Abstract
Ototoxicity is a main dose-limiting factor in the clinical application of aminoglycoside antibiotics. Despite longstanding research efforts, our understanding of the mechanisms underlying aminoglycoside ototoxicity remains limited. Here we report the discovery of a novel stress pathway that contributes to aminoglycoside-induced hair cell degeneration. Modifying the previously developed bioorthogonal noncanonical amino acid tagging method, we used click chemistry to study the role of protein synthesis activity in aminoglycoside-induced hair cell stress. We demonstrate that aminoglycosides inhibit protein synthesis in hair cells and activate a signaling pathway similar to ribotoxic stress response, contributing to hair cell degeneration. The ability of a particular aminoglycoside to inhibit protein synthesis and to activate the c-Jun N-terminal kinase (JNK) pathway correlated well with its ototoxic potential. Finally, we report that a Food and Drug Administration-approved drug known to inhibit ribotoxic stress response also prevents JNK activation and improves hair cell survival, opening up novel strategies to prevent and treat aminoglycoside ototoxicity.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Alanine / analogs & derivatives
-
Alkynes
-
Aminoglycosides / metabolism
-
Aminoglycosides / toxicity*
-
Animals
-
Anti-Bacterial Agents / metabolism
-
Anti-Bacterial Agents / toxicity*
-
Apoptosis / drug effects
-
Blotting, Western
-
Cell Count
-
Chick Embryo
-
Cytosol / metabolism*
-
Ear Diseases / chemically induced*
-
Enzyme Activation / drug effects
-
Evoked Potentials, Auditory, Brain Stem / drug effects
-
Glycine / analogs & derivatives
-
Hair Cells, Auditory / drug effects
-
Hair Cells, Auditory / pathology
-
Immunohistochemistry
-
JNK Mitogen-Activated Protein Kinases / metabolism
-
Mice
-
Mice, Inbred CBA
-
Niacinamide / analogs & derivatives
-
Niacinamide / pharmacology
-
Organ Culture Techniques
-
Phenylurea Compounds / pharmacology
-
Protein Kinase Inhibitors / pharmacology
-
Protein Synthesis Inhibitors / metabolism
-
Protein Synthesis Inhibitors / toxicity*
-
RNA, Ribosomal / metabolism
-
Sorafenib
Substances
-
Alkynes
-
Aminoglycosides
-
Anti-Bacterial Agents
-
Phenylurea Compounds
-
Protein Kinase Inhibitors
-
Protein Synthesis Inhibitors
-
RNA, Ribosomal
-
azidohomoalanine
-
homopropargylglycine
-
Niacinamide
-
Sorafenib
-
JNK Mitogen-Activated Protein Kinases
-
Alanine
-
Glycine