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; Shuangba He; Renjie Chai

doi:10.3389/fnmol.2022.963083

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

Front Mol Neurosci. 2022 Aug 3:15:963083. doi: 10.3389/fnmol.2022.963083. eCollection 2022.

Authors

Yunhao Wu¹, Wei Meng², Ming Guan³, Xiaolong Zhao⁴, Chen Zhang⁵, Qiaojun Fang¹, Yuhua Zhang¹, Zihui Sun², Mingjing Cai², Dongdong Huang², Xuechun Yang⁶, Yafeng Yu⁷, Yong Cui^{6

8

9}, Shuangba He², Renjie Chai^{1

4

10

11

12}

Affiliations

¹ 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.
² Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, Nanjing Tongren Hospital, Southeast University, Nanjing, China.
³ Department of Otolaryngology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
⁵ 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.
⁶ Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
⁷ Department of Otolaryngology, First Affiliated Hospital of Soochow University, Suzhou, China.
⁸ The Second School of Clinical Medicine, South Medical University, Guangzhou, China.
⁹ School of Medicine, South China University of Technology, Guangzhou, China.
¹⁰ Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
¹¹ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
¹² Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, China.

Abstract

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.

Keywords: endoplasmic reticulum stress; hair cell; hearing loss; neomycin; pitavastatin.