PUBLICATION
Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death
- Authors
- Kenyon, E.J., Kirkwood, N.K., Kitcher, S.R., O'Reilly, M., Derudas, M., Cantillon, D.M., Goodyear, R.J., Secker, A., Baxendale, S., Bull, J.C., Waddell, S.J., Whitfield, T.T., Ward, S.E., Kros, C.J., Richardson, G.P.
- ID
- ZDB-PUB-171222-3
- Date
- 2017
- Source
- JCI insight 2(24): (Journal)
- Registered Authors
- Baxendale, Sarah, Kenyon, Emma, Whitfield, Tanya T.
- Keywords
- Drug screens, Neuroscience
- MeSH Terms
-
- Aminoglycosides/antagonists & inhibitors
- Aminoglycosides/pharmacology*
- Animals
- Anti-Bacterial Agents/pharmacology*
- Cell Death/drug effects
- Cochlea/drug effects
- Drug Evaluation, Preclinical/methods
- Female
- Gentamicins/antagonists & inhibitors
- Gentamicins/pharmacology
- Hair Cells, Auditory/drug effects*
- Ion Channels/drug effects
- Male
- Mice
- Neuroprotective Agents/pharmacology*
- Tissue Culture Techniques
- Zebrafish
- PubMed
- 29263311 Full text @ JCI Insight
Citation
Kenyon, E.J., Kirkwood, N.K., Kitcher, S.R., O'Reilly, M., Derudas, M., Cantillon, D.M., Goodyear, R.J., Secker, A., Baxendale, S., Bull, J.C., Waddell, S.J., Whitfield, T.T., Ward, S.E., Kros, C.J., Richardson, G.P. (2017) Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death. JCI insight. 2(24).
Abstract
Aminoglycoside antibiotics are used to treat life-threatening bacterial infections but can cause deafness due to hair cell death in the inner ear. Compounds have been described that protect zebrafish lateral line hair cells from aminoglycosides, but few are effective in the cochlea. As the aminoglycosides interact with several ion channels, including the mechanoelectrical transducer (MET) channels by which they can enter hair cells, we screened 160 ion-channel modulators, seeking compounds that protect cochlear outer hair cells (OHCs) from aminoglycoside-induced death in vitro. Using zebrafish, 72 compounds were identified that either reduced loading of the MET-channel blocker FM 1-43FX, decreased Texas red-conjugated neomycin labeling, or reduced neomycin-induced hair cell death. After testing these 72 compounds, and 6 structurally similar compounds that failed in zebrafish, 13 were found that protected against gentamicin-induced death of OHCs in mouse cochlear cultures, 6 of which are permeant blockers of the hair cell MET channel. None of these compounds abrogated aminoglycoside antibacterial efficacy. By selecting those without adverse effects at high concentrations, 5 emerged as leads for developing pharmaceutical otoprotectants to alleviate an increasing clinical problem.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping