SUPPRESSION OF MELATONIN BY LIGHT AND NIMODIPINE

据估计，65岁以上的美国人中约有50%患有睡眠障碍。睡眠中断和夜间游荡是促使养老院制度化的第二大常见问题，随着美国人口的老龄化，预计未来十年需要养老院护理的老年人数量将急剧增加。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，内源性昼夜节律起搏器与年龄相关的变化，加上白天接触光线的减少，导致老年人睡眠/觉醒节律中断。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，最近动物衰老模型的结果表明，光疗法治疗睡眠障碍的有效性可能受到衰老时钟对光的反应性降低的限制。此外，动物研究表明，衰老的起搏器对光的反应性降低可能是由于钙稳态调节受损。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，逆转与衰老相关的运动和认知能力下降。最近的研究结果表明，钙通道拮抗剂也可以增加生物钟对光的反应性，因为尼莫地平增加了年轻和年老小鼠暴露于光后昼夜节律活动节律的相移幅度。这项提议的目的是测试尼莫地平会增加人类昼夜节律系统对光的反应性的假设。这将通过评估尼莫地平对光诱导的夜间褪黑激素水平抑制的影响来进行测试。本初步研究结果将为进一步全面研究尼莫地平是否能提高光疗治疗老年人睡眠/觉醒障碍的有效性提供基础。

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 hypothesis 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.