Oestreicher E, Arnold W, Ehrenberger K, Felix D
ENT Department, Technical University of Munich, Germany.
Acta Otolaryngol. 1999 Mar;119(2):174-8. doi: 10.1080/00016489950181611.
In the mammalian cochlea neurotransmission between inner hair cells and afferent auditory neurons is probably mediated by glutamate or another related excitatory amino acid. Neurotoxicity induced by excessive glutamate release seems to play a crucial role in some pathological conditions of the cochlea, such as ischaemia or noise trauma. Thus, glutamate antagonists may be a new therapeutic strategy for different inner ear diseases. Because of their potential severe side-effects only a few glutamate antagonists have so far been adopted for clinical use. We used microiontophoretic techniques to compare the effects of memantine and caroverine on the glutamatergic transmission of inner hair cells of the guinea pig and tested the possibility of a local administration of memantine to the cochlea with a micropump. Memantine selectively inhibited the NMDA (N-methyl-D-aspartate) stimulated activity while caroverine blocked NMDA as well as AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) induced activity of inner hair cell afferents. With a flow rate of 1 microl/h the local administration of memantine via a cochleotomy was succeeded in a reversible blockade of the spontaneous and the NMDA induced firing of inner hair cell afferents. These results suggest that local application to the cochlea could be a feasible way to administer glutamate antagonists in sufficient amounts while avoiding systemic side-effects.
在哺乳动物的耳蜗中，内毛细胞与传入听觉神经元之间的神经传递可能由谷氨酸或另一种相关的兴奋性氨基酸介导。谷氨酸过度释放所诱导的神经毒性似乎在耳蜗的某些病理状况（如局部缺血或噪声损伤）中起着关键作用。因此，谷氨酸拮抗剂可能是针对不同内耳疾病的一种新的治疗策略。由于其潜在的严重副作用，到目前为止只有少数谷氨酸拮抗剂被用于临床。我们使用微离子电泳技术比较了美金刚和卡维林对豚鼠内毛细胞谷氨酸能传递的影响，并测试了用微泵将美金刚局部给药至耳蜗的可能性。美金刚选择性地抑制N-甲基-D-天冬氨酸（NMDA）刺激的活性，而卡维林则阻断NMDA以及α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）诱导的内毛细胞传入神经的活性。以1微升/小时的流速，通过耳蜗切开术局部给药美金刚成功地可逆性阻断了内毛细胞传入神经的自发性放电和NMDA诱导的放电。这些结果表明，局部应用于耳蜗可能是一种可行的方法，能够在避免全身副作用的同时给予足够量的谷氨酸拮抗剂。
