Department of Otolaryngology, Ajou University School of Medicine, Suwon, Korea.
Department of Radiation Oncology, Ajou University School of Medicine, Suwon, Korea.
Neurotoxicology. 2014 Jan;40:111-22. doi: 10.1016/j.neuro.2013.12.006. Epub 2013 Dec 26.
Radiation is a widely used treatment for head and neck cancers, and one of its most severe side effects is ototoxicity. Radiation-induced ototoxicity has been demonstrated to be linked to the increased production of ROS and MAPK. We intended to investigate the effect of p38 inhibition on radiation-induced ototoxicity in cochlea-derived HEI-OC1 cells and in a zebrafish model. The otoprotective effect of p38 inhibition against radiation was tested in vitro in the organ of Corti-derived cell line, HEI-OC1, and in vivo in a zebrafish model. Radiation-induced apoptosis, mitochondrial dysfunction, and an increase of intracellular NO generation were demonstrated in HEI-OC1 cells. The p38-specific inhibitor, SB203580, ameliorated radiation-induced apoptosis and mitochondrial injury in HEI-OC1 cells. p38 inhibition reduced radiation-induced activation of JNK, p38, cytochrome c, and cleavage of caspase-3 and PARP in HEI-OC1 cells. Scanning electron micrography showed that SB203580 prevented radiation-induced destruction of kinocilium and stereocilia in zebrafish neuromasts. The results of this study suggest that p38 plays an important role in mediating radiation-induced ototoxicity and inhibition of p38 could be a plausible option for preventing radiation ototoxicity.
辐射是治疗头颈部癌症的常用方法，其最严重的副作用之一是耳毒性。已经证明，辐射诱导的耳毒性与 ROS 和 MAPK 的产生增加有关。我们旨在研究 p38 抑制对耳蜗来源的 HEI-OC1 细胞和斑马鱼模型中辐射诱导的耳毒性的影响。在体外，我们在 Corti 衍生细胞系 HEI-OC1 中以及在体内的斑马鱼模型中测试了 p38 抑制对辐射的耳保护作用。辐射诱导了 HEI-OC1 细胞中的细胞凋亡、线粒体功能障碍和细胞内 NO 生成的增加。p38 特异性抑制剂 SB203580 改善了 HEI-OC1 细胞中的辐射诱导的细胞凋亡和线粒体损伤。p38 抑制减少了辐射诱导的 JNK、p38、细胞色素 c 和 caspase-3 和 PARP 的切割在 HEI-OC1 细胞中的激活。扫描电子显微镜显示，SB203580 防止了辐射诱导的斑马鱼感觉毛细胞 kinocilium 和 stereocilia 的破坏。这项研究的结果表明，p38 在介导辐射诱导的耳毒性中起重要作用，抑制 p38 可能是预防辐射耳毒性的一种合理选择。
