PUBLICATION

Quinoline Ring Derivatives Protect Against Aminoglycoside-Induced Hair Cell Death in the Zebrafish Lateral Line

Authors
Ou, H.C., Keating, S., Wu, P., Simon, J.A., Raible, D.W., and Rubel, E.W.
ID
ZDB-PUB-121019-4
Date
2012
Source
Journal of the Association for Research in Otolaryngology : JARO   13(6): 759-770 (Journal)
Registered Authors
Raible, David
Keywords
quinoline ring, hair cell protection, zebrafish
MeSH Terms
  • Aminoglycosides/pharmacokinetics
  • Aminoglycosides/toxicity*
  • Animals
  • Anti-Bacterial Agents/toxicity*
  • Bacteria/drug effects
  • Cell Death/drug effects
  • Dose-Response Relationship, Drug
  • Gentamicins/pharmacokinetics
  • Gentamicins/toxicity
  • Hair Cells, Auditory/drug effects*
  • Hair Cells, Auditory/pathology
  • Neomycin/toxicity
  • Quinolines/pharmacology*
  • Zebrafish
PubMed
23053627 Full text @ J. Assoc. Res. Otolaryngol.
Abstract

We have previously published results from a screen of 1,040 FDA-approved drugs and bioactives (NINDS Custom Collection) for drugs that protect against neomycin-induced hair cell death (Ou et al., J Assoc Res Otolaryngol 10:191–203, 2009). Further evaluation of this drug library identified eight protective drugs that shared a common quinoline scaffold. These drugs were tested further in terms of their protection against other aminoglycosides, as well as their effect on aminoglycoside uptake. All of the eight quinolines that protected against neomycin were found to protect against short- and long-term gentamicin damage protocols. We then tested the structurally related compounds quinoline, isoquinoline, naphthalene, and indole for protective effects. Of these compounds, indole demonstrated a small but significant amount of protection against neomycin, while quinoline and isoquinoline partially protected against long-term gentamicin damage. We examined whether the protective activity of this group of compounds was related to known targets of the quinoline derivatives. The protective effects did not seem linked to either the cholinergic or histaminergic pathways that are regulated by some members of the quinoline family. However, all eight protective drugs were found to reduce the uptake of aminoglycosides into hair cells. Subsequent experiments suggest that reduction of uptake is the primary mechanism of protection among the quinoline drugs.

Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping