Glutamate excitotoxicity on the inner ear and its prorection

L-谷氨酸被认为是螺旋神经节I型细胞树突与内毛细胞之间第一听觉突触中的一种神经递质。它由多种机制释放，如缺氧、声创伤和一些耳毒性药物。尽管谷氨酸的过度释放被认为会对周围的神经元产生毒性，但耳蜗中的确切机制仍不清楚。首先，我们在豚鼠耳蜗处注射谷氨酸激动剂AMPA，观察谷氨酸对听力的影响。AMPA引起耳蜗肌动作电位(CAP)阈值可逆性升高。其次，通过结扎沙土鼠双侧椎动脉的方法，研究了短暂性耳蜗性缺氧对谷氨酸的兴奋毒性作用。结扎5min后CAP阈值显著升高，再灌流后恢复正常。阈值在第3天恢复到缺血前水平，但有些动物在第5天后再次升高，提示有迟发性神经元死亡的发生率。缺血损伤后外淋巴液中谷氨酸浓度升高。组织学研究显示，与内毛细胞构成突触的初级传入神经的树突上有严重的缺血性病变。这种缺血损伤可通过预先给予谷氨酸拮抗剂来预防。这些结果提示，缺氧时耳蜗内释放出过量的谷氨酸，对周围神经元尤其是初级传入神经的树突造成损害。因此，谷氨酸的兴奋性毒性被认为是各种原因引起的感觉性听力损失的基础。

L-Glutamate is believed to be a neurotransmitter in the first auditory synapse between the inner hair cell and the dendrite of spiral ganglion type I cell. It is released by a variety of mechanisms, such as anoxia, acoustic trauma and some ototoxic drugs. Although excessive release of glutamate is supposed to work toxic to the surrounding neurons, the exact mechanism in the cochlea remains unclear. In first, we investigated the effects of glutamate on hearing by administration of AMPA, an agonist of glutamate, in the cochlea of guinea pig. AMPA caused a reversible increase in the threshold of cochlear action potential (CAP). Secondly, we studied the glutamate excitotoxicity induced by transient cochlear anoxia by means of occlusion of the bilateral vertebral arteries in gerbil. Five minutes' occlusion caused a drastic increase in CAP threshold, which recovered after recirculation. The threshold returned to preischemic level on the 3rd day, but in some animals it increased again after the : 5th day, suggesting the incidence of delayed neuronal death. Glutamate concentration in the perilymph became higher following ischemic insult. Histological studies revealed the ischemic pathology was severe on the dendrite of the primary afferent auditory nerve constituting synapse with the inner hair cell. Such ischemic damages were prevented by prior administration of glutamate antagonist. These results suggested that excessive glutamate released in the cochlea by anoxia caused damage to the surrounding neurons especially to the dendrite of the primary afferent auditory nerve. Glutamate excitotoxicity is, therefore, supposed to underlie a sensory hearing loss of variety of causes.