Circadian vulnerability of cisplatin-induced ototoxicity in the cochlea.
Circadian vulnerability of cisplatin-induced ototoxicity in the cochlea.
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DOI：
10.1096/fj.202001236r
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Canlon B
中科院分区：
文献类型：
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作者：
Tserga E;Moreno-Paublete R;Sarlus H;Björn E;Guimaraes E;Göritz C;Cederroth CR;Canlon B
化疗药物顺铂以其耳毒性作用而闻名。虽然耳蜗中的毛细胞是顺铂的既定靶点，但对传入突触的了解较少，传入突触是声音在时间上的忠实传输的重要组成部分。谷氨酸转运蛋白(GLAST)保护听觉突触免受谷氨酸过度释放的影响，其功能的丧失增加了对噪声、水杨酸和氨基糖苷类物质的易感性。到目前为止，GLAST在顺铂介导的耳毒性中的作用尚不清楚。在这里，我们在缺乏GLAST的小鼠身上测试了一种已知不会导致听力阈值任何可检测到变化的低剂量顺铂的效果。在夜间给药时，在GLAST KO小鼠中发现了轻微的听力损失，但在白天没有发现，这揭示了顺铂介导的耳毒性的易感性的潜在的昼夜调节。我们发现，与WT小鼠和非活动阶段(白天)的治疗相比，GLAST KO小鼠的听觉突触在活动阶段(夜间)更容易受到顺铂治疗的影响。这种作用与耳蜗铂化合物的丰度无关，顺铂只有在夜间给药后才对耳蜗钟节律产生剂量依赖性的影响，提示顺铂可以调节分子钟。我们的发现表明，目前顺铂在白天给药的方案可能会对听觉突触造成尚未检测到的损害，对已经受损的耳朵更是如此，并严重影响癌症幸存者的听觉敏感度。
The chemotherapeutic agent cisplatin is renowned for its ototoxic effects. While hair cells in the cochlea are established targets of cisplatin, less is known regarding the afferent synapse, which is an essential component in the faithful temporal transmission of sound. The glutamate aspartate transporter (GLAST) shields the auditory synapse from excessive glutamate release, and its loss of function increases the vulnerability to noise, salicylate and aminoglycosides. Until now, the involvement of GLAST in cisplatin-mediated ototoxicity remains unknown. Here, we test in mice lacking GLAST the effects of a low-dose cisplatin known not to cause any detectable change in hearing thresholds. When administered at nighttime, a mild hearing loss in GLAST KO mice was found but not at daytime, revealing a potential circadian regulation of the vulnerability to cisplatin-mediated ototoxicity. We show that the auditory synapse of GLAST KO mice is more vulnerable to cisplatin administration during the active phase (nighttime) when compared to WT mice and treatment during the inactive phase (daytime). This effect was not related to the abundance of platinum compounds in the cochlea, rather cisplatin had a dose-dependent impact on cochlear clock rhythms only after treatment at nighttime suggesting that cisplatin can modulate the molecular clock. Our findings suggest that the current protocols of cisplatin administration in humans during daytime may cause a yet undetectable damage to the auditory synapse, more so in already damaged ears, and severely impact auditory sensitivity in cancer survivors.