Ralli M, Troiani D, Podda M V, Paciello F, Eramo S L M, de Corso E, Salvi R, Paludetti G, Fetoni A R
Institute of Otolaryngology, Università Cattolica del Sacro Cuore, Roma, Italy;
Institute of Physiology, Università Cattolica del Sacro Cuore, Roma, Italy;
Acta Otorhinolaryngol Ital. 2014 Jun;34(3):198-204.
Short-term tinnitus develops shortly after the administration of a high dose of salicylate. Since salicylate selectively potentiates N-methyl- D-aspartate (NMDA) currents in spiral ganglion neurons, it may play a vital role in tinnitus by amplifying NMDA-mediated neurotransmission. The aim of this study was to determine whether systemic treatment with a NMDA channel blocker, memantine, could prevent salicylate-induced tinnitus in animals. Additional experiments were performed to evaluate the effect of memantine on the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to test for changes in hearing function. Thirty-six rats were divided into 3 groups and treated daily for four consecutive days. One group (n = 12) was injected with salicylate (300 mg/kg/d, IP), the second (n = 12) was treated with memantine (5 mg/kg/d, IP) and the third group (n = 12) was injected with salicylate and memantine. All rats were tested for tinnitus and hearing loss at 2, 24, 48 and 72 h after the first drug administration and 24 h post treatment; tinnituslike behaviour was assessed with gap prepulse inhibition of acoustic startle (GPIAS), and hearing function was measured with DPOAE, ABR and noise burst prepulse inhibition of acoustic startle (NBPIAS). Rats in the salicylate group showed impaired GPIAS indicative of transient tinnitus-like behaviour near 16 kHz that recovered 24 h after the last salicylate treatment. Memantine did not cause a significant change in GPIAS. Combined injection of salicylate and memantine significantly attenuated GPIAS tinnitus-like behaviour at 48 hours after the first injection. None of the treatments induced permanent threshold shifts in the ABR and DPOAE, which recovered completely within one day post treatment. Animals treated with salicylate plus memantine showed results comparable to animals treated with salicylate alone, confirming that there is no effect of memantine on DPOAE which reflects OHC function. The present study confirms the role of cochlear NMDA receptors in the induction of salicylate-induced tinnitus.
短期耳鸣在大剂量水杨酸盐给药后不久就会出现。由于水杨酸盐能选择性增强螺旋神经节神经元中的N-甲基-D-天冬氨酸（NMDA）电流，它可能通过放大NMDA介导的神经传递在耳鸣中发挥重要作用。本研究的目的是确定用NMDA通道阻滞剂美金刚进行全身治疗是否能预防动物水杨酸盐诱导的耳鸣。进行了额外的实验来评估美金刚对听性脑干反应（ABR）和畸变产物耳声发射（DPOAE）的影响，以测试听力功能的变化。36只大鼠分为3组，连续4天每日给药。一组（n = 12）注射水杨酸盐（300 mg/kg/d，腹腔注射），第二组（n = 12）用美金刚治疗（5 mg/kg/d，腹腔注射），第三组（n = 12）注射水杨酸盐和美金刚。在首次给药后2、24、48和72小时以及治疗后24小时对所有大鼠进行耳鸣和听力损失测试；用听觉惊吓间隙前脉冲抑制（GPIAS）评估耳鸣样行为，用DPOAE以及听觉惊吓噪声猝发前脉冲抑制（NBPIAS）测量听力功能。水杨酸盐组的大鼠表现出GPIAS受损，表明在16 kHz附近有短暂的耳鸣样行为，在最后一次水杨酸盐治疗后24小时恢复。美金刚未引起GPIAS的显著变化。联合注射水杨酸盐和美金刚在首次注射后48小时显著减轻了GPIAS耳鸣样行为。所有治疗均未引起ABR和DPOAE的永久性阈值偏移，治疗后一天内完全恢复。用水杨酸盐加美金刚治疗的动物显示的结果与单独用水杨酸盐治疗的动物相当，证实美金刚对反映外毛细胞（OHC）功能的DPOAE没有影响。本研究证实了耳蜗NMDA受体在水杨酸盐诱导的耳鸣中的作用。
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