Department of Otorhinolaryngology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China.
Neurotox Res. 2012 Aug;22(2):158-69. doi: 10.1007/s12640-012-9320-0. Epub 2012 Apr 3.
Ouabain, a potent inhibitor of the Na+/K+-ATPase pump, selectively destroys spiral ganglion neurons (SGNs) in gerbils and mice, whereas in guinea pigs it preferentially damages cochlear hair cells. To elucidate the effects of ouabain on the rat inner ear, a species widely used in research, 5 μl of 1 or 10 mM ouabain was applied to the round window membrane. Distortion product otoacoustic emissions (DPOAE) and auditory brainstem responses (ABR) were used to identify functional deficits in hair cells and neurons, respectively, and histological techniques were used to characterize cochlear pathologies. High-frequency ABR thresholds were elevated after treatment with 1 mM ouabain, whereas DPOAEs remained normal. In contrast, 10 mM ouabain increased ABR thresholds and reduced DPOAE amplitudes. Consistent with the physiological changes, 1 mM ouabain only damaged the SGNs and auditory nerve fibers in the basal turn of the cochlea whereas 10 mM ouabain destroyed both SGNs and cochlear hair cells; damage was greatest near the base and decreased toward the apex. The nuclei of degenerating SGNs and hair cells were condensed and fragmented and many cells were TUNEL-positive, morphological features of apoptotic cell death. Thus, ouabain-induced cochlear degeneration in rats is apoptotic and concentration dependent; low concentrations preferentially damage SGNs in the base of the cochlea, producing an animal model of partial auditory neuropathy, whereas high concentrations damage both hair cells and SGNs with damage decreasing from the base toward the apex.
哇巴因是一种强效的 Na+/K+-ATP 酶泵抑制剂,可选择性地破坏沙鼠和小鼠的螺旋神经节神经元(SGN),而在豚鼠中,它优先损害耳蜗毛细胞。为了阐明哇巴因对大鼠内耳的影响,一种广泛用于研究的物种,将 1 或 10 mM 的哇巴因 5 μl 应用于圆窗膜。使用畸变产物耳声发射(DPOAE)和听性脑干反应(ABR)分别识别毛细胞和神经元的功能缺陷,并用组织学技术来描述耳蜗病理学。用 1 mM 哇巴因处理后高频 ABR 阈值升高,而 DPOAE 保持正常。相比之下,10 mM 的哇巴因增加了 ABR 阈值并降低了 DPOAE 幅度。与生理变化一致,1 mM 的哇巴因仅损伤耳蜗底部的 SGNs 和听神经纤维,而 10 mM 的哇巴因则破坏了 SGNs 和耳蜗毛细胞;损伤在基底附近最大,向顶点逐渐减少。变性 SGNs 和毛细胞的细胞核浓缩和碎片化,许多细胞呈 TUNEL 阳性,这是细胞凋亡的形态特征。因此,哇巴因诱导的大鼠耳蜗退行性变是凋亡性的且与浓度有关;低浓度优先损伤耳蜗底部的 SGNs,产生部分听觉神经病的动物模型,而高浓度则损伤毛细胞和 SGNs,损伤从基底向顶点逐渐减少。