Glutamate excitotoxicity on the inner ear and its prorection

谷氨酸对内耳的兴奋性毒性及其预防

• 批准号: 09671747
• 负责人: GYO Kiyofumi
• 金额: $ 2.05万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671747/
• 关键词: Inner ear ischemia; glutamete; excitotoxicity; inner ear deafness; delayed inner ear damage; electrocochleogram; damage of inner hair cell; primary afferent cochlear nerve; 内耳グルタミン酸; 遅発性神経障害; 蝸牛複合電位

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.

L-谷氨酸被认为是内毛细胞和 I 型螺旋神经节细胞树突之间第一听觉突触中的神经递质。它通过多种机制释放，例如缺氧、声损伤和一些耳毒性药物。尽管谷氨酸的过量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，我们通过在豚鼠的耳蜗中施用谷氨酸激动剂 AMPA 来研究谷氨酸对听力的影响。 AMPA 导致耳蜗动作电位 (CAP) 阈值可逆性增加。其次，我们通过阻断沙鼠双侧椎动脉，研究了暂时性耳蜗缺氧引起的谷氨酸兴奋毒性。五分钟的闭塞导致 CAP 阈值急剧增加，再循环后恢复。该阈值在第3天恢复到缺血前水平，但在一些动物中，该阈值在第5天后再次升高，表明延迟性神经元死亡的发生率。缺血性损伤后，外淋巴中的谷氨酸浓度变得更高。组织学研究表明，与内毛细胞构成突触的初级传入听神经树突缺血性病变严重。通过预先施用谷氨酸拮抗剂可以预防这种缺血性损伤。这些结果表明，缺氧导致耳蜗释放过量的谷氨酸，对周围神经元尤其是初级传入听神经的树突造成损害。因此，谷氨酸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。

项目成果

白馬伸洋 他: "虚血性内耳障害における内因性グルタミン酸の役割" 虚血性神経細胞死. 35-42 (1998)

Nobuhiro Hakuba 等人：“内源性谷氨酸在缺血性内耳疾病中的作用”，缺血性神经元死亡 35-42 (1998)。

Nobuhiro, Hakuba, et al.: "Hearing Loss and Glutamate Efflux in the perilymph caused by Transient Hidebrain Ischemia in the Gerbil" Ischemic neuronal death. 35-42 (1998)

Nobuhiro、Hakuba 等人：“沙鼠短暂性皮脑缺血引起的听力损失和外淋巴中的谷氨酸流出”缺血性神经元死亡。

Nobuhiro, Hakuba, et al.: "Efflux of glutamate into the perilymph of the cochlea following transien ischemia in the gerbil" Neuroscience Letters. 230. 69-71 (1997)

Nobuhiro、Hakuba 等人：“沙鼠短暂性缺血后谷氨酸流入耳蜗外淋巴”《神经科学快报》。

K.Gyo: "Role of glutamate in hearing loss" Practical otolaryhgology. (in prss).

K.Gyo：“谷氨酸在听力损失中的作用”实用耳鼻喉科。

Hakuba N.et al: "Efflux of glutamate into the perilymph of the cochlea following transient ischemia in the gerbil" Neuroscience Letters. 230. 69-71 (1997)

Hakuba N.等人：“沙鼠短暂缺血后谷氨酸流入耳蜗外淋巴”《神经科学快报》。