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
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.
Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, Nanjing Tongren Hospital, Southeast University, Nanjing, China.
Front Mol Neurosci. 2022 Aug 3;15:963083. doi: 10.3389/fnmol.2022.963083. eCollection 2022.
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.
氨基糖苷类抗生素引起的内耳毛细胞不可逆损伤会导致感音神经性听力损失的形成。匹伐他汀（PTV）是一种3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，据报道具有神经保护作用。然而，其在氨基糖苷类药物所致听力损失中的作用尚不清楚。本研究的目的是探讨PTV对新霉素诱导的耳毒性的有益作用及其作用机制。我们发现，PTV显著减少了小鼠耳蜗外植体中的毛细胞损失，并促进了新霉素刺激后听觉HEI-OC1细胞的存活。我们还观察到，新霉素升高的听觉脑干反应阈值在小鼠中通过PTV预处理显著降低。此外，PTV处理通过抑制PERK/eIF2α/ATF4信号通路减轻了新霉素诱导的毛细胞内质网应激。此外，我们发现PTV抑制了HEI-OC1细胞中由新霉素刺激激活的RhoA/ROCK/JNK信号通路。总的来说，我们的结果表明，PTV可能是一种有前途的抗氨基糖苷类耳毒性治疗药物。
