Astaxanthine attenuates cisplatin ototoxicity in vitro and protects against cisplatin-induced hearing loss in vivo  

作　　者：Benyu Nan Zirui Zhao Kanglun Jiang Xi Gu Huawei Li Xinsheng Huang 

机构地区：[1]Department of Otorhinolaryngology-Head and Neck Surgery,Zhongshan Hospital,Fudan University,Shanghai 200030,China [2]Department of Otorhinolaryngology-Head and Neck Surgery,Wenzhou Medical University,Affiliated Hospital 2,Wenzhou 325000,China [3]Department of Otolaryngology,Yueyang Hospital of Integrated Traditional Chinese and Western Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai 200437,China [4]Department of Otolaryngology,the First Affiliated Hospital of Fujian Medical University,Fuzhou 350005,China [5]ENT Institute and Department of Otorhinolaryngology,Eye&ENT Hospital,State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science,Fudan University,Shanghai 200031,China [6]Institutes of Biomedical Sciences,Fudan University,Shanghai 200031,China [7]NHC Key Laboratory of Hearing Medicine(Fudan University),Shanghai 200031,China [8]The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science,Fudan University,Shanghai 200031,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第1期167-181,共15页药学学报（英文版）

基　　金：financial support by the National Natural Science Foundation of China(82000980)。

摘　　要：Astaxanthine(AST) has important biological activities including antioxidant and antiinflammatory effects that could alleviate neurological and heart diseases, but its role in the prevention of cisplatin-induced hearing loss(CIHL) is not yet well understood. In our study, a steady interaction between AST and the E3 ligase adapter Kelch-like ECH-associated protein 1, a predominant repressor of nuclear factor erythroid 2-related factor 2(NRF2), was performed and tested via computer molecular docking and dynamics. AST protected against cisplatin-induced ototoxicity via NRF2 mediated pathwayusing quantitative PCR and Western blotting. The levels of reactive oxygen species(ROS) and mitochondrial membrane potential revealed that AST reduced ROS overexpression and mitochondrial dysfunction.Moreover, AST exerted anti-apoptosis effects in mouse cochlear explants using immunofluorescence staining and HEI-OC1 cell lines using quantitative PCR and Western blotting. Finally, AST combined with poloxamer was injected into the middle ear through the tympanum, and the protection against CIHL was evaluated using the acoustic brain stem test and immunofluorescent staining in adult mice. Our results suggest that AST reduced ROS overexpression, mitochondrial dysfunction, and apoptosis via NRF2-mediated pathway in cisplatin-exposed HEI-OC1 cell lines and mouse cochlear explants, finally promoting cell survival. Our study demonstrates that AST is a candidate therapeutic agent for CIHL.

关 键 词：Astaxanthine CISPLATIN Hearing loss Mitochondrial OTOTOXICITY Reactive oxygen species Apoptosis 

分 类 号：R764[医药卫生—耳鼻咽喉科]