Pre-treatment With Fasudil Prevents Neomycin-Induced Hair Cell Damage by Reducing the Accumulation of Reactive Oxygen Species
Pre-treatment With Fasudil Prevents Neomycin-Induced Hair Cell Damage by Reducing the Accumulation of Reactive Oxygen Species
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DOI：
10.3389/fnmol.2019.00264
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发表时间：
2019-11
影响因子：
4.8
通讯作者：
Yanqiu Zhang;Wei Li;Zuhong He;Yunfeng Wang;Buwei Shao;Cheng Cheng-Cheng;Shasha Zhang;Mingliang Tang
中科院分区：
文献类型：
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作者：
Yanqiu Zhang;Wei Li;Zuhong He;Yunfeng Wang;Buwei Shao;Cheng Cheng-Cheng;Shasha Zhang;Mingliang Tang
感音神经性聋是人类最常见的感觉障碍之一，耳毒性药物引起的毛细胞损伤是其主要原因之一。氨基糖苷类抗生素是常见的耳毒性药物，可引起毛细胞内氧自由基积聚，导致毛细胞凋亡。法舒地尔是一种Rho激酶抑制剂和血管扩张剂，已被广泛应用于临床，并已被证明具有神经保护作用。然而，尚未研究法舒地尔在预防氨基糖苷类药物诱导的HC损失和听力损失方面的可能应用。在这项研究中，我们研究了法舒地尔在体外和体内对新霉素诱导的HC损失的保护能力。我们发现，法舒地尔显着减少耳蜗全器官外植体培养的HC损失，并减少新霉素暴露后的听觉HEI-OC 1细胞的细胞死亡。此外，我们发现法舒地尔在体内新霉素损伤模型中显著预防小鼠的HC损失和听力损失。此外，我们发现，法舒地尔可以显着抑制Rho信号通路在听觉HEI-OC 1细胞后，新霉素暴露，从而进一步减少活性氧的积累和随后的凋亡HEI-OC 1细胞。这项研究表明，法舒地尔可能有助于通过抑制Rho信号通路增加新霉素暴露后HC的活力，并提出了一个新的治疗靶点，用于预防氨基糖苷类诱导的HC丧失和听力损失。
Ototoxic drug-induced hair cell (HC) damage is one of the main causes of sensorineural hearing loss, which is one of the most common sensory disorders in humans. Aminoglycoside antibiotics are common ototoxic drugs, and these can cause the accumulation of intracellular oxygen free radicals and lead to apoptosis in HCs. Fasudil is a Rho kinase inhibitor and vasodilator that has been widely used in the clinic and has been shown to have neuroprotective effects. However, the possible application of fasudil in protecting against aminoglycoside-induced HC loss and hearing loss has not been investigated. In this study, we investigated the ability of fasudil to protect against neomycin-induced HC loss both in vitro and in vivo. We found that fasudil significantly reduced the HC loss in cochlear whole-organ explant cultures and reduced the cell death of auditory HEI-OC1 cells after neomycin exposure in vitro. Moreover, we found that fasudil significantly prevented the HC loss and hearing loss of mice in the in vivo neomycin damage model. Furthermore, we found that fasudil could significantly inhibit the Rho signaling pathway in the auditory HEI-OC1 cells after neomycin exposure, thus further reducing the neomycin-induced accumulation of reactive oxygen species and subsequent apoptosis in HEI-OC1 cells. This study suggests that fasudil might contribute to the increased viability of HCs after neomycin exposure by inhibition of the Rho signaling pathway and suggests a new therapeutic target for the prevention of aminoglycoside-induced HC loss and hearing loss.