Calpain inhibitor alleviates permanent hearing loss induced by intense noise by preventing disruption of gap junction‐mediated intercellular communication in the cochlear spiral ligament
Calpain inhibitor alleviates permanent hearing loss induced by intense noise by preventing disruption of gap junction‐mediated intercellular communication in the cochlear spiral ligament
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DOI：
10.1016/j.ejphar.2017.03.058
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发表时间：
2017-05
影响因子：
5
通讯作者：
Taro Yamaguchi;M. Yoneyama;K. Ogita
中科院分区：
文献类型：
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作者：
Taro Yamaguchi;M. Yoneyama;K. Ogita
我们之前的研究表明，强噪声引起的听力损失可能至少部分是由于氧化应激导致小鼠耳蜗外侧壁螺旋韧带（SL）间隙连接蛋白连接蛋白水平下降。此外，小鼠在体内暴露于强噪声会激活耳蜗SL中的钙蛋白酶。基于这些研究，我们试图确定钙蛋白酶抑制剂是否会阻止强噪声暴露导致的听力损失、SL中间隙连接介导的细胞间通讯（GJIC）的中断。小鼠暴露于强噪声（8 hz倍频带噪声，110 db声压级，1小时）会导致永久性听力损失和耳蜗毛细胞死亡。对解剖侧壁结构进行光漂白后的间隙荧光恢复的体外实验结果显示，强噪声在暴露后第7天破坏了耳蜗SL中的GJIC。预先在耳蜗内注射钙蛋白酶抑制剂PD150606，在暴露后的第5天和第7天显著消除了这种噪音引起的听力损失。同样，PD150606在暴露后第7天阻止了噪声诱导的毛细胞死亡和GJIC破坏。强噪声在暴露后立即暂时增强了calpain亚型escapn1和capn2的基因表达。综上所述，我们的数据表明，钙蛋白酶抑制剂减轻了噪声性听力损失，至少在一定程度上是通过防止耳蜗SL中GJIC的破坏。钙蛋白酶抑制剂可能会成为突发性感音神经性听力损失的候选治疗药物。
Our previous studies demonstrated that intense noise-induced hearing loss might be at least in part due to an oxidative stress-induced decrease in the level of gap junction-composing protein connexins in the spiral ligament (SL) of the cochlear lateral wall structures in mice. Further, anin vivoexposure of mice to intense noise activates calpain in the cochlear SL. Based on these studies, we sought to determine whether a calpain inhibitor would prevent an intense noise exposure from causing hearing loss, disruption of gap junction-mediated intercellular communication (GJIC) in the SL. An exposure of mice to intense noise (8-Hz octave band noise, 110-dB sound pressure level, 1 h) produced permanent hearing loss and cochlear hair cell death. The results of anex vivoassay using gap-fluorescence recovery after photobleaching of dissected lateral wall structures revealed that the intense noise disrupted GJIC in the cochlear SL at day-7 post exposure. A prior intracochlear injection of the calpain inhibitor PD150606 significantly abolished this noise-induced hearing loss on days 5 and 7 post exposure. Similarly, PD150606 prevented noise-induced hair cell death and the GJIC disruption on day-7 post exposure. The intense noise temporarily enhanced the gene expression of calpain subtypesCapn1andCapn2immediately after exposure. Taken together, our data suggest that calpain inhibitor alleviated the noise-induced hearing loss, at least in part, by preventing disruption of GJIC in the cochlear SL. It possible that calpain inhibitors would be useful as a candidate of therapeutic drugs for sudden sensorineural hearing loss.