Department of Otolaryngology Head and Neck Surgery, Xiang Ya Hospital, Central South University, Changsha, Hunan, 410013, China.
Center for Hearing and Deafness, University at Buffalo, 137 Cary Hall, Buffalo, NY, 14214, USA.
Neurotox Res. 2017 Nov;32(4):603-613. doi: 10.1007/s12640-017-9773-2. Epub 2017 Jun 27.
Although aminoglycoside antibiotics such as kanamycin are widely used clinically to treat life-threatening bacterial infections, ototoxicity remains a significant dose-limiting side effect. The prevailing view is that the hair cells are the primary ototoxic target of aminoglycosides and that spiral ganglion neurons begin to degenerate weeks or months after the hair cells have died due to lack of neurotrophic support. To test the early developmental aspects of this issue, we compared kanamycin-induced hair cell and spiral ganglion pathology in rat postnatal day 3 cochlear organotypic cultures with adult whole cochlear explants. In both adult and postnatal day 3 cultures, hair cell damage began at the base of the cochleae and progressed toward the apex in a dose-dependent manner. In postnatal day 3 cultures, spiral ganglion neurons were rapidly destroyed by kanamycin prior to hair cell loss. In contrast, adult spiral ganglion neurons were resistant to kanamycin damage even at the highest concentration, consistent with in vivo models of delayed SGN degeneration. In postnatal day 3 cultures, kanamycin preferentially damaged type I spiral ganglion neurons, whereas type II neurons were resistant. Spiral ganglion degeneration of postnatal day 3 neurons was associated with upregulation of the superoxide radical and caspase-3-mediated cell death. These results show for the first time that kanamycin is toxic to postnatal day 3 spiral ganglion neurons, but not adult neurons.
尽管氨基糖苷类抗生素如卡那霉素在临床上被广泛用于治疗危及生命的细菌感染，但耳毒性仍然是一个重要的剂量限制副作用。目前的观点是，毛细胞是氨基糖苷类药物的主要耳毒性靶标，并且由于缺乏神经营养支持，毛细胞死亡后数周或数月，螺旋神经节神经元开始退化。为了测试这个问题的早期发育方面，我们将新生大鼠第 3 天耳蜗器官培养物与成年整个耳蜗外植体中的卡那霉素诱导的毛细胞和螺旋神经节病理学进行了比较。在成年和第 3 天的培养物中，毛细胞损伤从耳蜗的基底开始，并以剂量依赖性的方式向顶点发展。在第 3 天的培养物中，毛细胞丢失之前，卡那霉素迅速破坏螺旋神经节神经元。相比之下，即使在最高浓度下，成年螺旋神经节神经元也能抵抗卡那霉素的损伤，这与 SGN 延迟退化的体内模型一致。在第 3 天的培养物中，卡那霉素优先损伤 I 型螺旋神经节神经元，而 II 型神经元则不受影响。第 3 天的神经元的螺旋神经节退化与超氧自由基的上调和 caspase-3 介导的细胞死亡有关。这些结果首次表明，卡那霉素对新生大鼠第 3 天的螺旋神经节神经元有毒性，但对成年神经元没有毒性。
