Sha S H, Zajic G, Epstein C J, Schacht J
Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, Ann Arbor, Mich 48109-0506, USA.
Audiol Neurootol. 2001 May-Jun;6(3):117-23. doi: 10.1159/000046818.
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.
活性氧在氨基糖苷类药物所致耳毒性中的作用，是基于以下观察结果推断出来的：氨基糖苷 - 铁复合物在体外可催化超氧自由基的形成，以及抗氧化剂在体内可减轻耳毒性。因此，我们推测，铜/锌超氧化物歧化酶（h - SOD1）的过表达应该能保护转基因小鼠免受耳毒性影响。免疫细胞化学证实了h - SOD1在转基因C57BL / 6 - TgN[SOD1]3Cje小鼠内耳组织中的表达。转基因和非转基因同窝小鼠从出生后第10天开始，接受卡那霉素（400 mg/kg体重/天）处理，持续10天。在出生后1个月时，通过诱发听觉脑干反应测试听觉阈值。在非转基因动物中，卡那霉素处理组的阈值比注射生理盐水的对照组高45 - 50 dB。在转基因组中，卡那霉素使阈值仅比各自的对照组增加了15 dB。在12 kHz和24 kHz时效果相似。超氧化物歧化酶过表达的保护作用支持了氧化应激在氨基糖苷类药物所致耳毒性中起重要作用的假说。结果还表明，转基因动物是研究潜在机制和预防策略的合适模型。
