Prevention of aminoglycoside-induced outer hair cell loss by silencing CaMKKβ in an acute mouse model

Abstract

The use of ototoxic drugs remains a common cause of acquired hearing loss worldwide. Among them, aminoglycoside antibiotics are still widely used in clinical practice. Although the pathological mechanisms underlying aminoglycoside-induced hearing loss have been extensively studied, no clinically effective pharmacological treatment is currently available to prevent such ototoxicity. Our previous study demonstrated that calcium overload and activation of the Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKK) pathway play a critical role in noise-induced hearing loss. In this study, we assessed the activation of CaMKKβ in an acute ototoxicity model induced by kanamycin plus furosemide (KM + FU). We silenced CaMKKβ using small interfering RNA in young adult CBA/J mice and AAV-mediated shRNA in FVB/NJ mice to determine whether reduction of CaMKKβ in hair cells could prevent KM + FU-induced outer hair cell loss and hearing loss. Remarkably, both silencing approaches provided significant prevention of KM + FU-induced outer hair cell loss. Moreover, RNA interference targeting CaMKKβ did not alter the permeability of the stria vascularis or the uptake of kanamycin through mechanoelectrical transduction channels in hair cells. These findings suggest that CaMKKβ is a promising therapeutic target for prevention of aminoglycoside-induced hearing loss in acute model.