AMPKα Silencing Prevents Kanamycin-Induced Ototoxicity in an Acute Mouse Model.

Abstract

Kanamycin (KM), a widely used aminoglycoside antibiotic, is limited by its ototoxic side effects, primarily targeting cochlear outer hair cells (OHCs) and leading to irreversible sensorineural hearing loss. Our previous work showed that silencing AMP-activated protein kinase alpha 1 (AMPKα1) prevents noise-induced hearing loss through a redox-sensitive regulatory mechanism. Given that both noise-induced and aminoglycoside-induced hearing loss share oxidative stress as a key pathological feature, we tested whether AMPKα1 silencing could mitigate KM-induced damage using an acute ototoxic model combining KM with furosemide (KM + FU). KM + FU exposure markedly increased AMPKα phosphorylation at Thr172. Targeted siRNA-mediated silencing via posterior semicircular canal delivery in CBA/J mice significantly reduced AMPKα1 expression in OHCs and effectively prevented KM + FU-induced OHC loss and hearing impairment. This preventive effect was independent of stria vascularis permeability or cochlear KM uptake. These findings identify AMPKα as a contributor to KM + FU-induced acute ototoxicity and suggest that its inhibition may be a promising strategy for hearing preservation.