M40403, a superoxide dismutase mimetic, protects cochlear hair cells from gentamicin, but not cisplatin toxicity
M40403, a superoxide dismutase mimetic, protects cochlear hair cells from gentamicin, but not cisplatin toxicity
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DOI：
10.1016/s0041-008x(02)00017-0
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发表时间：
2003-01-01
影响因子：
3.8
通讯作者：
Salvi, RJ
中科院分区：
文献类型：
--
作者：
McFadden, SL;Ding, DL;Salvi, RJ
氨基糖苷类抗生素庆大霉素和铂类抗癌药物顺铂是临床常用的两种具有耳毒性副作用的药物。庆大霉素和顺铂的耳毒性与活性氧（ROS）的产生有关，尽管具体的活性氧途径尚未确定。一种可能在耳毒性中起作用的活性氧是超氧化物自由基，它被内源性超氧化物歧化酶（SOD）酶分解成分子氧和过氧化氢。M40403，一种锰基非肽基分子，模仿SOD的活性。在新生儿C57BL/10J小鼠耳蜗器官型培养物中检测其对庆大霉素和顺铂毒性的保护能力。培养用庆大霉素或顺铂单独或与M40403联合处理。单独的M40403在1、5和10 muM剂量下对外毛细胞（OHC）或内毛细胞（IHC）存活没有影响，但高剂量的30 muM可使毛细胞数量减少约30%。单用庆大霉素和单用顺铂杀死ohc和ihc呈剂量依赖性。在庆大霉素处理的培养物中添加M40403以剂量依赖的方式显著提高OHC和IHC存活率，而在顺铂处理的培养物中，M40403在任何剂量下都不能保护毛细胞。结果提示庆大霉素和顺铂对耳蜗毛细胞的毒性作用是通过不同的途径介导的。临床升高的SOD或SOD模拟物水平可能对氨基糖苷耳毒性提供显著的保护。(C) 2003 Elsevier Science（美国）版权所有。
Gentamicin, an aminoglycoside antibiotic, and cisplatin, a platinum-based anticancer drug, are two commonly used clinical drugs with ototoxic side effects. The ototoxicity of gentamicin and cisplatin has been linked to the production of reactive oxygen species (ROS), although the specific ROS pathways have not been identified. One ROS that might play a role in ototoxicity is the superoxide radical, which is enzymatically dismutated to molecular oxygen and hydrogen peroxide by endogenous superoxide dismutase (SOD) enzymes. M40403, a manganese-based nonpeptidyl molecule that mimics the activity of SOD. was tested for its ability to protect against gentamicin and cisplatin toxicity in cochlear organotypic cultures from neonatal C57BL/10J mice. Cultures were treated with gentamicin or cisplatin alone or in combination with M40403. M40403 alone had no effect on outer hair cell (OHC) or inner hair cell (IHC) survival at doses of 1, 5, and 10 muM, but a high dose of 30 muM reduced hair cell numbers by approximately 30%. Gentamicin alone and cisplatin alone killed OHCs and IHCs in a dose-dependent manner. The addition of M40403 to gentamicin-treated cultures significantly increased OHC and IHC survival in a dose-dependent manner, whereas M40403 failed to protect hair cells in cisplatin-treated Culture,, at any dose. The results suggest that the toxicity of gentamicin and cisplatin to cochlear hair cells are mediated by different pathways. Clinically increased levels of SOD or SOD mimetics might provide significant protection against aminoglycoside ototoxicity. (C) 2003 Elsevier Science (USA). All rights reserved.