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

Kenyon, Emma J., Kirkwood, Nerissa K., Kitcher, Siân R., O'reilly, Molly, Derudas, Marco, Cantillon, Daire M., Goodyear, Richard J., Secker, Abigail, Baxendale, Sarah, Bull, James C., Waddell, Simon J., Whitfield, Tanya T., Ward, Simon, Kros, Corné J. and Richardson, Guy P. 2017. Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death. JCI Insight 2 (24) , e96773. 10.1172/jci.insight.96773

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: American Society for Clinical Investigation
ISSN: 2379-3708
Date of First Compliant Deposit: 8 October 2018
Date of Acceptance: 15 November 2017
Last Modified: 08 Oct 2018 13:59
URI: http://orca-mwe.cf.ac.uk/id/eprint/109317

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