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ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Cellular Neuropathology
Volume 18 - 2024 |
doi: 10.3389/fncel.2024.1458720
This article is part of the Research Topic Cellular Neuropathology of Hearing Loss View all articles
COMBINATORIAL PROTECTION OF COCHLEAR HAIR CELLS: NOT TOO LITTLE BUT NOT TOO MUCH
Provisionally accepted- 1 School of Medicine, University of California San Diego, La Jolla, United States
- 2 College of Medicine, Jeonbuk National University, Jeonju, North Jeolla, Republic of Korea
- 3 VA San Diego Healthcare System, Veterans Health Administration, United States Department of Veterans Affairs, San Diego, California, United States
Background. A number of drugs are toxic to the cochlear sensory cells known as hair cells (HCs), resulting in hearing loss. Treatment with survival-promoting growth factors, antioxidants, and inhibitors of cell death pathways or proteinases have been shown to reduce HC damage in in vivo and/or in vitro animal models. Conversely, translation to humans has often been disappointing. This may be due to the complexity of intracellular damage processes. We hypothesized that combining treatments targeting different cellular processes would be more effective. Methods. Using an in vitro model of gentamicin ototoxicity for murine cochlear hair cells, we screened all 56 possible combinations of inhibitors targeting five different cell damage mechanisms, plus the activator of one cell survival pathway, each of which have been shown to be singly effective in preventing HC loss in experimental studies. A high dose of gentamicin (200 µM) was used over three days in culture. All compounds were added at a dosage below that required for significant protection in the assay, and only this single dose was then employed. This was done so that we could more easily detect interactive, as opposed to additive, effects. Results. Increasing protection of hair cells was observed as combinations of compounds were increased from two to four factors, although not all combinations were equally protective. The optimal combination of four compounds consisted of an anti-oxidant, an apoptosis inhibitor, an autophagy inhibitor and a protective growth factor. Increasing the number of factors to five or six resulted in decreased protection. Conclusions. The results support the hypothesis that targeting multiple cellular damage or survival pathways provides more an effective hair cell protection approach. The results help to identify critical interactions among the cellular processes that operate in gentamicin ototoxicity. They also suggest that inhibiting too many biological processes impairs functions critical to HC survival, resulting in decreased protection.
Keywords: Cochlea, ototoxicity, Hair Cell Protection, multi-target treatment combination, In vitro model culture system, Otoprotection,
Received: 02 Jul 2024; Accepted: 26 Aug 2024.
Copyright: © 2024 Kurabi, Pak, Lee and Ryan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Arwa Kurabi, School of Medicine, University of California San Diego, La Jolla, United States
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