice with gain-of-function nAChRs that provide enhanced olivocochlear inhibition, suggesting that efferent feedback is important for long-term maintenance of inner ear function. Our work provides evidence that olivocochlear-mediated resistance to presbycusis-ARHL occurs via the α9α10 nAChR complexes on outer hair cells. Thus, enhancement of the medial olivocochlear system could be a viable strategy to prevent age-related hearing loss.

R448 – Phex Mutation Causes Sensorineural Deafness in Mice

2008 ◽  
Vol 139 (2_suppl) ◽  
pp. P194-P195
Author(s):  
Gao Xia
Keyword(s):  
Electron Microscopy ◽  
Scanning Electron Microscopy ◽  
Hair Cells ◽  
Sensorineural Deafness ◽  
Organ Of Corti ◽  
Auditory Brainstem ◽  
Outer Hair Cells ◽  
Auditory Brainstem Responses ◽  
Phex Gene ◽  
Scanning Electron

Problem Pug is an ENU mutated mouse model for X-linked dominant hypophosphatemic rickets (XLH) in human. Mapping and sequence analysis revealed that Pug mutation is a unique Phe-to-Ser transition at amino acid 80 of PHEX protein leading to the loss of Phex function. Patients with XLH and Pug mutant mice exhibit abnormal phenotypes including growth retardation, hypophosphatemia and osteomalacia. In addition, hearing impairment was also found in some hypophosphatemic mouse models and patients. Here, we used the Pug mutant mice to study the role of Phex gene in the pathology of hearing impairment. Methods Auditory brainstem responses(ABR) to click and 8,16,32kHz stimuli were employed to measure pug mice of 1–8 months old. Serial sections were used to detect the abnormalities involving the temporal bone, stria vascularis, the organ of Corti, spiral ganglion cells, and scanning electron microscopy was performed to exam the basilar membrane of pug mice. Results Auditory brainstem responses test showed that Pug mice have elevated hearing thresholds. Histology analysis demonstrated a thickened temporal bone with many interspersed areas of nonmineralization surrounding the mutant cochlea and decreased numbers of neuronal processes in the organ of Corti, mostly in basal turns. Furthermore, abnormal stereocilia of inner and outer hair cells of the Corti organ were identified by scanning electron microscopy. Inner and outer hair cells were also greatly reduced in Pug mice. Conclusion The impaired hearing function and the morphological abnormalities of inner ears are induced by the mutation of Phex gene. Significance Pug mice have structural and functional defects in the inner ear and may serve as a new disease model of sensorineural deafness. Support This work was supported by the ground of JiangSu Province Femouse Doctor Project(RC2007010).

scholarly journals Effect of Electroacupuncture on Noise-Induced Hearing Loss in Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Chia-Hao Chang ◽  
Chia-Der Lin ◽  
Ching-Liang Hsieh
Keyword(s):  
Hearing Loss ◽  
Noise Exposure ◽  
Histopathological Examination ◽  
Spiral Ganglion ◽  
Auditory Brainstem ◽  
Auditory Threshold ◽  
Auditory Brainstem Responses ◽  
Control Group ◽  
Noise Induced Hearing Loss ◽  
Ganglion Neurons

Acupuncture has long been used to relieve some inner ear diseases such as deafness and tinnitus. The present study examined the effect of electroacupuncture (EA) on noise-induced hearing loss (NIHL) in animals. A NIHL rat model was established. Electroacupuncture pretreatment at 2 Hz or posttreatment at the right Zhongzhu (TE3) acupoint was applied for 1 hour. Auditory thresholds were measured using auditory brainstem responses (ABRs), and histopathology of the cochlea was examined. The results indicated that the baseline auditory threshold of ABR was not significantly different between the control (no noise), EA-only (only EA without noise), noise (noise exposure only), pre-EA (pretreating EA then noise), and post-EA (noise exposure then posttreating with EA) groups. Significant auditory threshold shifts were found in the noise, pre-EA, and post-EA groups in the immediate period after noise exposure, whereas auditory recovery was better in the pre-EA and post-EA groups than that in the noise group at the three days, one week (W1), two weeks (W2), three weeks (W3), and four weeks(W4) after noise stimulation. Histopathological examination revealed greater loss of the density of spiral ganglion neurons in the noise group than in the control group at W1 and W2. Although significant loss of spiral ganglion loss happened in pre-EA and post-EA groups, such loss was less than the loss of the noise group, especially W1. These results indicate that either pretreatment or posttreatment with EA may facilitate auditory recovery after NIHL. The detailed mechanism through which EA alleviates NIHL requires further study.

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