Inhibiting DNA methylation alleviates cisplatininduced hearing loss by decreasing oxidative stress-induced mitochondria-dependent apoptosis via the LRP1-PI3K/AKT pathway

作     者：Yingzi He Zhiwei Zheng Chang Liu Wen Li Liping Zhao Guohui Nie Huawei Li 

作者机构：ENT Institute and Otorhinolaryngology Department of Eye&ENT HospitalState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceFudan UniversityShanghai 200031China NHC Key Laboratory of Hearing Medicine(Fudan University)Shanghai 200031China Department of Otolaryngology and Institute of Translational MedicineShenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science CenterShanghai 200032China Institutes of Biomedical SciencesFudan UniversityShanghai 200032China The Institutes of Brain Science and the Collaborative Innovation Center for Brain ScienceFudan UniversityShenzhen 518035China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2022年第12卷第3期

页      面：1305-1321页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：was supported by grants from the National Key R&D Program of China(No.2017YFA0103900) the National Natural Science Foundation of China(Nos.82071045,81870728,81830029,and 81970875) Shanghai Rising-Star Program(19QA1401800) 

主　　题：Cisplatin DNMT Apoptosis Hair cell Spiral ganglion neurons RG108 Mitochondrial dysfunction ROS 

摘      要：Cisplatin-related ototoxicity is a critical side effect of chemotherapy and can lead to irreversible hearing *** study aimed to assess the potential effect of the DNA methyltransferase(DNMT)inhibitor RG108 on cisplatin-induced ***,apoptosis assay,and auditory brainstem response(ABR)were employed to determine the impacts of RG108 on cisplatin-induced injury in murine hair cells(HCs)and spiral ganglion neurons(SGNs).Rhodamine 123 and TMRM were utilized for mitochondrial membrane potential(MMP)*** oxygen species(ROS)amounts were evaluated by Cellrox green and Mitosox-red *** respiratory function evaluation was performed by determining oxygen consumption rates(OCRs).The results showed that RG108 can markedly reduce cisplatin induced damage in HCs and SGNs,and alleviate apoptotic rate by protecting mitochondrial function through preventing ROS ***,RG108 upregulated BCL-2 and downregulated APAF1,BAX,and BAD in HEI-OC1 cells,and triggered the PI3K/AKT *** expression of low-density lipoprotein receptor-related protein 1(LRP1)and high methylation of the LRP1 promoter were observed after cisplatin ***108 treatment can increase LRP1expression and decrease LRP1 promoter *** conclusion,RG108 might represent a new potential agent for preventing hearing loss induced by cisplatin via activating the LRP1-PI3K/AKT pathway.