Department of Speech and Hearing Science, The Ohio State University, 110 Pressey Hall, 1070 Carmack Road, Columbus, OH 43220, USA.
Neurosci Res. 2011 Dec;71(4):348-54. doi: 10.1016/j.neures.2011.07.1836. Epub 2011 Aug 5.
Apoptosis is a significant mechanism of cochlear hair cell loss from noise. Molecules that inhibit apoptotic intracellular signaling reduce cochlear damage and hearing loss from noise. The current study is an extension of a previous study of the protective value of Src-protein tyrosine kinase inhibitors against noise (Harris et al., 2005). The current study tested three Src-inhibitors: the indole-based KX1-141, the biaryl-based KX2-329, and the ATP-competitive KX2-328. Each of the three drugs was delivered into the chinchillas' cochleae by allowing the solutions to diffuse across the round window membrane thirty minutes prior to exposure to impulse noise. Hearing thresholds were measured using auditory evoked responses from electrodes in the inferior colliculi. Ears treated with KX2-329 showed significantly lower threshold shifts and outer hair cell losses than the control group. The cochleae treated with KX1-141 and KX2-328 did not show statistically significant protection from the impulse noise. The finding of protection with KX2-329 demonstrates that a biaryl-based Src inhibitor has protective capacity against noise-induced hearing loss that is as good as that demonstrated by KX1-004, a Src inhibitor drug that has been studied extensively as an otoprotectant against noise, and suggests that KX2-329 could be useful for protection against noise.
细胞凋亡是耳蜗毛细胞因噪声而丧失的一个重要机制。抑制细胞凋亡的内信号分子可减少噪声对耳蜗的损害和听力损失。本研究是对Src 蛋白酪氨酸激酶抑制剂对噪声保护作用的先前研究（Harris 等人，2005 年）的扩展。本研究测试了三种 Src 抑制剂：基于吲哚的 KX1-141、基于联苯的 KX2-329 和基于 ATP 的 KX2-328。在暴露于脉冲噪声前 30 分钟，通过让溶液扩散穿过圆窗膜，将这三种药物分别递送至沙鼠的耳蜗中。使用来自下丘电极的听觉诱发电位测量听力阈值。用 KX2-329 处理的耳朵与对照组相比，阈值移位和外毛细胞损失明显较低。用 KX1-141 和 KX2-328 处理的耳蜗没有显示出对脉冲噪声的统计学上显著保护作用。用 KX2-329 进行保护的发现表明，一种基于联苯的 Src 抑制剂对噪声性听力损失具有与 KX1-004 相当的保护能力，KX1-004 是一种作为噪声保护剂的 Src 抑制剂药物，已被广泛研究用于保护听力免受噪声的影响，这表明 KX2-329 可能对噪声保护有用。
