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Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death
Emma J. Kenyon, … , Corné J. Kros, Guy P. Richardson
Emma J. Kenyon, … , Corné J. Kros, Guy P. Richardson
Published December 21, 2017
Citation Information: JCI Insight. 2017;2(24):e96773. https://doi.org/10.1172/jci.insight.96773.
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Research Article Neuroscience

Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death

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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.

Authors

Emma J. Kenyon, Nerissa K. Kirkwood, Siân R. Kitcher, Molly O’Reilly, Marco Derudas, Daire M. Cantillon, Richard J. Goodyear, Abigail Secker, Sarah Baxendale, James C. Bull, Simon J. Waddell, Tanya T. Whitfield, Simon E. Ward, Corné J. Kros, Guy P. Richardson

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Figure 10

Summary of results and properties of compounds providing protection in mouse OHCs.

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Summary of results and properties of compounds providing protection in m...
(A) Proportional Venn diagram showing the number of compounds effective in the 3 zebrafish assays, with small circles identifying the compounds in each sector that were effective in the mouse OHCs. The 5 lead compounds are underlined. (B) Corresponding Venn numbers, identifier numbers, structure, commercial name, and known biological activity of the 13 compounds found to protect mouse OHCs from gentamicin-induced damage at 50 μM. MW, a measure of lipophilicity (cLogP and cLogD), polar surface area (PSA), and pKa (pH at which the compound is 50% ionized) for compounds are also included. Thick black lines separate compounds of differing biological activity.

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