COGNITIVE AGING: EFFECTS OF ESTRADIOL AND RALOXIFENE

认知老化：雌二醇和雷洛昔芬的影响

• 批准号: 6287168
• 负责人: Agnes Lacreuse
• 金额: $ 8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6287168
• 关键词: Macaca mulatta; aging; behavioral /social science research tag; estradiol; estrogen analog; estrogen inhibitor; estrogen receptors; female; hormone therapy; memory; memory disorders; nonhuman therapy evaluation; ovariectomy; postmenopause; women's health

Estrogens have a multiplicity of effects on a variety of systems and deficiency of these hormones at menopause can increase the risk of developing age-related problems such as osteoporosis, cardiovascular diseases, memory impairments and dementia. Estrogen Replacement Therapy (ERT) is often prescribed to menopausal women to protect against such adverse consequences of estrogen deficiency. ERT, however is associated with a grater risk of developing breast and urine cancers. Non-steroidal estrogens have been developed to mimic the beneficial effects of estrogens on specific systems, yet minimize their proliferative effects on breast and endometrial tissues. These compounds called selective Estrogen Receptor Modulators(SERMs), have a well-documented efficacy in peripheral target tissues, but their effects on cognitive function are not known. Clearly, the effects of SERMs on cognition must be characterized before these agents can be considered as a useful alternative to ERT. We will use a rhesus monkey model of human menopause to examine the effects of estradiol and the SERM raloxifene on female cognition. A preliminary study in aged ovariectomized (OVX) female rhesus monkeys suggested that long-term deprivation of estrogens may exaggerate visual recognition memory deficits, but protect against the development with aging of spatial memory deficits. This project will determine in the same OVX monkeys whether ethinyl estradiol (EE2) is able to reverse this pattern of cognitive performance and whether the SERM raloxifene has similar effects. Monkeys will be repeatedly tested on a battery of three memory tasks, during periods with and without hormonal treatment. Specific Aim 1 will determine whether EE2 enhances visual recognition memory and working memory, while impairing spatial memory in aged OVX female rhesus monkeys; Specific Aim 2 will determine whether the SERM raloxifene acts as an EE2 agonist on memory functions. These data in the rhesus monkey will provide valuable information on the efficacy of EE2 and raloxifene on female cognition and will help evaluating the risks and benefits of using these compounds in hypoestrogenic women, especially after menopause.

雌激素对多种系统有多种影响，更年期缺乏这些激素会增加患骨质疏松症、心血管疾病、记忆障碍和痴呆等与年龄相关的问题的风险。 雌激素替代疗法（ERT）通常用于绝经期妇女，以防止雌激素缺乏带来的不良后果。 然而，ERT 会增加患乳腺癌和尿癌的风险。非甾体雌激素的开发是为了模拟雌激素对特定系统的有益作用，同时最大限度地减少其对乳房和子宫内膜组织的增殖作用。 这些被称为选择性雌激素受体调节剂（SERM）的化合物在外周靶组织中具有良好的功效，但它们对认知功能的影响尚不清楚。 显然，在将这些药物视为 ERT 的有用替代品之前，必须先表征 SERM 对认知的影响。 我们将使用人类更年期恒河猴模型来研究雌二醇和 SERM 雷洛昔芬对女性认知的影响。 一项针对老年卵巢切除（OVX）雌性恒河猴的初步研究表明，长期缺乏雌激素可能会加剧视觉识别记忆缺陷，但可以防止空间记忆缺陷随着年龄的增长而发展。 该项目将在相同的 OVX 猴子中确定乙炔雌二醇 (EE2) 是否能够逆转这种认知表现模式，以及 SERM 雷洛昔芬是否具有类似的效果。 在接受和不接受激素治疗期间，猴子将被反复测试三项记忆任务。具体目标1将确定EE2是否增强老年OVX雌性恒河猴的视觉识别记忆和工作记忆，同时损害空间记忆；具体目标 2 将确定 SERM 雷洛昔芬是否充当记忆功能的 EE2 激动剂。 这些恒河猴数据将为 EE2 和雷洛昔芬对女性认知的功效提供有价值的信息，并将有助于评估在雌激素水平低下的女性中使用这些化合物的风险和益处，尤其是在绝经后。