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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Categories: Research Article Neuroscience

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

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 6

Interactions of otoprotectants with the basolateral potassium current IK,neo.

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Interactions of otoprotectants with the basolateral potassium current IK...
Representative currents from OHCs in cultures prepared from P2 pups were recorded before, during, and after exposure to 30 μM (A) 13097, (C) 13142, and (E) 13143 (for the number of cells tested with each compound see G). Currents, averaged from 2 stimulus presentations, were recorded in response to 10 mV hyperpolarizing and depolarizing voltage steps from a holding potential of –84 mV. Schematic representations of the voltage step protocols are shown below each trace. Small leakage currents have been subtracted. (B, D, and F) Activation curves derived from the tail currents in A, C, and E before (black traces) and during (red traces) compound exposure. (G) Box-and-whisker plot of maximum conductance (Gmax) as a percentage of control for all 13 otoprotective compounds: 13087 (n = 5), 13097 (n = 5), 13104 (n = 7), 13142 (n = 6), 13143 (n = 7), 13150 (n = 2), 13154 (n = 4), 13170 (n = 7), 13190 (n = 5), 13196 (n = 5), 13218 (n = 2), 13222 (n = 5), and 13228 (n = 3). Thick line = median; boxes = interquartile range (IQR). Whiskers extend an additional 1.5× IQR beyond the boxes. Outliers are shown as white circles. All recordings were performed at room temperature (20°C–23°C).