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 

机构地区：[1]ENT Institute and Otorhinolaryngology Department of Eye&ENT Hospital,State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science,Fudan University,Shanghai 200031,China [2]NHC Key Laboratory of Hearing Medicine(Fudan University),Shanghai 200031,China [3]Department of Otolaryngology and Institute of Translational Medicine,Shenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center,Shanghai 200032,China [4]Institutes of Biomedical Sciences,Fudan University,Shanghai 200032,China [5]The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science,Fudan University,Shenzhen 518035,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第3期1305-1321,共17页药学学报（英文版）

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)。

摘　　要：Cisplatin-related ototoxicity is a critical side effect of chemotherapy and can lead to irreversible hearing loss.This study aimed to assess the potential effect of the DNA methyltransferase(DNMT)inhibitor RG108 on cisplatin-induced ototoxicity.Immunohistochemistry,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)assessment.Reactive oxygen species(ROS)amounts were evaluated by Cellrox green and Mitosox-red probes.Mitochondrial 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 accumulation.Furthermore,RG108 upregulated BCL-2 and downregulated APAF1,BAX,and BAD in HEI-OC1 cells,and triggered the PI3K/AKT pathway.Decreased expression of low-density lipoprotein receptor-related protein 1(LRP1)and high methylation of the LRP1 promoter were observed after cisplatin treatment.RG108 treatment can increase LRP1expression and decrease LRP1 promoter methylation.In conclusion,RG108 might represent a new potential agent for preventing hearing loss induced by cisplatin via activating the LRP1-PI3K/AKT pathway.

关 键 词：CISPLATIN DNMT Apoptosis Hair cell Spiral ganglion neurons RG108 Mitochondrial dysfunction ROS 

分 类 号：R965[医药卫生—药理学]