Abstract
Hearing loss affects up to 10% of people worldwide. Yet currently, there is only one FDA-approved drug for its prevention in a subgroup of cisplatin-treated pediatric patients. Here, we performed an unbiased screen of 1,300 FDA-approved drugs for protection against cisplatin-induced cell death in an inner ear cell line, and identified oseltamivir phosphate (brand name Tamiflu), a common influenza antiviral drug, as a top candidate. Oseltamivir phosphate was found to be otoprotective by oral delivery in multiple established cisplatin and noise exposure mouse models. The drug conferred permanent hearing protection of 15-25 decibel Sound-Pressure Level (dB SPL) for both female and male mice. In mice, oseltamivir treatment reduced outer hair cell death after cisplatin treatment and mitigated cochlear synaptopathy after noise exposure. We showed that a potential binding protein, ERK1/2, associated with inflammation, was activated with cisplatin treatment and reduced with oseltamivir cotreatment in cochlear explants. Importantly, we also associated oseltamivir treatment with a significant reduction in the number of infiltrating immune cells to the cochleae in mice after noise exposure,suggesting an anti-inflammatory mechanism of action. Our results support oseltamivir, a widespread drug for influenza with low side effects, as a promising otoprotective therapeutic candidate in both cisplatin chemotherapy and traumatic noise exposure.