CITALOPRAM DECREASES AMYLOID-B SYNTHESIS IN HUMAN CSF

西酞普兰减少人脑脊液中淀粉样蛋白 B 的合成

• 批准号: 8321442
• 负责人: YVETTE I SHELINE
• 金额: $ 15.58万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8321442
• 关键词: Acute; Affect; Age; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animal Model; Antidepressive Agents; Appearance; Behavior; Binding; Biological Assay; Brain; Citalopram; Clinical Research; Clinical Trials; Consensus; Data; Depressed mood; Development; Diagnosis; Disease; Dose; Drops; Early treatment; Elderly; FDA approved; Failure; Generations; Hour; Human; Individual; Infusion procedures; Kinetics; Label; Length; Leucine; Link; Measures; Methods; Monitor; Moods; Mus; Neuronal Injury; Participant; Pathogenesis; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebo Control; Placebos; Play; Population; Positron-Emission Tomography; Preventive; Process; Production; Randomized; Role; Sampling; Selective Serotonin Reuptake Inhibitor; Senile Plaques; Serotonin; Signal Transduction; Stable Isotope Labeling; Symptoms; Techniques; Testing; Therapeutic; Transgenic Mice; United States; Universities; Washington; abeta accumulation; amyloid imaging; base; clinically relevant; design; human subject; in vivo; inhibitor/antagonist; mouse model; pre-clinical; prevent; prospective; secretase; success; tianeptine; time use

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating illness, estimated to affect 5 million patients in the United States alone and projected to increase dramatically over the next decades as the population ages unless preventive measures can be developed. While there is no currently approved treatment that modifies the underlying cause of the disease, there is intense activity towards developing anti-amyloid beta therapies. Recent trials of such treatments however have had no, or very limited, success in altering the course of AD. It is likely that these failures to benefit individuals with clinically diagnosed AD occurred because the treatments were administered too late in the disease process. We have preliminary evidence that selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with lower A¿ plaques in the human brain. We also found that in a transgenic mouse model of AD two SSRI antidepressants acutely reduced brain A¿ levels by 25% and direct infusion of serotonin reduced A¿ levels by 30% in vivo without affecting A2 elimination rates, suggesting that serotonin signaling is responsible for the reduction in A¿ generation. We now have data demonstrating that prospective treatment with 16 weeks of citalopram significantly reduced plaque burden in AD mice. The current proposal will test whether clinically relevant doses of an SSRI reduce A¿ production in healthy human subjects. This is made possible by the recent development of a stable isotope labeling kinetic (SILK) technique by our colleagues here at Washington University. The SILK assay assesses A¿ pharmacodynamics in human subjects. It uses administration of 13C6-leucine and monitors the rate of 13C6-labeled A¿ appearance in the CSF to determine the rate of A¿ synthesis and clearance. We propose to conduct a randomized placebo-controlled comparison in 12 subjects ages 18-40 who will undergo assessment of A¿ production during a 36-hour stay in our clinical research unit. Each subject will be randomized to treatment with a 4 week course of placebo or 20 mg/day of citalopram, prior to the initiation of the 13C6-leucine administration and CSF sampling. Hypothesis: Compared to the subjects receiving placebo, subjects receiving citalopram will show significantly (p< 0.05) lower A¿ production as measured by SILK. Significance: If our hypothesis is supported and citalopram is associated with a substantial reduction in A¿ production, we will use this data to assess the value of a prospective trial to test whether SSRIs reduce the rate of A¿ plaque formation. While many factors go into the design of such a trial, the potential significance for preventing AD would be large.

描述（由申请人提供）：阿尔茨海默病 (AD) 是一种毁灭性的疾病，估计仅在美国就有 500 万患者受到影响，并且预计随着人口老龄化，这种疾病在未来几十年内会急剧增加，除非能够制定预防措施。目前尚无批准的治疗方法可以改变该疾病的根本原因，因此人们对开发抗淀粉样蛋白疗法进行了积极的研究，但最近对此类治疗的试验在改变 AD 病程方面没有取得或非常有限的成功。很可能这些临床诊断的 AD 患者未能受益是因为治疗在疾病过程中实施得太晚，我们有初步证据表明选择性血清素再摄取抑制剂 (SSRI) 抗抑郁药与较低的 A¿我们还发现，在 AD 转基因小鼠模型中，两种 SSRI 抗抑郁药可显着降低人脑中的 A 斑块。水平降低 25% 并直接输注血清素可减少 A¿体内水平降低 30%，而不影响 A2 消除率，这表明血清素信号传导是 A 减少的原因我们现在有数据表明，16 周的西酞普兰前瞻性治疗可显着减少 AD 小鼠的斑块负荷。目前的提议将测试 SSRI 的临床相关剂量是否会减少 A¿我们华盛顿大学的同事最近开发了一种稳定同位素标记动力学 (SILK) 技术，可在健康人类受试者中进行生产。它使用 13C6-亮氨酸给药并监测 13C6 标记的​​ A¿出现在 CSF 中以确定 A¿我们建议对 12 名 18-40 岁的受试者进行随机安慰剂对照比较，他们将接受 A¿在开始 13C6-亮氨酸给药和脑脊液假设采样之前，每个受试者将被随机接受为期 4 周的安慰剂治疗或 20 毫克/天的西酞普兰治疗。 ：与接受安慰剂的受试者相比，接受西酞普兰的受试者将表现出显着 (p< 0.05) 较低的 A¿通过 SILK 测量的产量 意义：如果我们的假设得到支持，并且西酞普兰与 A¿ 的大幅减少有关。生产后，我们将使用这些数据来评估前瞻性试验的价值，以测试 SSRIs 是否会降低 A¿虽然此类试验的设计涉及许多因素，但预防 AD 的潜在意义是巨大的。