Enhancing autophagy by down-regulating GSK-3β alleviates cisplatin-induced ototoxicity in vivo and in vitro

• Published in: Toxicology letters 2019-10, Vol.313, p.11-18
• Main Authors: Liu, Tianyi, Zong, Shimin, Luo, Pan, Qu, Yanji, Wen, Yingying, Du, Peiyu, Xiao, Hongjun
• Format: Article
• Language: English
• Subjects: 3-MA; Autophagy; Cisplatin; Glycogen synthase kinase 3β; Ototoxicity
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2019.05.025

•Accompanied by hearing protection, autophagy was enhanced in outer hair cells of rat cochlea after GSK3β inhibition.•Suppression of autophagy can reverse the protective effect of GSK3β inhibition on cisplatin-induced ototoxicity in HEI-OC1 cell lines.•Enhancing autophagy may be an important downstream pathway in the protective effects of GSK3β inhibition on cisplatin-induced ototoxicity. Previous study reported that either selective GSK-3β inhibitor or up-regulating autophagy can alleviate cisplatin-induced ototoxicity. Other studies indicate that the activity of GSK-3β is closely associated with the autophagy level. The purpose of this study is to primarily explore the role of autophagy in the alleviation effect of GSK-3β inhibition on cisplatin-induced ototoxicity in vivo and in vitro. We observed the autophagy changes induced by GSK-3β inhibitor in outer hair cells (OHCs) in a cisplatin-induced ototoxicity rat model. In addition, autophagy inhibitor 3-MA was used in vitro experiments to observe the influence of autophagy inhibition on the cell protection effect due to GSK-3β inactivation. The relationship among autophagy, GSK-3β and cell damage were inferred. Negative regulation of GSK-3β significantly enhanced autophagy and alleviated cisplatin-induced hearing loss, OHC death in vivo and apoptosis in vitro. The autophagy inhibitor 3-MA inverted the protective effect of negative regulation of GSK-3β. These results indicated that enhancing autophagy may be a key downstream effect of GSK-3β inhibition in the alleviation of cisplatin-induced ototoxicity both in vivo and in vitro.