SLEEP/WAKE RHYTHMS IN AGING--TREATMENT WITH NIMODIPINE

衰老过程中的睡眠/觉醒节律——尼莫地平治疗

• 批准号: 2457518
• 负责人: SUSAN J BENLOUCIF
• 金额: $ 8.86万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2457518
• 关键词: adult human (21+); age difference; aging; body temperature; circadian rhythms; clinical research; electroencephalography; functional ability; human subject; laboratory mouse; melatonin; neuropsychological tests; nimodipine; nonhuman therapy evaluation; photobiology; polysomnography; protooncogene; sleep; sleep disorders; species difference; wakefulness

The purpose of this project is to gain a basic understanding of the causes of chronic sleep disturbances in older adults and to develop effective therapies for these problems. Altering the age-related changes in the endogenous circadian pacemaker and reducing exposure to bright light can improve the sleep performance in elderly persons. However, age-related changes in synaptic plasticity arising from impaired calcium regulation may decrease the responsiveness of the aging clock to light. Recent findings indicate that treatment with the L-type calcium channel antagonist, nimodipine, can improve light-induced phase shifts of circadian activity rhythms in old mice. This indicates that nimodipine may also improve the response of the clock to light. The goals of this project are to test the hypothesis that responsiveness to light is decreased in the clock of older humans, and that enhancing the responsiveness of the clock to light with nimodipine will normalize disrupted sleep/wake rhythms in an animal model of aging. The specific aims of the project are to 1) assess the conditions under which nimodipine reverse age-related deficits in responsiveness of the clock to light in mice by testing the effects of different treatment regimens on three measures of circadian responsiveness to light in young, middle aged, and old mice; 2) test the hypothesis that nimodipine will restore normal entrainment patterns to a light/dark cycle in aged C3H/HeN mice by measuring the amplitude of the diurnal activity rhythm and the phase angle of entrainment; 3) test the hypothesis that older humans exhibit a decrease in the responsiveness of the clock to light by assessing the light-induced suppression of nocturnal melatonin levels and phase shifts of circadian rhythms in young and old subjects; and 4) determine the light intensity required to improve sleep and daytime performance in elderly subjects by assessing the effect of daily administration of three different intensities of light on neuropsychological performance and sleep in older adults. The results of the animal and human experiments are designed to determine if nimodipine can enhance the effectiveness of light therapy for sleep/wake disorders in elderly humans.

这个项目的目的是获得一个基本的了解的原因 老年人的慢性睡眠障碍， 治疗这些问题。改变与年龄有关的变化， 内源性昼夜节律起搏器和减少暴露于强光可以 改善老年人的睡眠状况。然而，与年龄有关的 钙调节受损引起的突触可塑性变化 可能会降低老化时钟对光的响应性。最近 研究结果表明，用L型钙通道治疗 拮抗剂尼莫地平可以改善光诱导的相移， 老年小鼠的昼夜活动节律。这表明尼莫地平可能 也改善了时钟对光的响应。本项目的目标 是为了验证一个假设，即在大脑中， 老年人的生物钟，以及增强老年人的反应能力， 尼莫地平可以使睡眠/觉醒节律正常化 在一个衰老的动物模型中该项目的具体目标是：（1） 评估尼莫地平逆转年龄相关缺陷的条件 在小鼠的生物钟对光的反应，通过测试的影响， 不同治疗方案对三种昼夜节律反应性的影响 年轻，中年和老年小鼠的光照; 2）测试假设， 尼莫地平将使正常的夹带模式恢复到亮/暗循环 在老年C3 H/HeN小鼠中，通过测量昼夜活动的幅度 节律和夹带的相位角; 3）测试假设， 老年人表现出生物钟的反应性下降， 通过评估光诱导的夜间褪黑激素抑制 年轻和老年受试者的昼夜节律水平和相移; 以及4）确定改善睡眠和白天所需的光强度 老年受试者的表现，通过评估每日 管理三种不同强度的光 老年人的神经心理表现和睡眠。的结果 设计动物和人体实验以确定尼莫地平是否 可以提高光疗法对睡眠/觉醒障碍的有效性， 老年人