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Prevention of aminoglycoside-induced outer hair cell loss by silencing CaMKKβ in an acute mouse model
Fan Wu1, Shan Xu1, Hongguo Su1
1Department of Pathology and Laboratory Medicine, The Medical University of South Carolina, Charleston, SC 29425, USA.
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.
Insights
Aminoglycoside antibiotics cause hearing loss, but blocking CaMKKβ in hair cells protected against this damage in mice. This suggests CaMKKβ is a potential target for preventing drug-induced hearing loss.
Area of Science:
- Ototoxicity research
- Molecular biology
- Auditory neuroscience
Background:
- Aminoglycoside antibiotics are a common cause of acquired hearing loss globally.
- Current treatments lack clinical efficacy in preventing drug-induced ototoxicity.
- Previous research linked Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKK) pathway activation to noise-induced hearing loss.
Purpose of the Study:
- To investigate the role of CaMKKβ in aminoglycoside-induced ototoxicity.
- To determine if reducing CaMKKβ in hair cells can prevent kanamycin plus furosemide (KM + FU)-induced hearing loss.
Main Methods:
- Assessed CaMKKβ activation in an acute ototoxicity model (KM + FU).
- Utilized small interfering RNA (siRNA) and adeno-associated virus (AAV)-mediated shRNA to silence CaMKKβ in mouse hair cells.
- Evaluated outer hair cell loss and hearing function post-treatment.
Main Results:
- Both siRNA and AAV-mediated shRNA silencing of CaMKKβ significantly prevented KM + FU-induced outer hair cell loss.
- CaMKKβ reduction did not affect stria vascularis permeability or kanamycin uptake via mechanoelectrical transduction channels.
- Demonstrated significant protection against KM + FU-induced hearing loss.
Conclusions:
- CaMKKβ plays a critical role in aminoglycoside-induced ototoxicity.
- Targeting CaMKKβ in hair cells offers a promising therapeutic strategy for preventing aminoglycoside-induced hearing loss.
- Further research into CaMKKβ inhibition could lead to effective clinical interventions for ototoxicity.
