Research Service, VA Loma Linda Healthcare System, CA 92357, USA.
Research Service, VA Loma Linda Healthcare System, CA 92357, USA; Department of Otolaryngology - Head and Neck Surgery, Loma Linda University Health, Loma Linda, CA 92354, USA.
Neurotoxicology. 2021 May;84:73-83. doi: 10.1016/j.neuro.2021.02.007. Epub 2021 Mar 2.
It is well-established that aminoglycoside antibiotics are ototoxic, and the toxicity can be drastically enhanced by the addition of loop diuretics, resulting in rapid irreversible hair cell damage. Using both electrophysiologic and morphological approaches, we investigated whether this combined treatment affected the cochlea at the region of ribbon synapses, consequently resulting in auditory synaptopathy. A series of varied gentamicin and furosemide doses were applied to C57BL/6 mice, and auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE) were measured to assess ototoxic damage within the cochlea. In brief, the treatment effectively induced cochlear damage and promoted a certain reorganization of synaptic ribbons, while a reduction of ribbon density only occurred after a substantial loss of outer hair cells. In addition, both the ABR wave I amplitude and the ribbon density were elevated in low-dose treatment conditions, but a correlation between the two events was not significant for individual cochleae. In sum, combined gentamicin and furosemide treatment, at titrated doses below those that produce hair cell damage, typically triggers synaptic plasticity rather than a permanent synaptic loss.
已证实，氨基糖苷类抗生素具有耳毒性，而加入利尿剂可极大增强其毒性，导致毛细胞迅速不可逆地损伤。我们采用电生理和形态学方法研究了这种联合治疗是否会影响到具有 ribbon 突触的耳蜗区域，进而导致听觉突触病。用一系列不同剂量的庆大霉素和呋塞米处理 C57BL/6 小鼠，测量听觉脑干反应（ABR）和畸变产物耳声发射（DPOAE），以评估耳蜗内的耳毒性损伤。简单来说，该治疗有效诱导了耳蜗损伤，并促进了突触 ribbon 的一定程度的重组，而 ribbon 密度的降低仅在外毛细胞大量丢失后才会发生。此外，在低剂量处理条件下，ABR 波 I 幅度和 ribbon 密度均升高，但对于单个耳蜗，两者之间没有显著相关性。总的来说，在不会引起毛细胞损伤的滴定剂量下，庆大霉素和呋塞米联合治疗通常会引发突触可塑性，而不是永久性的突触丢失。
