title: Alpha-lipoic acid protects against cisplatin-induced ototoxicity via the regulation of MAPKs and proinflammatory cytokines.
abstract: Cisplatin is an effective antineoplastic drug that is widely used to treat various cancers; however, it causes side effects such as ototoxicity via the induction of apoptosis of hair cells in the cochlea. Alpha-lipoic acid (ALA) has been reported to exert a protective effect against both antibiotic-induced and cisplatin-induced hearing loss. Therefore, this study was conducted to (1) elucidate the mechanism of the protective effects of ALA against cisplatin-induced ototoxicity using in vitro and ex vivo culture systems of HEI-OC1 auditory cells and rat cochlear explants and (2) to gain additional insight into the apoptotic mechanism of cisplatin-induced ototoxicity. ALA pretreatment significantly reduced apoptotic cell death of the inner and outer hair cells in cisplatin-treated organ of Corti explants and attenuated ototoxicity via marked inhibition of the increase in the expression of IL-1β and IL-6, the phosphorylation of ERK and p38, the degradation of IκBα, the increase in intracellular levels of ROS, and the activation of caspase-3 in cisplatin-treated HEI-OC1 cells. This study represents the first histological evaluation of the organ of Corti following treatment with ALA, and these results indicate that the protective effects of ALA against cisplatin-induced ototoxicity are mediated via the regulation of MAPKs and proinflammatory cytokines.
authors.affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Jeongho
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Borum
authors.initials: B
authors.lastname: Sagong
authors.affiliation: Vestibulocochlear Research Center, Center for Metabolic Function Regulation and Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, Republic of Korea.
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Nuclear Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Jae-Tae
authors.initials: JT
authors.lastname: Lee
authors.affiliation: Vestibulocochlear Research Center, Center for Metabolic Function Regulation and Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, Republic of Korea.
authors.forename: Hong-Seob
authors.initials: HS
authors.lastname: So
authors.affiliation: Department of Internal Medicine, Research Institute of Aging and Metabolism, World Class University Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu, Republic of Korea. Electronic address: kimuk@knu.ac.kr.
authors.forename: Un-Kyung
authors.initials: UK
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Kyungpook National University, Daegu, Republic of Korea. Electronic address: kylee@knu.ac.kr.
authors.forename: Kyu-Yup
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Yon-Sik
authors.initials: YS
authors.lastname: Choo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D009925:Organ of Corti / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000072000:NF-KappaB Inhibitor alpha; D008063:Thioctic Acid; D053148:Caspase 3; D002945:Cisplatin
keywords: Alpha-lipoic acid; Cisplatin; Cochlear explant; MAPKs; Ototoxicity; Proinflammatory cytokines