Department of Otorhinolaryngology, Xiangya Hospital Central South University, Changsha, PR China; Province Key Laboratory of Otolaryngology Critical Diseases, Changsha, PR China; Department of Geriatrics, National Clinical Research Centre for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, PR China.
Department of Otorhinolaryngology, Xiangya Hospital Central South University, Changsha, PR China; Province Key Laboratory of Otolaryngology Critical Diseases, Changsha, PR China; Department of Geriatrics, National Clinical Research Centre for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, PR China; Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, PR China.
Hear Res. 2023 Dec;440:108910. doi: 10.1016/j.heares.2023.108910. Epub 2023 Nov 4.
Aminoglycoside antibiotics are among the most common agents that can cause sensorineural hearing loss. From clinical experience, premature babies, whose inner ear is still developing, are more susceptible to aminoglycoside-induced ototoxicity, which is echoed by our previous study carried out in organotypic cultures. This study aimed to investigate whether a nonselective cation channel, TRPV1, contributes to the susceptibility of immature spiral ganglion neurons (SGNs) to the damage caused by aminoglycosides. Through western blotting and immunofluorescence, we found that the TRPV1 expression levels were much higher in immature SGNs than in their mature counterparts. In postnatal day 7 cochlear organotypic cultures, AMG-517 reduced reactive oxygen species generation and inhibited SGN apoptosis under aminoglycoside challenge. However, in adult mice, AMG-517 did not ameliorate the ABR threshold increase at high frequencies (16 kHz and 32 kHz) after aminoglycoside administration, and the SGNs within the cochleae had no morphological changes. By further regulating the function of TRPV1 in primary cultured SGNs with its inhibitor AMG-517 and agonist capsaicin, we demonstrated that TRPV1 is a major channel for aminoglycoside uptake: AMG-517 can significantly reduce, while capsaicin can significantly increase, the uptake of GTTR. In addition, TRPV1 knockdown in SGNs can also significantly reduce the uptake of GTTR. Taken together, our results demonstrated that aminoglycosides can directly enter immature SGNs through the TRPV1 channel. High expression of TRPV1 contributes to the susceptibility of immature SGNs to aminoglycoside-induced damage. The TRPV1 inhibitor AMG-517 has the potential to be a therapeutic agent for preventing aminoglycoside-induced ototoxicity in immature SGNs.
氨基糖苷类抗生素是最常见的导致感音神经性听力损失的药物之一。从临床经验来看，内耳仍在发育的早产儿更容易受到氨基糖苷类药物引起的耳毒性的影响，我们之前在器官型培养物中进行的研究也证实了这一点。本研究旨在探讨非选择性阳离子通道 TRPV1 是否有助于未成熟螺旋神经节神经元 (SGN) 对氨基糖苷类药物损伤的敏感性。通过 Western blot 和免疫荧光，我们发现未成熟 SGN 中的 TRPV1 表达水平明显高于成熟 SGN。在出生后 7 天的耳蜗器官型培养物中，AMG-517 可减少活性氧的产生并抑制氨基糖苷类药物刺激下 SGN 的凋亡。然而，在成年小鼠中，AMG-517 并不能改善氨基糖苷类药物给药后高频（16 kHz 和 32 kHz）ABR 阈值的升高，并且耳蜗内的 SGN 没有形态变化。通过进一步用其抑制剂 AMG-517 和激动剂辣椒素调节原代培养 SGN 中 TRPV1 的功能，我们证明 TRPV1 是氨基糖苷类摄取的主要通道：AMG-517 可显著减少，而辣椒素可显著增加 GTTR 的摄取。此外，SGN 中的 TRPV1 敲低也可以显著减少 GTTR 的摄取。总之，我们的结果表明，氨基糖苷类可以通过 TRPV1 通道直接进入未成熟的 SGN。TRPV1 的高表达有助于未成熟 SGN 对氨基糖苷类药物诱导损伤的敏感性。TRPV1 抑制剂 AMG-517 有可能成为预防未成熟 SGN 氨基糖苷类耳毒性的治疗药物。
