Ryan Allen F, Pak Kwang, Lee Eun Jung, Kurabi Arwa
Department of Otolaryngology, University of California San Diego, La Jolla, CA 92093, USA.
Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA.
Molecules. 2025 Sep 17;30(18):3772. doi: 10.3390/molecules30183772.
Many forms of damage to cochlear sensory cells involve reactive oxygen species (ROS). We previously screened 81 antioxidants in vitro for the ability to reduce cochlear hair cell (HC) damage by the ototoxic aminoglycoside gentamicin. Only 13 antioxidants produced significant reduction in HC loss, with the quinone antioxidants seratrodast and idebenone being most protective. Why so few antioxidants were protective is unclear, but most antioxidants have other properties that could enhance or detract from protection. In particular, seratrodast is a potent thromboxane A (TXA2) antagonist, while idebenone also strongly supports cell metabolism by enhancing mitochondrial function. We therefore asked whether a different TXA2 inhibitor (SQ-29548) or mitochondrial function enhancer (mitochonic acid) exhibited any HC protective ability in the same assay. In both cases, no significant protection from gentamicin was observed, indicating that the ROS scavenging activity of seratrodast and idebenone accounted for HC protection. Additionally, to assess the generality of HC protection by the two antioxidants, we assessed their potential for protection against cisplatin, an ototoxic anti-cancer drug that produces HC damage through a different mechanism than aminoglycosides, but which also involves ROS. High-dose seratrodast tested protected HCs from cisplatin damage, but not to the extent observed for gentamicin. High-dose idebenone was also protective, but even less than for seratrodast. Neither mitochonic acid nor SQ-29548 was protective against cisplatin. The results indicate that seratrodast and idebenone provide HC protection from gentamicin and cisplatin due to their free radical scavenging properties, but protection from cisplatin was less effective, presumably due to its different mechanism of ototoxicity.
耳蜗感觉细胞的多种损伤形式都涉及活性氧（ROS）。我们之前在体外筛选了81种抗氧化剂，以评估其减少耳毒性氨基糖苷类药物庆大霉素对耳蜗毛细胞（HC）损伤的能力。只有13种抗氧化剂能显著减少毛细胞损失，其中醌类抗氧化剂司来吉兰和艾地苯醌的保护作用最强。目前尚不清楚为何只有少数抗氧化剂具有保护作用，但大多数抗氧化剂具有其他可能增强或削弱保护作用的特性。特别是，司来吉兰是一种有效的血栓素A（TXA2）拮抗剂，而艾地苯醌还通过增强线粒体功能有力地支持细胞代谢。因此，我们询问在相同实验中，另一种TXA2抑制剂（SQ - 29548）或线粒体功能增强剂（线粒体酸）是否具有任何毛细胞保护能力。在这两种情况下，均未观察到对庆大霉素的显著保护作用，这表明司来吉兰和艾地苯醌的ROS清除活性是毛细胞保护的原因。此外，为了评估这两种抗氧化剂对毛细胞保护作用的普遍性，我们评估了它们对顺铂的保护潜力，顺铂是一种耳毒性抗癌药物，其导致毛细胞损伤的机制与氨基糖苷类药物不同，但同样涉及ROS。高剂量的司来吉兰测试显示可保护毛细胞免受顺铂损伤，但程度不如对庆大霉素的保护作用。高剂量的艾地苯醌也具有保护作用，但甚至比对司来吉兰的保护作用更弱。线粒体酸和SQ - 29548对顺铂均无保护作用。结果表明，司来吉兰和艾地苯醌因其自由基清除特性为毛细胞提供了对庆大霉素和顺铂的保护作用，但对顺铂的保护效果较差，可能是由于其耳毒性机制不同。
