title: 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.
authors.affiliation: Department of Otolaryngology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Yoo Seob
authors.initials: YS
authors.lastname: Shin
authors.affiliation: Department of Otolaryngology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Hwang
authors.affiliation: Department of Otolaryngology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Sung Un
authors.initials: SU
authors.lastname: Kang
authors.affiliation: Department of Otolaryngology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Chang
authors.affiliation: Department of Radiation Oncology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Young-Taek
authors.initials: YT
authors.lastname: Oh
authors.affiliation: Department of Otolaryngology, Ajou University School of Medicine, Suwon, Korea. Electronic address: ostium@ajou.ac.kr.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D016923:Cell Death; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000528:radiation effects / Q000648:ultrastructure; D007093:Imidazoles / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000528:radiation effects; D009925:Organ of Corti / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects*; D017785:Photons; D011725:Pyridines / Q000627:therapeutic use*; D011833:Radiation Injuries, Experimental / Q000188:drug therapy*; D015027:Zebrafish; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: Apoptosis; DMEM,; DMSO,; Dulbecco's modified Eagle's medium; ERK,; FBS,; FITC,; HNSCC,; IHC,; Inner hair cell; JNK,; MAPK,; MMP,; NO,; PARP,; PBS,; PI,; ROS,; SB203580; SEM,; SNHL,; TUNEL,; c-Jun N-terminal kinase; days post-fertilization; dimethyl sulfoxide; dpf,; extracellular signal-regulated kinases; fetal bovine serum; fluorescein isothiocyanate; head and neck squamous cell carcinoma; hearing preservation; mitochondrial membrane potential; mitogen-activated protein kinase; nitric oxide; p38; p38, p38; phosphate buffered saline; poly ADP ribose polymerase; propidium iodide; radiation; reactive oxygen species; scanning electron microscopy; sensorineural hearing loss; terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling; zebrafish