Attenuation of hearing loss in DBA/2J mice by anti-apoptotic treatment
Attenuation of hearing loss in DBA/2J mice by anti-apoptotic treatment
复制标题
抗凋亡治疗减轻 DBA/2J 小鼠听力损失
DOI：
10.1016/j.heares.2015.05.006
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发表时间：
2015-09-01
期刊：
影响因子：
2.8
通讯作者：
Han, Fengchan
中科院分区：
文献类型：
--
作者：
Yang, Linlin;Zhang, Heng;Han, Fengchan
DBA/2 J小鼠的特征在于在约3-4周龄时的早发性听力损失。钙粘蛋白23（Cdh 23）和肌成束蛋白2（Fscn 2）的突变是导致表型的原因，但潜在的机制尚不清楚。在本研究中，DBA/2 J小鼠表现出进行性毛细胞损失和螺旋神经节神经元（SGNs）变性后，2周龄的内耳Caspase-3的mRNA水平远高于4或8周龄。此外，Caspase-3和Caspase-9在DBA/2 J小鼠内耳中的转录水平显著高于2或8周龄的C57 BL/6 J小鼠。免疫组化显示Caspase-3和Caspase-9主要分布于耳蜗毛细胞、SGN和血管纹。为了确定半胱天冬酶依赖性细胞凋亡在听力损失中的意义，从一周龄开始，将泛半胱天冬酶抑制剂Z-VAD-FMK腹膜内给予DBA/J2小鼠8周。阻断半胱天冬酶可使小鼠的听力保持在ABR阈值的10 dB（dB）以上声压级（SPL），并显著减少耳蜗基底匝处的外毛细胞损失。这些结果表明DBA/J2小鼠耳蜗中的细胞凋亡有助于听力损失的早期发作，其可以通过抗凋亡治疗来减弱。(C)2015 Elsevier B. V.版权所有。
DBA/2J mice are characterized by early onset hearing loss at about 3-4 weeks of age. Mutations in cadherin 23 (Cdh23) and fascin-2 (Fscn2) are responsible for the phenotypes, but the underlying mechanism is unknown. In the present study, DBA/2J mice displayed progressive hair cell loss and degeneration of spiral ganglion neurons (SGNs) after 2 weeks of age; however, the mRNA level of Caspase-3 in the inner ears was much higher at 2 weeks of age than that at 4 or 8 weeks of age. Moreover, transcriptional levels of Caspase-3 and Caspase-9 in the inner ears of DBA/2J mice were significantly higher than those of C57BL/6J mice at 2 or 8 weeks of age. Immunohistochemistry localized Caspase-3 and Caspase-9 mainly to the hair cells, SGNs and stria vascularis of the cochleae. To determine the significance of caspase-dependent apoptosis in the hearing loss, the pan-caspase inhibitor Z-VAD-FMK was given intraperitoneally to DBA/J2 mice over an 8-week period starting at one week of age. Blockage of caspases preserved hearing in the mice by more than 10 dB (dB) sound pressure level (SPL) of the ABR thresholds and significantly reduced outer hair cell loss at the basal turns of the cochleae. These results demonstrate that apoptosis in the cochleae of DBA/J2 mice contributes to the early onset of hearing loss, which can be attenuated by anti-apoptotic treatment. (C) 2015 Elsevier B.V. All rights reserved.