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 8

Kinetics of ORC-13661 block.

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Kinetics of ORC-13661 block. Mechanoelectrical transducer (MET) currents...
Mechanoelectrical transducer (MET) currents measured in response to fluid-jet step stimuli in the presence and absence of ORC-13661. Saturating excitatory and inhibitory step stimuli (±40 V driver voltage shown above each trace; DV) were delivered to mid-coil outer hair cells (OHCs) in a 2-day-old culture prepared from a P2 mouse before and during exposure to 0.3 μM (A) and 3 μM (B) ORC-13661 from a holding potential of –84 mV. Opening of the MET channels resulted in rapidly activating inward currents. Control currents (black traces) and currents during ORC-13661 block (red traces) have been superimposed to compare the kinetic information. In all cases, minimal current inactivation is observed during the steps, with no differences seen in offset kinetics. Cell capacitances were 7.1 pF (A) and 8.0 pF (B). Similar results were obtained from all OHCs examined (n = 7 at 0.3 μM; n = 2 at 3 μM). Experiments were performed at room temperature (20°C–22°C).