Comparative Antioxidant Protection of Cochlear Hair Cells from Ototoxins

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 A₂ (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.