In a recent pre-print study posted on bioRxiv, researchers have identified oseltamivir, commonly known by its brand name Tamiflu®, as a potential otoprotective therapeutic candidate. The study highlights oseltamivir’s protective effects against hearing loss induced by both cisplatin chemotherapy and traumatic noise exposure.
Currently, sodium thiosulfate (STS) is the only FDA-approved drug available to prevent hearing loss, specifically for use in pediatric patients undergoing cisplatin treatment. However, there is a pressing need for additional protective agents, especially for individuals exposed to excessive noise and for patients with metastatic cancer.
Study Purpose and Methods
The study aimed to explore oseltamivir’s potential as a protective agent against cisplatin- and noise-induced hearing loss. Oseltamivir is an FDA-approved antiviral drug used to treat influenza. Given its well-documented safety profile and existing regulatory approval, it was an attractive candidate for repurposing.
Researchers conducted a high-throughput screening of 1,300 FDA-approved drugs using an inner ear cell line (HEI-OC1) to identify compounds that could prevent cisplatin-induced cell death. Oseltamivir emerged as a top candidate, demonstrating significant protective effects.
The team then tested oseltamivir’s efficacy in various preclinical models. They used both the prodrug (oseltamivir phosphate) and its active form (oseltamivir carboxylate) to assess protection against cisplatin-induced outer hair cell death in cochlear explants. They also evaluated the drug’s impact on cisplatin’s tumor-killing efficacy in lung carcinoma and neuroblastoma cell lines to ensure it did not interfere with cancer treatment.
Further experiments involved in vivo testing on mice models. The researchers assessed the protective effects of oseltamivir against cisplatin ototoxicity and noise-induced hearing loss through auditory brainstem response (ABR) measurements and outer hair cell counts.
Key Findings
Cisplatin-Induced Hearing Loss:
- Cochlear Explant Protection: Oseltamivir phosphate and oseltamivir carboxylate both significantly protected against cisplatin-induced outer hair cell death in mouse cochlear explants. The effective concentration (EC50) for protection was similar for both forms.
- Tumor Cell Line Tests: Oseltamivir did not interfere with cisplatin’s ability to kill cancer cells in lung carcinoma and neuroblastoma cell lines, confirming its non-interference with cisplatin’s therapeutic action.
- In Vivo Mouse Models: In a single high-dose cisplatin model, oseltamivir significantly reduced ABR threshold shifts and outer hair cell loss in treated mice. In a clinically relevant multi-cycle cisplatin model, mice treated with oseltamivir showed significantly lower ABR threshold shifts and better preservation of outer hair cells compared to untreated mice.
Noise-Induced Hearing Loss:
- Protection in Noise-Exposed Mice: Oseltamivir treatment initiated within 24 hours after noise exposure significantly reduced ABR threshold shifts in noise-exposed mice. Higher doses (100 mg/kg) provided robust protection across all tested frequencies.
- Inflammation Reduction: Oseltamivir treatment decreased immune cell infiltration in the cochlea following noise exposure, suggesting an anti-inflammatory mechanism of action.
Molecular Mechanism:
- MAPK Pathway Inhibition: The study identified ERK1/2, part of the MAPK pathway, as a potential molecular target of oseltamivir. The drug reduced MAPK activation in cisplatin-treated cochlear explants.
- Non-viral Target: Oseltamivir’s protective effects were not mediated through inhibition of mammalian neuraminidases, indicating a novel, yet undescribed target.
Promising Candidate for Hearing Loss Prevention
Researchers conclude that oseltamivir shows great potential as an otoprotective agent against both cisplatin- and noise-induced hearing loss. Its pre-existing FDA approval for influenza treatment, coupled with its demonstrated efficacy and safety in preclinical models, makes it a promising candidate for repurposing.
The findings indicate that oseltamivir can significantly reduce hearing loss in various mouse models, suggesting its potential application in clinical settings. Oseltamivir’s ability to protect hearing without interfering with cisplatin’s tumor-killing effectiveness is particularly noteworthy.
This discovery holds significant promise for improving the quality of life for individuals at risk of hearing loss due to chemotherapy or noise exposure. By potentially expanding the range of available treatments, oseltamivir could play a crucial role in mitigating the impact of hearing impairment on global health.
Reference:
- Ingersoll, M. A., Lutze, A., He, X., Ramkumar, V., Frye, M. D., Kim, J., … & Teitz, T. (2024). Oseltamivir as an otoprotective therapeutic candidate for cisplatin and noise-induced hearing loss. bioRxiv. https://doi.org/10.1101/2024.05.06.592815
