Overexpression of copper/zinc-superoxide dismutase protects from kanamycin-induced hearing loss.
The participation of reactive oxygen species in aminoglycoside-induced ototoxicity has been deduced from observations that aminoglycoside-iron complexes catalyze the formation of superoxide radicals in vitro and that antioxidants attenuate ototoxicity in vivo. We therefore hypothesized that overexpression of Cu/Zn-superoxide dismutase (h-SOD1) should protect transgenic mice from ototoxicity. Immunocytochemistry confirmed expression of h-SOD1 in inner ear tissues of transgenic C57BL/6-TgN[SOD1]3Cje mice. Transgenic and nontransgenic littermates received kanamycin (400 mg/kg body weight/day) for 10 days beginning on day 10 after birth. Auditory thresholds were tested by evoked auditory brain stem responses at 1 month after birth. In nontransgenic animals, the threshold in the kanamycin-treated group was 45-50 dB higher than in saline-injected controls. In the transgenic group, kanamycin increased the threshold by only 15 dB over the respective controls. The effects were similar at 12 and 24 kHz. The protection by overexpression of superoxide dismutase supports the hypothesis that oxidant stress plays a significant role in aminoglycoside-induced ototoxicity. The results also suggest transgenic animals as suitable models to investigate the underlying mechanisms and possible strategies for prevention.
Sha
S H
SH
Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, Ann Arbor, Mich 48109-0506, USA.
Zajic
G
G
Epstein
C J
CJ
Schacht
J
J
D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000097:blood; D001309:Auditory Threshold / Q000187:drug effects; D001806:Blood Urea Nitrogen; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003300:Copper / Q000378:metabolism*; D006311:Hearing Disorders / Q000139:chemically induced* / Q000517:prevention & control*; D007150:Immunohistochemistry; D007612:Kanamycin / Q000009:adverse effects* / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D014722:Vestibule, Labyrinth / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015032:Zinc / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D017382:Reactive Oxygen Species; D007612:Kanamycin; D003300:Copper; D013482:Superoxide Dismutase; D015032:Zinc