PUBLICATION

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

Authors
Kitcher, S.R., Kirkwood, N.K., Camci, E.D., Wu, P., Gibson, R.M., Redila, V.A., Simon, J.A., Rubel, E.W., Raible, D.W., Richardson, G.P., Kros, C.J.
ID
ZDB-PUB-190809-4
Date
2019
Source
JCI insight   4(15): (Journal)
Registered Authors
Raible, David
Keywords
Drug screens, Drug therapy, Ion channels, Neuroscience, Therapeutics
MeSH Terms
  • Amikacin/toxicity
  • Aminoglycosides/toxicity
  • Animals
  • Anti-Bacterial Agents/toxicity*
  • Antineoplastic Agents/toxicity*
  • Cell Culture Techniques
  • Cells, Cultured
  • Cisplatin/toxicity
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hair Cells, Auditory/drug effects*
  • Hair Cells, Auditory/metabolism
  • Humans
  • Intravital Microscopy
  • Ion Channels/antagonists & inhibitors
  • Ion Channels/metabolism
  • Male
  • Mechanotransduction, Cellular/drug effects
  • Mice
  • Ototoxicity/etiology
  • Ototoxicity/prevention & control*
  • Patch-Clamp Techniques
  • Protective Agents/pharmacology*
  • Protective Agents/therapeutic use
  • Rats
  • Time-Lapse Imaging
  • Zebrafish
PubMed
31391343 Full text @ JCI Insight
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping