PUBLICATION

Extracellular divalent cations modulate aminoglycoside-induced hair cell death in the zebrafish lateral line

Authors
Coffin, A.B., Owens, K.N., Raible, D.W., and Rubel, E.W.
ID
ZDB-PUB-090319-8
Date
2009
Source
Hearing Research   253(1-2): 42-51 (Journal)
Registered Authors
Owens, Kelly, Raible, David
Keywords
Hair cell, Ototoxicity, Aminoglycoside, Lateral line, Calcium, Magnesium
MeSH Terms
  • Aminoglycosides/antagonists & inhibitors*
  • Aminoglycosides/toxicity*
  • Animals
  • Anti-Bacterial Agents/antagonists & inhibitors
  • Anti-Bacterial Agents/toxicity
  • Calcium/pharmacology
  • Cations, Divalent/pharmacology*
  • Cell Death/drug effects
  • Gentamicins/antagonists & inhibitors
  • Gentamicins/toxicity
  • Lateral Line System/drug effects*
  • Lateral Line System/pathology*
  • Magnesium/pharmacology
  • Mechanoreceptors/drug effects*
  • Mechanoreceptors/pathology*
  • Neomycin/antagonists & inhibitors
  • Neomycin/toxicity
  • Zebrafish/anatomy & histology
PubMed
19285547 Full text @ Hear. Res.
Abstract
Aminoglycoside antibiotics cause death of sensory hair cells. Research over the past decade has identified several key players in the intracellular cascade. However, the role of the extracellular environment in aminoglycoside ototoxicity has received comparatively little attention. The present study uses the zebrafish lateral line to demonstrate that extracellular calcium and magnesium ions modulate hair cell death from neomycin and gentamicin invivo, with high levels of either divalent cation providing significant protection. Imaging experiments with fluorescently tagged gentamicin show that drug uptake is reduced under high calcium conditions. Treating fish with the hair cell transduction blocker amiloride also reduces aminoglycoside uptake, preventing the toxicity, and experiments with variable calcium and amiloride concentrations suggest complementary effects between the two protectants. Elevated magnesium, in contrast, does not appear to significantly attenuate drug uptake, suggesting that the two divalent cations may protect hair cells from aminoglycoside damage through different mechanisms. These results provide additional evidence for calcium- and transduction-dependent aminoglycoside uptake. Divalent cations provided differential protection from neomycin and gentamicin, with high cation concentrations almost completely protecting hair cells from neomycin and acute gentamicin toxicity, but offering reduced protection from continuous (6 hr) gentamicin exposure. These experiments lend further support to the hypothesis that aminoglycoside toxicity occurs via multiple pathways in a both a drug and time course-specific manner.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping