Effectiveness of 4-hydroxy phenyl N-tert-butylnitrone (4-OHPBN) alone and in combination with other antioxidant drugs in the treatment of acute acoustic trauma in chinchilla
Effectiveness of 4-hydroxy phenyl N-tert-butylnitrone (4-OHPBN) alone and in combination with other antioxidant drugs in the treatment of acute acoustic trauma in chinchilla
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DOI：
10.1016/j.freeradbiomed.2008.02.005
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发表时间：
2008-05-01
影响因子：
7.4
通讯作者：
Kopke, Richard D.
中科院分区：
文献类型：
--
作者：
Choi, Chul-Hee;Chen, Kejian;Kopke, Richard D.
急性声损伤（AAT）通过细胞活性氧、氮和其他自由基的过量产生导致耳蜗氧化应激，这些自由基在噪声暴露后1 - 10天内出现。已有研究表明，谷胱甘肽前药n -乙酰- l-半胱氨酸（NAC）和线粒体生物发生剂乙酰- l-肉碱（ALCAR）可有效降低噪声性听力损失。苯基n -叔丁基硝基酮（PBN）是一种基于硝基的自由基陷阱，似乎可以抑制多种疾病和几种生物模型中的氧化应激。在这项研究中，我们测试了噪声暴露后4小时给予4-羟基PBN (4- ohpbn)， PBN的主要代谢物，是否能有效治疗噪声性听力损失，以及抗氧化药物（4- ohpbn + NAC和4- ohpbn + NAC + ALCAR）是否能更有效地减弱AAT，因为每种药物针对不同的损伤机制。鼠鼠暴露于以4 kHz为中心的105 dB倍频噪声中，并在噪声暴露后第4天开始腹腔注射抗氧化药物。听觉脑干反应的听阈移位和外毛细胞计数缺失。4-OHPBN以剂量依赖的方式降低阈值移位，而两种药物组合均显示出更大的效果。结果表明，4-OHPBN联合抗氧化剂可有效治疗急性声损伤，联合用药可提高治疗效果，降低个体用药剂量。(c) 2008爱思唯尔公司版权所有。
Acute acoustic trauma (AAT) results in oxidative stress to the cochlea through overproduction of cellular reactive oxygen, nitrogen, and other free radical species appearing from I It to 10 days after noise exposure. It has been shown that N-acetyl-L-cysteine (NAC), a glutathione prodrug, and acetyl-L-carnitine (ALCAR), a mitochondrial biogenesis agent, are effective in reducing noise-induced hearing loss. Phenyl N-tert-butylnitrone (PBN), a nitrone-based free radical trap, appears to suppress oxidative stress in a variety of disorders and several biological models. In this study, we tested whether 4-hydroxy PBN (4-OHPBN), a major metabolite of PBN, administered 4 h after noise exposure is effective in treating noise-induced hearing loss and whether a combination of antioxidant drugs (4-OHPBN plus NAC and 4-OHPBN plus NAC plus ALCAR) provides greater efficacy in attenuating AAT since each agent addresses different injury mechanisms. Chinchilla were exposed to a 105 dB octave-band noise centered at 4 kHz for 6 It. 4-OHPBN and combinations of antioxidant drugs were intraperitoneally administered beginning 4 It after noise exposure. Hearing threshold shifts in auditory brainstem responses and missing outer hair cell counts were obtained. 4-OHPBN reduced threshold shifts in a dose-dependent manner while both drug combinations showed greater effects. These results demonstrate that 4-OHPBN and combinations of antioxidants can effectively treat acute acoustic trauma and drug combinations may increase the effectiveness of treatment and decrease the required individual medication dose. (c) 2008 Elsevier Inc. All rights reserved.