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Published on: January 9, 2019
Adeno-associated virus-mediated Bcl-xL prevents aminoglycoside-induced hearing loss in mice
Yu-He Liu1, Xiao-Mei Ke, Yong Qin
1Department of Otolaryngology, Head and Neck Surgery, Peking University First Hospital, Beijing 100034, China. liuyuhe@xinhuanet.com
Background:
Recent studies showed that aminoglycosides destroyed the cochlear cells and induced ototoxicity by producing reactive oxygen species, including free radicals in the mitochondria, damaging the membrane of mitochondria and resulting in apoptotic cell death. Bcl-x(L) is a well characterized anti-apoptotic member of the Bcl-2 family. The aim of this study was to determine the potential cochlear protective effect of Bcl-x(L) as a therapeutic agent in the murine model of aminoglycoside ototoxicity.
Methods:
Serotype 2 of adeno-associated virus (AAV2) as a vector encoding the mouse Bcl-x(L) gene was injected into mice cochleae prior to injection of kanamycin. Bcl-x(L) expression in vitro and in vivo was examined with Western blotting and immunohistochemistry separately. Cochlear dissection and auditory steady state responses were checked to evaluate the cochlear structure and function.
Results:
The animals in the AAV2-Bcl-x(L)/kanamycin group displayed better auditory steady state responses hearing thresholds and cochlear structure than those in the artificial perilymph/kanamycin or AAV2-enhanced humanized green fluorescent protein/kanamycin control group at all tested frequencies. The auditory steady state responses hearing thresholds and cochlear structure in the inoculated side were better than that in the contralateral side.
Conclusions:
AAV2-Bcl-x(L) afforded significant preservation of the cochlear hair cells against ototoxic insults and protected the cochlear function. AAV2-mediated Bcl-x(L) might be an approach with respect to potential therapeutic application in the cochlear degeneration.
Insights
Aminoglycosides cause ototoxicity by damaging cochlear cells. Adeno-associated virus vector-mediated Bcl-x(L) gene transfer protected cochlear hair cells and function in a mouse model, suggesting a potential therapy for aminoglycoside-induced hearing loss.
Area of Science:
- Ototoxicity and inner ear research
- Gene therapy and molecular biology
- Cellular and molecular mechanisms of hearing loss
Background:
- Aminoglycosides induce ototoxicity by generating reactive oxygen species (ROS) in mitochondria, leading to apoptotic cell death.
- Bcl-x(L) is a known anti-apoptotic protein within the Bcl-2 family.
- Understanding mechanisms of ototoxicity is crucial for developing protective therapies.
Purpose of the Study:
- To investigate the potential cochlear protective effects of Bcl-x(L) against aminoglycoside-induced ototoxicity.
- To evaluate Bcl-x(L) as a therapeutic agent in a murine model.
- To assess the efficacy of adeno-associated virus (AAV) mediated gene delivery for Bcl-x(L).
Main Methods:
- Adeno-associated virus serotype 2 (AAV2) encoding mouse Bcl-x(L) was delivered to mouse cochleae before kanamycin administration.
- Bcl-x(L) expression was confirmed using Western blotting and immunohistochemistry.
- Cochlear structure and auditory function were assessed via cochlear dissection and auditory steady-state responses.
Main Results:
- Mice treated with AAV2-Bcl-x(L) exhibited significantly better auditory thresholds and cochlear structure compared to control groups.
- Protection was observed across all tested frequencies.
- The treated (inoculated) cochlear side showed superior outcomes compared to the contralateral side.
Conclusions:
- AAV2-mediated delivery of Bcl-x(L) effectively preserved cochlear hair cells from ototoxic damage.
- This approach demonstrated significant protection of cochlear function.
- AAV2-Bcl-x(L) represents a promising therapeutic strategy for preventing aminoglycoside-induced cochlear degeneration.
