Novel compounds protect auditory hair cells against gentamycin-induced apoptosis by maintaining the expression level of H3K4me2

Drug Delivery

Dan You¹  Yingzi He¹  Yan Chen¹  Wenyan Li¹  Wen Li¹  Shan Sun¹  Ao Li²  Huawei Li³  Renjie Chai⁴  Yingjie Cui⁵  Xiao Feng⁵ 

[1] ENT Institute and Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, Key Laboratory of Hearing Medicine of NHFPC, Shanghai Engineering Research Centre of Cochlear Implant, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China;ENT Institute and Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, Key Laboratory of Hearing Medicine of NHFPC, Shanghai Engineering Research Centre of Cochlear Implant, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China;Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Research Institution of Otorhinolaryngology, Jiangsu Provincial Key Medical Discipline (Laboratory), Nanjing, China;ENT Institute and Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, Key Laboratory of Hearing Medicine of NHFPC, Shanghai Engineering Research Centre of Cochlear Implant, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China;Institutes of Biomedical Sciences and The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, Chin;Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Institute of Life Sciences, Southeast University, Nanjing, China;Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China;Knowshine (Shanghai) Pharmaceuticals Inc, Shanghai, China;

关键词: Apoptosis;    gentamycin;    H3K4me2;    hair cell;    compounds;   

DOI  :  10.1080/10717544.2018.1461277

来源: publisher

【 摘 要 】

Aminoglycoside-induced hair cell (HC) loss is a major cause of hearing impairment, and the effective prevention of HC loss remains an unmet medical need. Epigenetic mechanisms have been reported to be involved in protecting cochlear cells against ototoxic drug injury, and in this study we developed new bioactive compounds that have similar chemical structures as the epigenetics-related lysine-specific demethylase 1 (LSD1) inhibitors. LSD1 inhibitors have been reported to protect cochlear cells by preventing demethylation of dimethylated histone H3K4 (H3K4me2). To determine whether these new compounds exert similar protective effects on HCs, we treated mouse cochlear explant cultures with the new compounds together with gentamycin. There was a severe loss of HCs in the organ of Corti after gentamycin exposure, while co-treatment with the new compounds significantly protected against gentamycin-induced HC loss. H3K4me2 levels in the nuclei of HCs decreased after exposure to gentamycin, but H3K4me2 levels were maintained in the presence of the new compounds. Apoptosis is also involved in the injury process, and the new compounds protected the inner ear HCs against apoptosis by reducing caspase-3 activation. Together, our findings demonstrate that our new compounds prevent gentamycin-induced HC loss by preventing the demethylation of H3K4me2 and by inhibiting apoptosis, and these results might provide the theoretical basis for novel drug development for hearing protection.

【 授权许可】

CC BY