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

Kitcher, Siân R, Kirkwood, Nerissa K, Camci, Esra D, Wu, Patricia, Gibson, Robin M, Redila, Van A, Ogelman, Roberto, Simon, Julian A, Rubel, Edwin W, Raible, David W, Richardson, Guy P and Kros, Corné J (2019) ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity. JCI Insight, 4 (15). pp. 1-19. ISSN 2379-3708

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Neuroscience
Research Centres and Groups: Sussex Neuroscience
Subjects: Q Science > QP Physiology > QP0351 Neurophysiology and neuropsychology > QP0431 Senses > QP0448 Special senses > QP0461 Hearing. Physiological acoustics
Depositing User: Corne Kros
Date Deposited: 24 Sep 2019 17:39
Last Modified: 25 Sep 2019 07:01
URI: http://sro.sussex.ac.uk/id/eprint/86215

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Project NameSussex Project NumberFunderFunder Ref
Mechanisms of aminoglyscoside ototoxicity and drug damage repair in sensory hair cells: towards the design of otoprotective strategies.G1025MRC-MEDICAL RESEARCH COUNCILMR/K005561/1