Mechanisms of Cisplatin-Induced Ototoxicity and Otoprotection.
Mechanisms of Cisplatin-Induced Ototoxicity and Otoprotection.
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DOI：
10.3389/fncel.2017.00338
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发表时间：
2017
影响因子：
5.3
通讯作者：
Ramkumar V
中科院分区：
文献类型：
--
作者：
Sheth S;Mukherjea D;Rybak LP;Ramkumar V
在癌症患者使用顺铂作为化疗剂的早期，有证据表明听力损失严重，这刺激了对这种副作用的原因和治疗的研究。人们普遍认为，耳蜗细胞内活性氧（reactive oxygen species，ROS）的过度产生是导致听力损失的重要原因，因此，抗氧化剂被开发出来作为耳保护剂。后来的研究表明，ROS可以刺激耳蜗炎症，提示使用抗炎剂治疗听力损失。在这方面，G蛋白偶联受体，如腺苷A1受体和大麻素2受体，通过增加ROS清除、抑制ROS产生或通过减少炎症，在治疗实验动物的听力损失中显示出功效。炎症可以通过激活耳蜗中的瞬时受体电位香草酸1（TRPV1）通道和可能的其他TRP通道来触发。靶向TRPV1进行敲低也已被证明是确保耳保护的有用策略。顺铂进入耳蜗毛细胞是由各种转运蛋白介导的，其抑制剂已被证明对治疗听力损失有效。最后，顺铂诱导的DNA损伤和细胞凋亡过程的激活可能是顺铂诱导的听力损失的靶点。本文综述了顺铂引起听力损失的机制的最新进展，并提供了如何根据这些机制制定药物治疗的例子。
Evidence of significant hearing loss during the early days of use of cisplatin as a chemotherapeutic agent in cancer patients has stimulated research into the causes and treatment of this side effect. It has generally been accepted that hearing loss is produced by excessive generation of reactive oxygen species (ROS) in cell of the cochlea, which led to the development of various antioxidants as otoprotective agents. Later studies show that ROS could stimulate cochlear inflammation, suggesting the use of anti-inflammatory agents for treatment of hearing loss. In this respect, G-protein coupled receptors, such as adenosine A1 receptor and cannabinoid 2 receptors, have shown efficacy in the treatment of hearing loss in experimental animals by increasing ROS scavenging, suppressing ROS generation, or by decreasing inflammation. Inflammation could be triggered by activation of transient receptor potential vanilloid 1 (TRPV1) channels in the cochlea and possibly other TRP channels. Targeting TRPV1 for knockdown has also been shown to be a useful strategy for ensuring otoprotection. Cisplatin entry into cochlear hair cells is mediated by various transporters, inhibitors of which have been shown to be effective for treating hearing loss. Finally, cisplatin-induced DNA damage and activation of the apoptotic process could be targeted for cisplatin-induced hearing loss. This review focuses on recent development in our understanding of the mechanisms underlying cisplatin-induced hearing loss and provides examples of how drug therapies have been formulated based on these mechanisms.
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影响因子：
2.8
作者：
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通讯作者：
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