Pitavastatin protects against neomycin-induced ototoxicity through inhibition of endoplasmic reticulum stress

Yunhao Wu; Wei Meng; Ming Guan; Xiaolong Zhao; Chen Zhang; Qiaojun Fang; Yuhua Zhang; Zihui Sun; Mingjing Cai; Dongdong Huang; Xuechun Yang; Yafeng Yu; Yong Cui; Yong Cui; Yong Cui; Shuangba He; Renjie Chai; Renjie Chai; Renjie Chai; Renjie Chai; Renjie Chai

doi:10.3389/fnmol.2022.963083

Frontiers in Molecular Neuroscience (Aug 2022)

Pitavastatin protects against neomycin-induced ototoxicity through inhibition of endoplasmic reticulum stress

Yunhao Wu,
Wei Meng,
Ming Guan,
Xiaolong Zhao,
Chen Zhang,
Qiaojun Fang,
Yuhua Zhang,
Zihui Sun,
Mingjing Cai,
Dongdong Huang,
Xuechun Yang,
Yafeng Yu,
Yong Cui,
Yong Cui,
Yong Cui,
Shuangba He,
Renjie Chai,
Renjie Chai,
Renjie Chai,
Renjie Chai,
Renjie Chai

Affiliations

Yunhao Wu: State Key Laboratory of Bioelectronics, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Department of Otolaryngology Head and Neck Surgery, School of Life Sciences and Technology, Zhongda Hospital, Advanced Institute for Life and Health, Southeast University, Nanjing, China
Wei Meng: Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, Nanjing Tongren Hospital, Southeast University, Nanjing, China
Ming Guan: Department of Otolaryngology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
Xiaolong Zhao: Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
Chen Zhang: Beijing Key Laboratory of Neural Regeneration and Repair, Department of Neurobiology, Advanced Innovation Center for Human Brain Protection, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Qiaojun Fang: State Key Laboratory of Bioelectronics, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Department of Otolaryngology Head and Neck Surgery, School of Life Sciences and Technology, Zhongda Hospital, Advanced Institute for Life and Health, Southeast University, Nanjing, China
Yuhua Zhang: State Key Laboratory of Bioelectronics, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Department of Otolaryngology Head and Neck Surgery, School of Life Sciences and Technology, Zhongda Hospital, Advanced Institute for Life and Health, Southeast University, Nanjing, China
Zihui Sun: Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, Nanjing Tongren Hospital, Southeast University, Nanjing, China
Mingjing Cai: Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, Nanjing Tongren Hospital, Southeast University, Nanjing, China
Dongdong Huang: Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, Nanjing Tongren Hospital, Southeast University, Nanjing, China
Xuechun Yang: Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
Yafeng Yu: Department of Otolaryngology, First Affiliated Hospital of Soochow University, Suzhou, China
Yong Cui: Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
Yong Cui: The Second School of Clinical Medicine, South Medical University, Guangzhou, China
Yong Cui: School of Medicine, South China University of Technology, Guangzhou, China
Shuangba He: Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, Nanjing Tongren Hospital, Southeast University, Nanjing, China
Renjie Chai: State Key Laboratory of Bioelectronics, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Department of Otolaryngology Head and Neck Surgery, School of Life Sciences and Technology, Zhongda Hospital, Advanced Institute for Life and Health, Southeast University, Nanjing, China
Renjie Chai: Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
Renjie Chai: 0Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
Renjie Chai: 1Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
Renjie Chai: 2Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, China

DOI: https://doi.org/10.3389/fnmol.2022.963083
Journal volume & issue: Vol. 15

Abstract

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Irreversible injury to inner ear hair cells induced by aminoglycoside antibiotics contributes to the formation of sensorineural hearing loss. Pitavastatin (PTV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been reported to exert neuroprotective effects. However, its role in aminoglycoside-induced hearing loss remains unknown. The objectives of this study were to investigate the beneficial effects, as well as the mechanism of action of PTV against neomycin-induced ototoxicity. We found that PTV remarkably reduced hair cell loss in mouse cochlear explants and promoted auditory HEI-OC1 cells survival after neomycin stimulation. We also observed that the auditory brainstem response threshold that was increased by neomycin was significantly reduced by pretreatment with PTV in mice. Furthermore, neomycin-induced endoplasmic reticulum stress in hair cells was attenuated by PTV treatment through inhibition of PERK/eIF2α/ATF4 signaling. Additionally, we found that PTV suppressed the RhoA/ROCK/JNK signal pathway, which was activated by neomycin stimulation in HEI-OC1 cells. Collectively, our results showed that PTV might serve as a promising therapeutic agent against aminoglycoside-induced ototoxicity.

Published in Frontiers in Molecular Neuroscience

ISSN: 1662-5099 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.frontiersin.org/journals/molecular-neuroscience

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