Natural Bizbenzoquinoline Derivatives Protect Zebrafish Lateral Line Sensory Hair Cells from Aminoglycoside Toxicity.
Natural Bizbenzoquinoline Derivatives Protect Zebrafish Lateral Line Sensory Hair Cells from Aminoglycoside Toxicity.
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DOI：
10.3389/fncel.2016.00083
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发表时间：
2016
影响因子：
5.3
通讯作者：
Coffin AB
中科院分区：
文献类型：
--
作者：
Kruger M;Boney R;Ordoobadi AJ;Sommers TF;Trapani JG;Coffin AB
中度至重度听力损失影响着全球3.6亿人，大多数情况下是由感觉毛细胞损伤引起的。毛细胞损伤可由衰老、基因突变、过度噪音暴露和某些药物（包括氨基糖苷类抗生素）引起。氨基糖苷类药物可有效治疗囊性纤维化相关感染和其他危及生命的疾病，如败血症，但会导致20-30%的患者听力损失。因此，必须开发新的治疗方法来对抗听力损失，并允许安全使用这些强效抗生素。我们使用幼斑马鱼侧线来解决这个药物发现问题，因为斑马鱼毛细胞在结构和功能上与哺乳动物内耳毛细胞相似，对毒素的反应也相似。我们筛选了502天然化合物的库，以确定新的毛细胞保护剂。我们的筛选确定了四个bisbenzylisoquinoline衍生物：小檗胺，E6小檗胺，hernandezine，和isotetrandrine，其中每一个都有力地保护毛细胞免受氨基糖苷类药物诱导的损伤。使用荧光显微镜和电生理学，我们证明了天然化合物通过减少抗生素摄取到毛细胞中来提供保护，并表明毛细胞在E6小檗胺中孵育期间和之后保持功能。我们还确定这些天然化合物不会降低抗生素的功效。总之，这些天然化合物代表了可能的耳保护药物的新来源，可以为接受氨基糖苷类药物治疗的患者提供治疗选择。
Moderate to severe hearing loss affects 360 million people worldwide and most often results from damage to sensory hair cells. Hair cell damage can result from aging, genetic mutations, excess noise exposure, and certain medications including aminoglycoside antibiotics. Aminoglycosides are effective at treating infections associated with cystic fibrosis and other life-threatening conditions such as sepsis, but cause hearing loss in 20–30% of patients. It is therefore imperative to develop new therapies to combat hearing loss and allow safe use of these potent antibiotics. We approach this drug discovery question using the larval zebrafish lateral line because zebrafish hair cells are structurally and functionally similar to mammalian inner ear hair cells and respond similarly to toxins. We screened a library of 502 natural compounds in order to identify novel hair cell protectants. Our screen identified four bisbenzylisoquinoline derivatives: berbamine, E6 berbamine, hernandezine, and isotetrandrine, each of which robustly protected hair cells from aminoglycoside-induced damage. Using fluorescence microscopy and electrophysiology, we demonstrated that the natural compounds confer protection by reducing antibiotic uptake into hair cells and showed that hair cells remain functional during and after incubation in E6 berbamine. We also determined that these natural compounds do not reduce antibiotic efficacy. Together, these natural compounds represent a novel source of possible otoprotective drugs that may offer therapeutic options for patients receiving aminoglycoside treatment.