Otoprotective effects of ethosuximide in NOD/LtJ mice with age-related hearing loss

Sang,Lu; Zheng,Tihua; Min,Lingqian; Zhang,Xiaolin; Ma,Xiufang; Entenman,Shami; Su,Yipeng; Zheng,Qingyin

doi:10.3892/ijmm.2017.3004

Otoprotective effects of ethosuximide in NOD/LtJ mice with age-related hearing loss

Authors:
- Lu Sang
- Tihua Zheng
- Lingqian Min
- Xiaolin Zhang
- Xiufang Ma
- Shami Entenman
- Yipeng Su
- Qingyin Zheng
View Affiliations

Affiliations: Transformative Otology and Neuroscience Center, Binzhou Medical University, Yantai, Shandong 264000, P.R. China, Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH 44106-4952, USA
Published online on: May 26, 2017 https://doi.org/10.3892/ijmm.2017.3004
Pages: 146-154
Copyright: © Sang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Despite long-term efforts to elucidate the mechanisms responsible for age-related hearing loss (AHL), there is currently no available treatment strategy able to provide a cure. Apoptotic cell death, including that of hair cells and spiral ganglion neurons (SGNs) in the cochlea has been proposed to be the classic theory behind the development of AHL. As calcium signaling plays key roles in signal transduction in apoptosis, in this study, we selected ethosuximide, which is able to block T-type calcium (Ca2+ion) channels, suppressing Ca2+. We hypothesized that the apoptotic pathway may be blocked through the inhibition of T-type Ca2+ channels in cochlear cells in NOD/LtJ mice. NOD/LtJ mice were divided into 2 groups as follows: the ethosuximide-treated and untreated (control) groups. Ethosuximide was administered by intraperitoneal injection every other day from post-natal day seven (P7) until the mice were 8 weeks of age. Following treatment, auditory-evoked brainstem response (ABR) thresholds and distortion product oto-acoustic emission (DPOAE) of the mice in the 2 groups were measured at different time points. Morphometric analysis and the expression of genes involved in the T-type Ca2+-mediated apoptotic pathway were monitored. The ABR and DPOAE results revealed that the NOD/LtJ mice exhibited early-onset and rapidly progressive AHL. A histological examination revealed that hair cell degeneration coincided with the progression of hearing loss. Hair cell and SGN was were significantly lower and auditory function was significantly improved in the ethosuximide-treated group compared to the untreated group. Our data thus indicate that ethosuximide prevents the degeneration of cochlear cells by regulating the expression of genes in apoptotic pathways. Our findings suggest that activating the T-type Ca2+ channel and downstream genes may be key pathological mechanisms responsible for AHL in NOD/LtJ mice.

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