Molecular biological investigation for the mechanisms and treatment of NO induced inner ear damage

NO诱发内耳损伤机制及治疗的分子生物学研究

• 批准号: 12470357
• 负责人: TAKUMIDA Masaya
• 金额: $ 8.7万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470357/
• 关键词: inner ear; free radical; nitric oxide; reactive oxygen species; apoptosis; neurotrophine; gentamicin; treatment; 抗酸化剤; リポポリサッカライド

The aim of this study is to investigate the effects of free radicals (NO, ROS) to the inner ear disorders and to develop the new treatments for the inner ear disease by modulating and/or inhibit the various steps of the mechanisms of inner ear disorders.As a result, certain stimuli induce the formation of free radicals, such as NO, ROS, resulting in a damage of inner ear. Subsequently, the sensory cells began to death by apoptosis. Calpain and caspase may play an important role for the apoptosis. These mechanisms were suggested to be a common pathway for almost all inner ear disorders. Based on these results, we investigated the attenuation of inner ear disorders by scavenging free radicals, inhibition of caspase or calpain and the addition of neurotrophines. All drugs used limited the hair cell damage and the combinations of drugs, such as inhibition of free radicals + neurotrophine, inhibition of free radicals + calpain or caspase inhibitors, had a significantly stronger preventive effect on haii cell damage. Based on these basic research, we have applied radical scavengers (rebamipide, vitamin C, glutathione) to the poor controlled Meniere s disease. The results of this clinical trial is sufficient revealing control of vertigo is 84% and improved rate of hearing loss was 44%.These results were presented at meeting (23th meeting of the Japan Society of Inflamaiion and Regeneration, 10th, 11th and 12th meeting of the Otological Society of Japan, 59th, 60th and 61th meeting of Japan Society for Equilibrium Reseach, 37th Workshop on Inner Ear Biology, 20th meeting of Japan Society of Immunology & Allergology in Otolaryngology, 64th meeting of Society of Practical Otolaryngology) and were presented by 19 papers

本研究的目的是探讨自由基（NO、ROS）对内耳疾病的影响，并通过调节和/或抑制内耳疾病机制的各个步骤来开发治疗内耳疾病的新疗法。因此，某些刺激会诱导自由基（如NO、ROS）的形成，从而导致内耳损伤。随后，感觉细胞开始凋亡。 Calpain和Caspase可能在细胞凋亡中发挥重要作用。这些机制被认为是几乎所有内耳疾病的共同途径。基于这些结果，我们研究了通过清除自由基、抑制半胱天冬酶或钙蛋白酶以及添加神经营养素来减轻内耳疾病。所用药物均限制了毛细胞损伤，且药物组合如抑制自由基+神经营养素、抑制自由基+钙蛋白酶或caspase抑制剂，对毛细胞损伤有明显更强的预防作用。基于这些基础研究，我们将自由基清除剂（瑞巴派特、维生素C、谷胱甘肽）应用于控制不佳的梅尼埃病。该临床试验的结果充分表明，眩晕控制率为84%，听力损失改善率为44%。这些结果在会议上发表（日本炎症与再生学会第23次会议，日本耳科学会第10次、第11次和第12次会议，日本平衡研究会第59次、第60次和第61次会议，第37次内耳研讨会日本学会第20次会议生物学 耳鼻喉科免疫学和变态反应学，实用耳鼻喉科学会第 64 届会议）并发表了 19 篇论文

项目成果

Takumida M: "Pharmacological models for inner ear therapy with emphasis on nitric oxide"Acta Otolaryngol. 121. 16-20 (2001)

Takumida M：“内耳治疗的药理学模型，重点是一氧化氮”Acta Otolaryngol。

Takumida M: "Medical treatment of vertigo."Otolaryngol Head Neck Surg (Tokyo). 74. 94-99 (2002)

Takumida M：“眩晕的药物治疗。”Otolaryngol 头颈外科（东京）。

Takumida M: "Nitric oxide and inner ear disorders."Otolaryngol Head Neck Surg (Tokyo). 74. 255-264 (2002)

Takumida M：“一氧化氮和内耳疾病。”Otolaryngol 头颈外科（东京）。

Takumida M: "Localization of soluble guanylate cyclase activity in the guinea pig inner ear"Acta Otolaryngol. 120. 28-33 (2000)

Takumida M：“豚鼠内耳中可溶性鸟苷酸环化酶活性的定位”Acta Otolaryngol。

Takumida M: "Simultaneous detection of both nitric oxide and reactive oxygen species in Guinea pig vestibular sensory cells"ORL. 64. 143-147 (2002)

Takumida M：“同时检测豚鼠前庭感觉细胞中的一氧化氮和活性氧”ORL。