Adeno-associated virus-mediated Bcl-xL prevents aminoglycoside-induced hearing loss in mice.
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.
Liu
Yu-He
YH
Department of Otolaryngology, Head and Neck Surgery, Peking University First Hospital, Beijing 100034, China. liuyuhe@xinhuanet.com
Ke
Xiao-Mei
XM
Qin
Yong
Y
Gu
Zhi-Ping
ZP
Xiao
Shui-Fang
SF
D000617:Aminoglycosides / Q000633:toxicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects / Q000502:physiology; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D034381:Hearing Loss / Q000139:chemically induced*; D007612:Kanamycin / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D051020:bcl-X Protein / Q000235:genetics*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D051020:bcl-X Protein; D007612:Kanamycin