Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Neuroscience Therapeutics

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

  • Text
  • PDF
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

×

Figure 1

ORC-13661 protects zebrafish lateral line hair cells from AG toxicity in vivo.

Options: View larger image (or click on image) Download as PowerPoint
ORC-13661 protects zebrafish lateral line hair cells from AG toxicity in...
Hair cell survival in wild-type *AB zebrafish at 5–7 dpf treated with aminoglycosides (AGs). (A) Twenty-four-hour treatment with gentamicin (1–200 μM) or amikacin (100–1500 μM) or one-hour treatment with neomycin (50–200 μM). (B) Treatment with varying doses of ORC-13661 (0.10–8.3 μM) with 50 μM gentamicin, 200 μM neomycin, or 1000 μM amikacin. Counts from controls without any ORC-13661 are also shown. Means were calculated from α parvalbumin–positive hair cell counts from 4 neuromasts/fish (SO1, SO2, O1, and OC1) after treatment, with 9–11 fish/treatment group. Percentages reflect the average number of hair cells remaining in treated fish, relative to hair cells remaining in vehicle control fish. Vertical arrows in A show LD50 for each of the AGs tested; vertical arrows in B show HC50 for ORC-13661 in the presence of AGs. Error bars represent SD. ORC-13661 protects against toxicity from all 3 AGs in a dose-dependent manner.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts