homopropargylglycine and Ear-Diseases

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.

Topics: Alanine; Alkynes; Aminoglycosides; Animals; Anti-Bacterial Agents; Apoptosis; Blotting, Western; Cell Count; Chick Embryo; Cytosol; Ear Diseases; Enzyme Activation; Evoked Potentials, Auditory, Brain Stem; Glycine; Hair Cells, Auditory; Immunohistochemistry; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Inbred CBA; Niacinamide; Organ Culture Techniques; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Synthesis Inhibitors; RNA, Ribosomal; Sorafenib