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.

拟议工作的目标是提供合理的 记忆胆碱能替代疗法的科学依据 疾病，特别是阿尔茨海默病（AD）。 这个目标是 基于两个密切相关的主题。 首先是M1 毒蕈碱受体机制值得深入研究 自己的权利，因为 M1 受体主要位于 前脑，对于正常的大脑兴奋和 短期记忆，尚未得到充分研究。 第二个 M1 激动剂的胆碱能疗法是最好的疗法之一 治疗AD的希望。 大多数人的出发点 实验是一种新的结合测定，可以进行详细研究 激动剂与高和低亲和力状态的相互作用 M1 受体的 (KH, KL) 以及其性质的测量 正常哺乳动物神经细胞中的 M1 受体机制 膜。 很明显，不同条件下的 KL/KH 比率 激动剂与生物化学活性密切相关 相同的激动剂可促进膜内细胞的分解 磷酸肌醇 (PI) 及其生理活性 兴奋皮质细胞的激动剂。 这些测量表明 尚未测试 AD Rx 的五种激动剂中没有一个是好的 M1 激动剂。 计划进行三个系列的实验，基于 广泛的初步数据。 激动剂的研究将在兔子身上进行 海马、脑干和颌下腺膜 M1、M2h（心脏型）和 M2g（腺体型）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 选择性的新型激动剂。 其他研究探讨了主要结合位点的性质 以及双功能激动剂的假设二级结合位点。 兔海马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好的支持 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+++、 生长抑素等直接干扰M1机制。 这 M1机制的状态与体内干预将是 在大鼠大脑中进行评估。 慢性去神经支配的研究 受体阻断将显示该机制如何响应 长时间不活动。 研究与注入 四氢氨基吖啶和 M2 激动剂氧化震颤素将 表明两者是否会扭曲有益的反应。 最后 M1 激动剂 AF102B 的替代疗法将是 检查对正常和胆碱能的慢性影响 去神经支配的受体。