Virginia Merrill Bloedel Hearing Research Center, University of Washington, Box 357923, Seattle, WA 98195-7923, USA.
Hear Res. 2012 Dec;294(1-2):153-65. doi: 10.1016/j.heares.2012.08.002. Epub 2012 Aug 31.
Loss of mechanosensory hair cells in the inner ear accounts for many hearing loss and balance disorders. Several beneficial pharmaceutical drugs cause hair cell death as a side effect. These include aminoglycoside antibiotics, such as neomycin, kanamycin and gentamicin, and several cancer chemotherapy drugs, such as cisplatin. Discovering new compounds that protect mammalian hair cells from toxic insults is experimentally difficult because of the inaccessibility of the inner ear. We used the zebrafish lateral line sensory system as an in vivo screening platform to survey a library of FDA-approved pharmaceuticals for compounds that protect hair cells from neomycin, gentamicin, kanamycin and cisplatin. Ten compounds were identified that provide protection from at least two of the four toxins. The resulting compounds fall into several drug classes, including serotonin and dopamine-modulating drugs, adrenergic receptor ligands, and estrogen receptor modulators. The protective compounds show different effects against the different toxins, supporting the idea that each toxin causes hair cell death by distinct, but partially overlapping, mechanisms. Furthermore, some compounds from the same drug classes had different protective properties, suggesting that they might not prevent hair cell death by their known target mechanisms. Some protective compounds blocked gentamicin uptake into hair cells, suggesting that they may block mechanotransduction or other routes of entry. The protective compounds identified in our screen will provide a starting point for studies in mammals as well as further research discovering the cellular signaling pathways that trigger hair cell death.
内耳机械感觉毛细胞的丧失是许多听力损失和平衡障碍的原因。几种有益的药物会产生毛细胞死亡的副作用。这些药物包括氨基糖苷类抗生素，如新霉素、卡那霉素和庆大霉素，以及几种癌症化疗药物，如顺铂。由于内耳难以接近，因此发现能够保护哺乳动物毛细胞免受毒性侵害的新化合物在实验上具有挑战性。我们使用斑马鱼侧线感觉系统作为体内筛选平台，对 FDA 批准的药物库进行筛选，以寻找能够保护毛细胞免受新霉素、庆大霉素、卡那霉素和顺铂损伤的化合物。鉴定出 10 种化合物，它们至少能保护两种毒素。结果化合物属于几种药物类别，包括 5-羟色胺和多巴胺调节剂、肾上腺素能受体配体和雌激素受体调节剂。这些保护性化合物对不同的毒素表现出不同的作用，这支持了这样一种观点，即每种毒素通过不同但部分重叠的机制导致毛细胞死亡。此外，来自同一药物类别的一些化合物具有不同的保护特性，这表明它们可能不会通过其已知的靶机制来预防毛细胞死亡。一些保护性化合物阻止庆大霉素进入毛细胞，这表明它们可能阻止机械转导或其他进入途径。我们在筛选中发现的保护性化合物将为在哺乳动物中的研究以及进一步发现触发毛细胞死亡的细胞信号通路的研究提供起点。
