BASIC AND CLINICAL RESEARCHES ON THE DYSFUNCTION OF COCHLEAR EFFERENT SIGNAL TRANSDUCTION AS A MECHANISM OF TINNITUS

耳蜗传出信号传导功能障碍导致耳鸣的基础与临床研究

• 批准号: 07457405
• 负责人: KANZAKI Jin
• 金额: $ 4.74万
• 依托单位: KEIO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457405/
• 关键词: TINNITUS; OTOACOUSTIC EMISSION; EFFERENT NERVE; OUTER HAIR CELL; PKC; CALCIUM; LIDOCAINE; 蝸牛遠心性神経; PKC; 蝸牛; イノシトール三リン酸

In the clinical studies, the effects of sound stimulation and lidocaine on the otoacoustic emissions which reflect the function of cochlear efferent system, were investigated. The ipsi- and contra-lateral sound stimulations reduced the otoacoustic emissions, suggesting that the cochlear efferent nerve stimulation may inhibit the cochlear outer hair cell motility. Lidocaine is well known to be capable of releasing tinnitus. We introduced an intravenous continuous lidocaine infusion therapy, and showed that this therapy might be useful for tinnitus management. However, the effects of lidocaine on the otoacoustic emissions varied in each tinnitus patients. Therefore, we basically investigated the effects of lidocaine on the cochlear efferent signal transduction. At first, we studied the signal transduction mechanisms in the cochlear efferent system including the outer hair cells. The IP3 second messenger system in the outer hair cells regulated by the efferent nerves via muscarinic receptors. Acethylcholine stimulates PLC via G-protein, which results in the release of IP3 and diacylglycerol. The efferent nerve stimulates the release of IP3 with mobilizes intracellular calcium in the outer hair cells. These second messengers are postulated to modulate the active motile property of the outer hair cells. We also showed the heterogeneity of PLC and PKC isozymes in the cochlear sensory epithelia. Lidocaine induced the release of inositol phosphates (IPs) in the dose-dependent manner. This effect of lidocaine was independent of the cholinergic receptor nor G-protein mediated releases of IPs, indicating that lidocaine may directly activate PLC.In addition, lidocainc increased intracellular Ca^<2+> concentration of OHCs and shortened OHCs. From these results, we hypothesized that lidocaine stimulates the IP3 second messenger system of OHCs, which results in the suppression of tinnitus. Further study will be conducted on the mechanisms of tinnitus.

在临床研究中，探讨了声刺激和利多卡因对反映耳蜗传出系统功能的耳声发射的影响。耳蜗传出神经刺激可能抑制了耳蜗外毛细胞的运动。利多卡因是众所周知的能够释放耳鸣。我们介绍了静脉持续利多卡因输注治疗，并表明这种治疗可能对耳鸣管理有用。然而，利多卡因对每位耳鸣患者耳声发射的影响各不相同。因此，我们主要研究利多卡因对耳蜗传出信号传导的影响。首先，我们研究了包括外毛细胞在内的耳蜗传出系统的信号转导机制。外毛细胞IP3第二信使系统受传出神经通过毒蕈碱受体调节。乙酰胆碱通过g蛋白刺激PLC，导致IP3和二酰基甘油的释放。传出神经通过动员外毛细胞的胞内钙刺激IP3的释放。这些第二信使被认为可以调节外毛细胞的主动运动特性。我们还发现了PLC和PKC同工酶在耳蜗感觉上皮中的异质性。利多卡因诱导肌醇磷酸（IPs）的释放呈剂量依赖性。利多卡因的这种作用不依赖于胆碱能受体，也不依赖于g蛋白介导的IPs释放，表明利多卡因可能直接激活PLC。此外，利多卡因增加了细胞内Ca^<2+>的ohc浓度，缩短了ohc。根据这些结果，我们假设利多卡因刺激ohc的IP3第二信使系统，从而导致耳鸣的抑制。耳鸣的发病机制有待进一步研究。

项目成果

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井上 泰宏 他: "メニエール病における諸発耳音響放射の臨床応用" Audiology Japan. 40. 95-99 (1997)

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神崎 仁: "耳鳴・難聴の診断と治療" 振興交易, 13 (1998)

神崎仁：“耳鸣和听力损失的诊断和治疗” Shinko Koeki，13（1998）

Inoue Y,Kanzaki J,Ogawa K,Saito H,Harada T: "Clinical application of otoacoustic emissions in Meniere's disease." Audiology Japan. 40. 95-99 (1997)

Inoue Y、Kanzaki J、Okawa K、Saito H、Harada T：“耳声发射在梅尼埃病中的临床应用。”

Iuoue Y.et al: "Clinical application of transiently evoked otoacoustic emissions after glycerol administration for diagnosis of sensorineural hearing loss" Auvis Nasus Laryux. 24. 143-149 (1997)

Iuoue Y.等人：“甘油给药后瞬态诱发耳声发射用于诊断感音神经性听力损失的临床应用”Auvis Nasus Laryux。