Otoprotective effects of ethosuximide in NOD/LtJ mice with age-related hearing loss.
Otoprotective effects of ethosuximide in NOD/LtJ mice with age-related hearing loss.
复制标题
乙舒酰亚胺对年龄相关性听力损失 NOD/LtJ 小鼠的耳保护作用
DOI：
10.3892/ijmm.2017.3004
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发表时间：
2017-07
影响因子：
5.4
通讯作者：
Zheng Q
中科院分区：
文献类型：
--
作者：
Sang L;Zheng T;Min L;Zhang X;Ma X;Entenman S;Su Y;Zheng Q
尽管长期努力阐明年龄相关性听力损失（阿勒）的机制，但目前还没有可用的治疗策略能够提供治愈。耳蜗毛细胞和螺旋神经节神经元（SGN）的凋亡是阿勒发生的经典理论。由于钙信号在细胞凋亡的信号转导中起着关键作用，在本研究中，我们选择了乙琥胺，它能够阻断T型钙（Ca 2+离子）通道，抑制Ca 2+。我们推测NOD/LtJ小鼠耳蜗细胞凋亡途径可能通过抑制T型钙通道而被阻断。将NOD/LtJ小鼠分成如下2组：乙琥胺治疗组和未治疗（对照）组。从出生后第7天（P7）开始，每隔一天通过腹膜内注射给予乙琥胺，直至小鼠8周龄。治疗后不同时间点分别测定2组小鼠的脑干诱发电位（ABR）阈值和畸变产物耳声发射（DPOAE）。形态分析和参与T型钙离子介导的凋亡途径的基因的表达进行了监测。ABR和DPOAE结果显示NOD/LtJ小鼠表现出早发性和快速进展的阿勒。组织学检查显示，毛细胞变性与听力损失的进展一致。与未治疗组相比，乙琥胺治疗组的毛细胞和SGN显著降低，听功能显著改善。因此，我们的数据表明，乙琥胺通过调节凋亡途径中的基因表达来防止耳蜗细胞的变性。我们的研究结果表明，激活T-型钙通道和下游基因可能是负责NOD/LtJ小鼠阿勒的关键病理机制。
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.