Oral Epigallocatechin Gallate (EGCG) for Treatment of Alzheimer's Disease Induced Hearing Loss

口服表没食子儿茶素没食子酸酯 (EGCG) 用于治疗阿尔茨海默病引起的听力损失

• 批准号: 10288729
• 负责人: Vickram Ramkumar
• 金额: $ 36.17万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288729
• 关键词: 3xTg-AD mouse; AD transgenic mice; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid deposition; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptotic; Auditory; Biological Assay; Brain; Cell Death; Cisplatin; Clinical; Cochlea; Cognitive deficits; Data; Development; Disease model; Epigallocatechin Gallate; Event; Exposure to; Funding; Generations; Grant; Green tea; Hearing Protection; Human; Inflammation; Inflammatory; Knowledge; Laboratories; Mus; NOS2A gene; Natural Products; Neurons; Oral; Parents; Pharmaceutical Preparations; Property; Rattus; Reporting; TNF gene; Testing; Therapeutic Uses; Time; Tissues; Transgenic Mice; abeta accumulation; abeta deposition; age related; base; cisplatin induced hearing loss; experimental study; factor A; hearing impairment; inflammatory marker; mouse model; ototoxicity; postnatal period; preclinical trial; protective effect; transgenic model of alzheimer disease

Current Abstract - Supplement Recent data suggest an association between Alzheimer’s disease and hearing loss. Some reports suggest that amyloid β (Aβ) deposition in the cochlea could account for the hearing loss. In transgenic mouse models of Alzheimer’s disease, it has been shown that the loss of hearing was associated with Aβ deposition in the cochlea. Previous studies from our laboratory indicate that Aβ increases Ca2+ and increased inflammatory markers in primary neuron cultures from rats. In addition, we observed that cortical tissues from 3xTg mouse model (also known as 3xTg-AD model) have increased levels of TNF-α. We speculate that a similar event occurs in the cochleae of Alzheimer’s disease mouse models which could contribute to hearing loss in these mice. Since our current RO1 proposal is based on the hypothesis that cochlear inflammation produces hearing loss, we believe that a Supplement on Alzheimer’s disease is within the general scope of the original grant. Therefore, experiments outlined in the supplement will test the hypothesis that Alzheimer’s transgenic mice show a time- dependent loss of hearing which is associated with Aβ accumulation in the cochlea. Specific aim 1 will explore the age-dependent loss of hearing in the 5XFAD mouse model covering the postnatal period 0 to 6 months during which these mice show amyloid deposition in the brain and cognitive deficits. Various inflammatory and apoptotic markers will be examined by immunohistochemical and real time PCR assays. Specific aim 2 will examine the effect of oral epigallocatechin gallate (EGCG), a natural product with antioxidant and anti- inflammatory properties, on the development of hearing loss in this mouse model. This drug shows promise for treatment of Alzheimer’s disease in preclinical trials. EGCG is currently being used in the current parent RO1 to treat cisplatin ototoxicity. It was shown to particularly effective for this indication. We believe this product stands a good chance in providing hearing protection in these animals and ultimately in humans suffering from Alzheimer’s-induced hearing loss.

当前摘要-补充 最近的数据表明阿尔茨海默病和听力损失之间存在联系。一些报告指出， β淀粉样蛋白（Aβ）在耳蜗的沉积可能是导致听力损失的原因。在转基因小鼠模型中， 在阿尔茨海默病中，已经表明听力损失与耳蜗中的Aβ沉积有关。 我们实验室以前的研究表明，Aβ增加了Ca 2+和炎性标志物， 大鼠的原代神经元培养物。此外，我们观察到来自3xTg小鼠模型的皮质组织（也 称为3xTg-AD模型）具有增加的TNF-α水平。我们推测，类似的事件发生在 阿尔茨海默病小鼠模型的耳蜗，这可能有助于这些小鼠的听力损失。由于我们 我们认为，目前的RO 1建议是基于耳蜗炎症导致听力损失的假设， 阿尔茨海默氏症的补充是在原来的补助金的一般范围内。因此，我们认为， 增刊中概述的实验将检验阿尔茨海默氏症转基因小鼠显示时间- 依赖性听力丧失，与耳蜗中Aβ蓄积相关。具体目标1将探索 出生后0 - 6个月的5XFAD小鼠模型中的年龄依赖性听力损失 在此期间，这些小鼠表现出大脑中的淀粉样蛋白沉积和认知缺陷。各种炎症和 通过免疫组织化学和真实的时间PCR分析来检测凋亡标记物。具体目标2将 检查口服表没食子儿茶素没食子酸酯（EGCG）的效果，这是一种具有抗氧化和抗衰老作用的天然产品。 炎症特性，对该小鼠模型中听力损失的发展的影响。这种药有希望 治疗阿尔茨海默病的临床前试验。EGCG目前用于当前的亲本RO 1， 治疗顺铂耳毒性。它被证明对这种适应症特别有效。我们相信这个产品 这是一个很好的机会，可以为这些动物提供听力保护，并最终为患有 阿尔茨海默氏症引起的听力损失。