PDF(Pubmed)
Abstract：
BACKGROUND: Ototoxicity is a major side effect of many broadly used aminoglycoside antibiotics (AGs) and no FDA-approved otoprotective drug is available currently. The zebrafish has recently become a valuable model to investigate AG-induced hair cell toxicity and an expanding list of otoprotective compounds that block the uptake of AGs have been identified from zebrafish-based screening; however, it remains to be established whether inhibiting intracellular cell death pathway(s) constitutes an effective strategy to protect against AG-induced ototoxicity.
RESULTS: We used the zebrafish model as well as in vitro cell-based assays to investigate AG-induced cell death and found that ferroptosis is the dominant type of cell death induced by neomycin. Neomycin stimulates lipid reactive oxygen species (ROS) accumulation through mitochondrial pathway and blocking mitochondrial ferroptosis pathway effectively protects neomycin-induced cell death. We screened an alkaloid natural compound library and identified seven small compounds that protect neomycin-induced ototoxicity by targeting ferroptosis pathway: six of them are radical-trapping agents (RTAs) while the other one (ellipticine) regulates intracellular iron homeostasis, which is essential for the generation of lipid ROS to stimulate ferroptosis.
CONCLUSIONS: Our study demonstrates that blocking intracellular ferroptosis pathway is an alternative strategy to ameliorate neomycin-induced ototoxicity and provides multiple hit compounds for further otoprotective drug development.
RESULTS: We used the zebrafish model as well as in vitro cell-based assays to investigate AG-induced cell death and found that ferroptosis is the dominant type of cell death induced by neomycin. Neomycin stimulates lipid reactive oxygen species (ROS) accumulation through mitochondrial pathway and blocking mitochondrial ferroptosis pathway effectively protects neomycin-induced cell death. We screened an alkaloid natural compound library and identified seven small compounds that protect neomycin-induced ototoxicity by targeting ferroptosis pathway: six of them are radical-trapping agents (RTAs) while the other one (ellipticine) regulates intracellular iron homeostasis, which is essential for the generation of lipid ROS to stimulate ferroptosis.
CONCLUSIONS: Our study demonstrates that blocking intracellular ferroptosis pathway is an alternative strategy to ameliorate neomycin-induced ototoxicity and provides multiple hit compounds for further otoprotective drug development.
摘要：
背景：耳毒性是许多广泛使用的氨基糖苷类抗生素（AG）的主要副作用，目前尚无FDA批准的耳保护药物。斑马鱼最近已成为研究AG诱导的毛细胞毒性的有价值的模型，并且已经从斑马鱼的筛选中确定了越来越多的阻碍AG摄取的耳保护化合物;然而，抑制细胞内细胞死亡途径是否构成防止AG诱导的耳毒性的有效策略还有待确定。
结果：我们使用斑马鱼模型以及体外基于细胞的测定法来研究AG诱导的细胞死亡，发现铁死亡是新霉素诱导的细胞死亡的主要类型。新霉素通过线粒体途径刺激脂质活性氧（ROS）积累，阻断线粒体铁凋亡途径有效保护新霉素诱导的细胞死亡。我们筛选了一个生物碱天然化合物库，并鉴定了7种通过靶向铁凋亡途径保护新霉素诱导的耳毒性的小化合物：其中6种是自由基捕获剂（RTAs），而另一种（椭圆碱）调节细胞内铁稳态，这对于脂质ROS的产生以刺激铁凋亡是必不可少的。
结论：我们的研究表明，阻断细胞内铁凋亡途径是改善新霉素诱导的耳毒性的替代策略，并为进一步的耳保护药物开发提供了多种化合物。
结果：我们使用斑马鱼模型以及体外基于细胞的测定法来研究AG诱导的细胞死亡，发现铁死亡是新霉素诱导的细胞死亡的主要类型。新霉素通过线粒体途径刺激脂质活性氧（ROS）积累，阻断线粒体铁凋亡途径有效保护新霉素诱导的细胞死亡。我们筛选了一个生物碱天然化合物库，并鉴定了7种通过靶向铁凋亡途径保护新霉素诱导的耳毒性的小化合物：其中6种是自由基捕获剂（RTAs），而另一种（椭圆碱）调节细胞内铁稳态，这对于脂质ROS的产生以刺激铁凋亡是必不可少的。
结论：我们的研究表明，阻断细胞内铁凋亡途径是改善新霉素诱导的耳毒性的替代策略，并为进一步的耳保护药物开发提供了多种化合物。
