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

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 amin...

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Published inFrontiers in molecular neuroscience Vol. 15; p. 963083
Main Authors Wu, Yunhao, Meng, Wei, Guan, Ming, Zhao, Xiaolong, Zhang, Chen, Fang, Qiaojun, Zhang, Yuhua, Sun, Zihui, Cai, Mingjing, Huang, Dongdong, Yang, Xuechun, Yu, Yafeng, Cui, Yong, He, Shuangba, Chai, Renjie
Format Journal Article
LanguageEnglish
Published Lausanne Frontiers Research Foundation 03.08.2022
Frontiers Media S.A
Subjects
Aminoglycoside antibiotics
Antibiotics
Antibodies
Apoptosis
Brain stem
Cochlea
Coenzyme A
Endoplasmic reticulum
endoplasmic reticulum stress
Explants
Flow cytometry
Fluorides
hair cell
Hair cells
Hearing loss
Homeostasis
Hydroxymethylglutaryl-CoA reductase
Inner ear
Neomycin
Neuroprotection
Neuroscience
Ototoxicity
pitavastatin
Proteins
Rho-associated kinase
RhoA protein
Variance analysis
Germany
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Summary: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.
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This article was submitted to Methods and Model Organisms, a section of the journal Frontiers in Molecular Neuroscience
Reviewed by: Yan Chen, Fudan University, China; Yaodong Dong, ShengJing Hospital of China Medical University, China; Yunfeng Wang, Fudan University, China
These authors have contributed equally to this work
Edited by: Yu Sun, Huazhong University of Science and Technology, China
ISSN:1662-5099
1662-5099
DOI:10.3389/fnmol.2022.963083