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 6

ORC-13661 blocks the hair cell’s mechanoelectrical transducer channel.

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ORC-13661 blocks the hair cell’s mechanoelectrical transducer channel. (...
(A–C and E–G) Mechanoelectrical transducer (MET) currents measured from mid-coil outer hair cells in a 2-day-old culture prepared from a P2 mouse before, during, and after extracellular exposure to 0.3 μM (A–C) and 3 μM (E–G) ORC-13661. Currents were measured at membrane potentials ranging from –164 to +96 mV. A sinusoidal stimulus delivered to the fluid-jet (shown above each trace; driver voltage [DV]) resulted in the opening and closure of the MET channels. Currents are reduced during exposure to ORC-13661, predominantly at hyperpolarized potentials, and recover partially following reexposure to control solution. (D and H) Current-voltage relations measured from the cell exposed to 0.3 μM (D) and 3 μM (H) ORC-13661 before, during, and after ORC-13661 superfusion. These relations further reveal a greater reduction in current size at hyperpolarized potentials and partial recovery during washout. Cell capacitances were 8.4 pF (A–C) and 8.0 pF (E–G). Number of cells recorded from exposure to 0.3 μM n = 10 and 3 μM n = 5. All experiments were performed at room temperature (20°C–22°C).