JCI Insight. 2021 Mar 8;6(5):141561. doi: 10.1172/jci.insight.141561.
Hair cell loss is the leading cause of hearing and balance disorders in humans. It can be caused by many factors, including noise, aging, and therapeutic agents. Previous studies have shown the therapeutic potential of quinoxaline against drug-induced ototoxicity. Here, we screened a library of 68 quinoxaline derivatives for protection against aminoglycoside-induced damage of hair cells from the zebrafish lateral line. We identified quinoxaline-5-carboxylic acid (Qx28) as the best quinoxaline derivative that provides robust protection against both aminoglycosides and cisplatin in zebrafish and mouse cochlear explants. FM1-43 and aminoglycoside uptake, as well as antibiotic efficacy studies, revealed that Qx28 is neither blocking the mechanotransduction channels nor interfering with aminoglycoside antibacterial activity, suggesting that it may be protecting the hair cells by directly counteracting the ototoxin's mechanism of action. Only when animals were incubated with higher doses of Qx28 did we observe a partial blockage of the mechanotransduction channels. Finally, we assessed the regulation of the NF-κB pathway in vitro in mouse embryonic fibroblasts and in vivo in zebrafish larvae. Those studies showed that Qx28 protects hair cells by blocking NF-κB canonical pathway activation. Thus, Qx28 is a promising and versatile otoprotectant that can act across different species and toxins.
毛细胞损失是人类听力和平衡障碍的主要原因。它可能由多种因素引起，包括噪声、衰老和治疗药物。先前的研究表明，喹喔啉类化合物对药物诱导的耳毒性具有治疗潜力。在这里，我们筛选了一个包含 68 个喹喔啉衍生物的文库，以寻找对抗氨基糖苷类药物诱导的斑马鱼侧线毛细胞损伤的保护作用。我们确定喹喔啉-5-羧酸（Qx28）是最好的喹喔啉衍生物，可在斑马鱼和小鼠耳蜗外植体中提供对氨基糖苷类药物和顺铂的强大保护作用。FM1-43 和氨基糖苷类摄取以及抗生素功效研究表明，Qx28 既不阻断机械转导通道，也不干扰氨基糖苷类的抗菌活性，这表明它可能通过直接对抗耳毒素的作用机制来保护毛细胞。只有当动物在较高剂量的 Qx28 孵育时，我们才观察到机械转导通道的部分阻断。最后，我们在体外的小鼠胚胎成纤维细胞和体内的斑马鱼幼虫中评估了 NF-κB 通路的调节。这些研究表明，Qx28 通过阻断 NF-κB 经典途径的激活来保护毛细胞。因此，Qx28 是一种有前途的、多功能的耳保护剂，可在不同物种和毒素中发挥作用。
