PDF(Pubmed)
Abstract：
Although sudden sensorineural hearing loss (SSNHL) is a serious condition, there are currently no approved drugs for its treatment. Nevertheless, there is a growing understanding that the cochlear pathologies that underlie SSNHL include apoptotic death of sensory outer hair cells (OHCs) as well as loss of ribbon synapses connecting sensory inner hair cells (IHCs) and neurites of the auditory nerve, designated synaptopathy. Noise-induced hearing loss (NIHL) is a common subtype of SSNHL and is widely used to model hearing loss preclinically. Here, we demonstrate that a single interventive application of a small pyridoindole molecule (AC102) into the middle ear restored auditory function almost to prenoise levels in a guinea pig model of NIHL. AC102 prevented noise-triggered loss of OHCs and reduced IHC synaptopathy suggesting a role of AC102 in reconnecting auditory neurons to their sensory target cells. Notably, AC102 exerted its therapeutic properties over a wide frequency range. Such strong improvements in hearing have not previously been demonstrated for other therapeutic agents. In vitro experiments of a neuronal damage model revealed that AC102 protected cells from apoptosis and promoted neurite growth. These effects may be explained by increased production of adenosine triphosphate, indicating improved mitochondrial function, and reduced levels of reactive-oxygen species which prevents the apoptotic processes responsible for OHC death. This action profile of AC102 might be causal for the observed hearing recovery in in vivo models.
摘要：
尽管突发性感觉神经性听力损失（SSNHL）是一种严重的疾病，目前没有批准的治疗药物。然而，越来越多的人认识到，SSNHL背后的耳蜗病变包括感觉外毛细胞（OHCs）的凋亡死亡以及连接感觉内毛细胞（IHCs）和听神经神经突的带状突触的丧失，指定的突触病。噪声性听力损失（NIHL）是SSNHL的常见亚型，广泛用于临床前听力损失的建模。这里,我们证明，在豚鼠NIHL模型中，将小的吡啶并吲哚分子（AC102）单次介入式应用于中耳可恢复听觉功能，几乎达到噪声前水平。AC102可防止噪声触发的OHC损失并减少IHC突触病，这表明AC102在将听觉神经元重新连接到其感觉靶细胞中的作用。值得注意的是,AC102在宽频率范围内发挥其治疗特性。这种听力的强烈改善以前没有被证明用于其他治疗剂。神经元损伤模型的体外实验表明，AC102保护细胞免于凋亡并促进神经突生长。这些影响可以解释为三磷酸腺苷的产量增加，表明线粒体功能改善，和减少活性氧的水平，这防止了负责OHC死亡的凋亡过程。AC102的这种作用曲线可能是体内模型中观察到的听力恢复的原因。
