Dataset Information

ER stress inhibitor attenuates hearing loss and hair cell death in Cdh23erl/erl mutant mice.

ABSTRACT: Hearing loss is one of the most common sensory impairments in humans. Mouse mutant models helped us to better understand the mechanisms of hearing loss. Recently, we have discovered that the erlong (erl) mutation of the cadherin23 (Cdh23) gene leads to hearing loss due to hair cell apoptosis. In this study, we aimed to reveal the molecular pathways upstream to apoptosis in hair cells to exploit more effective therapeutics than an anti-apoptosis strategy. Our results suggest that endoplasmic reticulum (ER) stress is the earliest molecular event leading to the apoptosis of hair cells and hearing loss in erl mice. We also report that the ER stress inhibitor, Salubrinal (Sal), could delay the progression of hearing loss and preserve hair cells. Our results provide evidence that therapies targeting signaling pathways in ER stress development prevent hair cell apoptosis at an early stage and lead to better outcomes than those targeting downstream factors, such as tip-link degeneration and apoptosis.

SUBMITTER: Hu J

PROVIDER: S-EPMC5260868 | biostudies-other | 2016 Nov

REPOSITORIES: biostudies-other

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Publications

ER stress inhibitor attenuates hearing loss and hair cell death in Cdh23<sup>erl/erl</sup> mutant mice.

Hu Juan J Li Bo B Apisa Luke L Yu Heping H Entenman Shami S Xu Min M Stepanyan Ruben R Guan Bo-Jhih BJ Müller Ulrich U Hatzoglou Maria M Zheng Qing Yin QY

Cell death & disease 20161124 11

Hearing loss is one of the most common sensory impairments in humans. Mouse mutant models helped us to better understand the mechanisms of hearing loss. Recently, we have discovered that the erlong (erl) mutation of the cadherin23 (Cdh23) gene leads to hearing loss due to hair cell apoptosis. In this study, we aimed to reveal the molecular pathways upstream to apoptosis in hair cells to exploit more effective therapeutics than an anti-apoptosis strategy. Our results suggest that endoplasmic reti ...[more]

PMID: 27882946

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Project description:Noise induced hearing loss (NIHL) is accompanied by a reduction of cochlear hair cells and spiral ganglion neurons. Different approaches have been applied to prevent noise induced apoptosis / necrosis. Physical intervention is one technique currently under investigation. Specific wavelengths within the near-infrared light (NIR)-spectrum are known to influence cytochrome-c-oxidase activity, which leads in turn to a decrease in apoptotic mechanisms. It has been shown recently that NIR can significantly decrease the cochlear hair cell loss if applied daily for 12 days after a noise exposure. However, it is still unclear if a single NIR-treatment, just before a noise exposure, could induce similar protective effects. Therefore, the present study was conducted to investigate the effect of a single NIR-pre-treatment aimed at preventing or limiting NIHL. The cochleae of adult NMRI-mice were pre-treated with NIR-light (808 nm, 120 mW) for 5, 10, 20, 30 or 40 minutes via the external ear canal. All animals were noised exposed immediately after the pre-treatment by broad band noise (5-20 kHz) for 30 minutes at 115 dB SPL. Frequency specific ABR-recordings to determine auditory threshold shift were carried out before the pre-treatment and two weeks after the noise exposure. The amplitude increase for wave IV and cochlear hair cell loss were determined. A further group of similar mice was noise exposed only and served as a control for the NIR pre-exposed groups. Two weeks after noise exposure, the ABR threshold shifts of NIR-treated animals were significantly lower (p < 0.05) than those of the control animals. The significance was at three frequencies for the 5-minute pre-treatment group and across the entire frequency range for all other treatment groups. Due to NIR light, the amplitude of wave four deteriorates significantly less after noise exposure than in controls. The NIR pre-treatment had no effect on the loss of outer hair cells, which was just as high with or without NIR-light pre-exposure. Relative to the entire number of outer hair cells across the whole cochlea, outer hair cell loss was rather negligible. No inner hair cell loss whatever was detected. Our results suggest that a single NIR pre-treatment induces a very effective protection of cochlear structures from noise exposure. Pre-exposure of 10 min seems to emerge as the optimal dosage for our experimental setup. A saturated effect occurred with higher dosage-treatments. These results are relevant for protection of residual hearing in otoneurosurgery such as cochlear implantation.

Dataset Information

ER stress inhibitor attenuates hearing loss and hair cell death in Cdh23erl/erl mutant mice.

Publications

ER stress inhibitor attenuates hearing loss and hair cell death in Cdh23<sup>erl/erl</sup> mutant mice.

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