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Updated: Jun 21, 2025
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action
Patricia Wu1,2, Francisco Barros Becker1,3, Roberto Ogelman1,2
1Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA 98195, United States.
Abstract:
Mechanosensory hair cells of the inner ears and lateral line of vertebrates display heightened vulnerability to environmental insult, with damage resulting in hearing and balance disorders. An important example is hair cell loss due to exposure to toxic agents including therapeutic drugs such as the aminoglycoside antibiotics such as neomycin and gentamicin and antineoplastic agents. We describe two distinct cellular pathways for aminoglycoside-induced hair cell death in zebrafish lateral line hair cells. Neomycin exposure results in death from acute exposure with most cells dying within 1 hour of exposure. By contrast, exposure to gentamicin results primarily in delayed hair cell death, taking up to 24 hours for maximal effect. Washout experiments demonstrate that delayed death does not require continuous exposure, demonstrating two mechanisms where downstream responses differ in their timing. Acute damage is associated with mitochondrial calcium fluxes and can be alleviated by the mitochondrially-targeted antioxidant mitoTEMPO, while delayed death is independent of these factors. Conversely delayed death is associated with lysosomal accumulation and is reduced by altering endolysosomal function, while acute death is not sensitive to lysosomal manipulations. These experiments reveal the complexity of responses of hair cells to closely related compounds, suggesting that intervention focusing on early events rather than specific death pathways may be a successful therapeutic strategy.
Insights
Aminoglycoside antibiotics like neomycin and gentamicin cause hair cell death through distinct pathways. Understanding these mechanisms is crucial for developing therapies to prevent hearing and balance disorders.
Area of Science:
- Ototoxicity and cellular toxicology
- Mechanosensory cell biology
- Vertebrate sensory systems
Background:
- Mechanosensory hair cells are vulnerable to environmental toxins, leading to hearing and balance disorders.
- Aminoglycoside antibiotics (e.g., neomycin, gentamicin) are common ototoxic agents causing hair cell loss.
- Zebrafish lateral line hair cells serve as a model to study hair cell death mechanisms.
Purpose of the Study:
- To elucidate the distinct cellular death pathways induced by aminoglycoside antibiotics in zebrafish hair cells.
- To differentiate the timing and molecular mechanisms of neomycin- and gentamicin-induced hair cell death.
- To identify potential therapeutic targets for mitigating ototoxicity.
Main Methods:
- Exposure of zebrafish lateral line hair cells to neomycin and gentamicin.
- Time-course analysis of cell death following drug exposure and washout.
- Assessment of mitochondrial calcium fluxes and lysosomal function.
- Utilizing mitochondrially-targeted antioxidants and endolysosomal modulators.
Main Results:
- Neomycin induces acute hair cell death within 1 hour, linked to mitochondrial calcium fluxes.
- Gentamicin causes delayed hair cell death up to 24 hours, associated with lysosomal accumulation.
- Acute death is mitigated by mitoTEMPO; delayed death is sensitive to endolysosomal manipulation.
- Washout experiments confirm distinct downstream responses independent of continuous exposure.
Conclusions:
- Aminoglycoside ototoxicity involves at least two distinct cellular death pathways with different kinetics and molecular underpinnings.
- Acute and delayed cell death mechanisms differ significantly, involving mitochondria and lysosomes respectively.
- Therapeutic strategies targeting early cellular events may offer broader protection against aminoglycoside-induced hair cell damage.
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