Inhibition of p38 mitogen-activated protein kinase ameliorates radiation-induced ototoxicity in zebrafish and cochlea-derived cell lines.

ABSTRACT

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.