CHOLINERGIC REPLACEMENT THERAPY

胆碱能替代疗法

• 批准号: 3412130
• 负责人: Lincoln T. Potter
• 金额: $ 16.79万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1991-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3412130
• 关键词: Alzheimer's disease; aluminum; aminoacridines; brain disorder chemotherapy; brain stem; cholinergic agents; denervation; hippocampus; ion transport; laboratory rabbit; laboratory rat; membrane activity; membrane permeability; memory disorders; muscarinic receptor; neurochemistry; neurotransmitter metabolism; somatostatin

The objective of the proposed work is to provide a rational scientific basis for cholinergic replacement therapy for memory disorders, specifically Alzheimer's disease (AD). This objective is based upon two closely related themes. The first is that the M1 muscarine receptor mechanism is worthy of intense study in its own right, because M1 receptors are primarily localized in the forebrain, appear essential for normal cerebral excitation and short-term memory, and have not been well studied. The second is that cholinergic therapy with M1 agonists is one of the best hopes for treating AD. The starting point for most of the experiments is a new binding assay which permits detailed studies of the interaction of agonists with the high and low affinity states (KH, KL) of M1 receptors, and measurements of the nature of the M1 receptor mechanism in normal, mammalian nerve cell membranes. It is clear that the KL/KH ratio for different agonists correlates closely with the biochemical activity of the same agonists in promoting the breakdown of intramembranous phosphoinositides (PI) and the physiological activity of these agonists in exciting cortical cells. These measurements show that none of the five agonists yet tested for the Rx of AD is a good M1 agonist. Three series of experiments are planned, based on extensive preliminary data. Studies of agonists will be with rabbit hippocampal, brainstem and submaxillary gland membranes for M1, M2h (heart type) and M2g (gland type) receptors, respectively. Measurements of KL/KH and PI breakdown will define the structure of good M1 agonists, and permit the selection of new agonists with high M1 efficacy and M1/M2 selectivity. Additional studies probe the nature of the primary binding site and hypothetical secondary binding sites for bifunctional agonists. Studies of the M1 receptor mechanism in rabbit hippocampal membranes will test our working hypothesis that M1 receptors work in pairs, show which transition metal ion(s) best support(s) the KH state, demonstrate whether allosteric agents can improve the binding or efficacy of M1 agonists, and show whether A1+++, somatostatin etc. directly interfere with the M1 mechanism. The status of the M1 mechanism with interventions in vivo will be assessed in rat brains. Studies of chronic denervation and receptor blockage will show how the mechanism responds to prolonged inactivity. Studies with infused tetrahydroaminoacridine and the M2 agonist, oxotremorine, will show whether either distorts beneficial responses. Finally replacement therapy with the M1 agonist AF102B will be examined for chronic effects on normal and cholinergically- denervated receptors.

拟议工作的目的是提供合理的 记忆的胆碱能替代疗法的科学基础 疾病，特别是阿尔茨海默氏病（AD）。 这个目标是 基于两个密切相关的主题。 首先是M1 毒arine受体机制值得在其中进行激烈的研究 自己的权利，因为M1受体主要位于 前脑，对于正常的脑激发至关重要 短期记忆，尚未得到很好的研究。 第二个 是使用M1激动剂的胆碱能疗法是最好的一种 希望治疗广告。 大多数的起点 实验是一种新的结合测定法，允许详细研究 激动剂与高和低亲和力状态的相互作用 M1受体的（KH，KL），以及测量的性质 正常，哺乳动物神经细胞中的M1受体机制 膜。 显然，不同的KL/KH比率 激动剂与 促进膜内分解的同样激动剂 磷酸肌醇（PI）和这些的生理活性 激动人心的皮质细胞中的激动剂。 这些测量表明 尚未对AD的RX进行测试的五个激动剂是一个很好的M1 激动剂。 根据计划进行三个系列实验 广泛的初步数据。 激动剂的研究将与兔子一起 海马，脑干和层间腺膜 M1，M2H（心脏类型）和M2G（腺体类型）受体， 分别。 KL/KH和PI分解的测量将 定义良好的M1激动剂的结构，并允许选择 具有高M1功效和M1/M2选择性的新激动剂。 其他研究探究了主要结合位点的性质 和双功能激动剂的假设次要结合位点。 兔海马中M1受体机制的研究 膜将测试我们的工作假设，即M1受体 成对工作，显示哪种过渡金属离子最佳支撑 KH状态证明变构剂是否可以改善 M1激动剂的结合或功效，并显示A1 +++是否 生长抑素等直接干扰M1机制。 这 通过体内干预措施的M1机制的状态将是 在大鼠大脑中进行评估。 慢性神经和 受体阻塞将显示机制如何响应 长期不活动。 对注入的研究 四氢氨基酸和M2激动剂Oxotremorine将会 显示任何一种是否扭曲有益的反应。 最后 用M1激动剂AF102B替代疗法将是 检查了对正常和胆碱的慢性影响 - 被取消的受体。