SUPPRESSION OF MELATONIN BY LIGHT AND NIMODIPINE

据估计，大约50%的65岁以上的美国人有睡眠障碍。睡眠障碍和夜间走失是导致养老院制度化的第二大常见问题，随着美国人口老龄化，预计未来十年需要养老院护理的老年人数量将大幅增加。我们的长期目标是了解老年人慢性睡眠障碍的基础并开发有效的治疗方法。对人类和动物的研究表明，内源性昼夜节律的年龄相关变化，加上白天暴露在阳光下的减少，导致老年人睡眠/醒来节奏被打乱。定时暴露在强光下可以提高老年人的睡眠效率和白天的表现。然而，最近在衰老动物模型中的结果表明，光疗法治疗睡眠障碍的有效性可能因衰老时钟对光的反应性降低而受到限制。此外，动物研究表明，老化的起搏器对光的反应性降低可能是由于钙稳态调节受损所致。降低细胞内钙水平的治疗，如钙通道拮抗剂尼莫地平，已被证明具有神经保护作用，改善神经可塑性，扭转与衰老相关的运动和认知能力下降。最近的结果表明，钙通道拮抗剂也可以增加时钟对光的反应，因为尼莫地平增加了幼年和老年小鼠暴露于光后昼夜活动节律的相移幅度。这项提议的目的是测试尼莫地平将增加人体昼夜节律系统对光的反应的低应答性。这将通过评估尼莫地平对光诱导的夜间褪黑素水平的抑制的影响来进行测试。这项先导性研究的结果将为一项全面研究提供基础，以确定尼莫地平是否可以增强光疗法治疗老年人睡眠/觉醒障碍的有效性。

It is estimated that approximately 50% of Americans over the age of 65 have sleep disturbances. Sleep disruption and nocturnal wandering is the second most common problem which precipitates nursing home institutionalization, and with the aging of the American population, it is expected that the number of elderly who require nursing home care will increase dramatically over the next decade. Our long term goal is to understand the basis of and develop effective therapies for chronic sleep disturbances in older adults. Research in both humans and animals has suggested that age-related changes in the endogenous circadian pacemaker, combined with reduced exposure to light during the day, contribute to disruptions of sleep/wake rhythms in the elderly. Timed exposure to bright light can improve sleep efficiency and daytime performance in older adults. However, recent results in animal models of aging suggest that the effectiveness of light therapy for the treatment of sleep disorders may be limited by reduced responsiveness of the aging clock to light. In addition, animal studies indicate that the reduction in responsiveness to light by the aging pacemaker may be due to impaired regulation of calcium homeostasis. Treatments that decrease intracellular calcium levels, such as the calcium channel antagonist nimodipine, have been shown to exhibit neuroprotective effects, improve neural plasticity and reverse aging-associated declines in motor and cognitive performance. Recent results indicate that calcium channel antagonists can also increase the responsiveness of the clock to light, since nimodipine increases the magnitude of phase shifts of circadian activity rhythms following exposure to light in both young and old mice. The goal of this proposal is to test the hyposthesis that nimodipine will increase responsiveness of the human circadian system to light. This will be tested by assessing the effect of nimodipine on light-induced suppression of nocturnal melatonin levels. The results from this pilot study will provide the basis for a comprehensive study to determine whether nimodipine can enhance the effectiveness of light therapy for the treatment of sleep/wake disorders in the elderly.