Salicylate Selectively Kills Cochlear Spiral Ganglion Neurons by Paradoxically Up-regulating Superoxide
Salicylate Selectively Kills Cochlear Spiral Ganglion Neurons by Paradoxically Up-regulating Superoxide
复制标题
水杨酸盐通过反常地上调超氧化物选择性地杀死耳蜗螺旋神经节神经元
DOI：
10.1007/s12640-013-9384-5
复制
发表时间：
2013-10-01
影响因子：
3.7
通讯作者：
Salvi, Richard
中科院分区：
文献类型：
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作者：
Deng, Lili;Ding, Dalian;Salvi, Richard
阿司匹林及其活性成分水杨酸盐是有效的抗氧化剂，已被报道具有神经和耳部保护作用。然而，当大量服用这些药物时，可能会导致暂时性听力损失和耳鸣。此外，最近的研究表明，经过几天的治疗，水杨酸盐选择性地破坏螺旋神经节神经元和听神经纤维，这些神经纤维将声音从感觉毛细胞传递到大脑。为什么水杨酸盐选择性地损害螺旋神经节神经元，而不损害毛细胞和支持细胞，目前尚不清楚。在这里，我们发现高剂量的水杨酸盐在药物治疗开始几天后触发螺旋神经节神经元的凋亡反应，其形态特征是胞体萎缩、核固缩和碎裂，以及外源性启动子caspase-8和内在启动子caspase-9的激活。水杨酸盐治疗仅在螺旋神经节神经元中引发了有毒超氧阴离子自由基的激增，而在邻近的毛细胞和支持细胞中则没有。细胞通透性超氧化物清除剂五氯TMPyP阻断了螺旋神经节神经元超氧化物歧化染色的表达，几乎完全阻断了神经纤维和螺旋神经节神经元的损伤。已知激活NMDA受体可增加神经元超氧化物水平。由于NMDA受体主要存在于螺旋神经节神经元上，且水杨酸盐增强NMDA受体电流，因此选择性杀伤螺旋神经节神经元可能是水杨酸增强和持续激活NMDA受体的结果。
Aspirin and its active ingredient salicylate are potent antioxidants that have been reported to be neuro- and otoprotective. However, when consumed in large quantities, these drugs can cause temporary hearing loss and tinnitus. Moreover, recent studies indicate that after several days of treatment, salicylate selectively destroys the spiral ganglion neurons and auditory nerve fibers that relay sounds from the sensory hair cells to the brain. Why salicylate selectively damages spiral ganglion neurons while sparing the hair cells and supports cells is unclear. Here we show that high dose of salicylate trigger an apoptotic response in spiral ganglion neurons characterized morphologically by soma shrinkage and nuclear condensation and fragmentation plus activation of extrinsic initiator caspase-8 and intrinsic initiator caspase-9 several days after the onset of drug treatment. Salicylate treatment triggered an upsurge in the toxic superoxide radical only in spiral ganglion neurons, but not in neighboring hair cells and support cells. Mn TMPyP pentachloride, a cell permeable scavenger of superoxide blocked the expression of superoxide staining in spiral ganglion neurons and almost completely blocked the damage to the nerve fibers and spiral ganglion neurons. NMDA receptor activation is known to increase neuronal superoxide levels. Since NMDA receptors are mainly found on spiral ganglion neurons and since salicylate enhances NMDA receptor currents, the selective killing of spiral ganglion neurons is likely a consequence of enhanced and sustained activation of NMDA receptors by salicylate.