ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity
Siân R. Kitcher, … , Guy P. Richardson, Corné J. Kros
Siân R. Kitcher, … , Guy P. Richardson, Corné J. Kros
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e126764. https://doi.org/10.1172/jci.insight.126764.
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Research Article Neuroscience Therapeutics

ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity

Abstract

Aminoglycoside (AG) antibiotics are widely used to prevent life-threatening infections, and cisplatin is used in the treatment of various cancers, but both are ototoxic and result in loss of sensory hair cells from the inner ear. ORC-13661 is a new drug that was derived from PROTO-1, a compound first identified as protective in a large-scale screen utilizing hair cells in the lateral line organs of zebrafish larvae. Here, we demonstrate, in zebrafish larvae and in mouse cochlear cultures, that ORC-13661 provides robust protection of hair cells against both ototoxins, the AGs and cisplatin. ORC-13661 also prevents both hearing loss in a dose-dependent manner in rats treated with amikacin and the loading of neomycin-Texas Red into lateral line hair cells. In addition, patch-clamp recordings in mouse cochlear cultures reveal that ORC-13661 is a high-affinity permeant blocker of the mechanoelectrical transducer (MET) channel in outer hair cells, suggesting that it may reduce the toxicity of AGs by directly competing for entry at the level of the MET channel and of cisplatin by a MET-dependent mechanism. ORC-13661 is therefore a promising and versatile protectant that reversibly blocks the hair cell MET channel and operates across multiple species and toxins.

Authors

Siân R. Kitcher, Nerissa K. Kirkwood, Esra D. Camci, Patricia Wu, Robin M. Gibson, Van A. Redila, Roberto Ogelman, Julian A. Simon, Edwin W. Rubel, David W. Raible, Guy P. Richardson, Corné J. Kros

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Figure 7

ORC-13661 acts as a high-affinity permeant blocker of the mechanoelectrical transducer channel.

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ORC-13661 acts as a high-affinity permeant blocker of the mechanoelectri...
(A) Average, normalized current-voltage functions for control currents and currents during ORC-13661 exposure (0.01–10 μM) reveal both the increase in block with increasing ORC-13661 concentration and the voltage dependence of the block. The block is strongest at hyperpolarized potentials, but some degree of block can also be observed at depolarized potentials. (B) Fractional block plots showing the current during ORC-13661 superfusion relative to the control current at each membrane potential. At intermediate concentrations (0.1–1 μM) the block can be seen to increase with increasing hyperpolarization, with a release of the block at extreme hyperpolarized potentials, indicative of a permeant blocker. Cell numbers for both A and B are as follows: control, 33; 0.01 μM, 3; 0.03 μM, 4; 0.1 μM, 4; 0.3 μM, 10; 1 μM, 5; 3 μM, 5; 10 μM, 2. (C) Dose-response function derived from the currents measured at –104 mV, revealing a half-blocking concentration of 0.14 μM at this membrane potential. Between 2 and 10 cells were used for each data set. (D) Equilibrium dissociation constants (KD) and Hill coefficients obtained from dose-response functions derived from the currents measured at each membrane potential. KD values vary between 0.12 and 2.62 μM and the Hill coefficient ranges from 0.26 to 0.59.