SELECTIVE ESTROGEN RECEPTOR MODULATORS AND COGNITION

选择性雌激素受体调节剂和认知

• 批准号: 7562593
• 负责人: JAMES G HERNDON
• 金额: $ 3.16万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562593
• 关键词: Address; Agonist; Animals; Clinical; Cognition; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Crossover Design; Endocrine; Estradiol Benzoate; Estrogen Receptors; Face; Funding; Gonadal Steroid Hormones; Grant; Institution; Life; Macaca mulatta; Memory; Modeling; Monkeys; Nicotinamide adenine dinucleotide; Oils; Ovarian; Performance; Pharmaceutical Preparations; Placebos; Randomized; Reaction Time; Research; Research Personnel; Resources; Sampling; Score; Selective Estrogen Receptor Modulators; Source; Specificity; Tamoxifen; Testing; United States National Institutes of Health; Week; cognitive function; human ESR1 protein

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Selective estrogen receptor modulators (SERMs) are used to address life-threatening clinical problems but the effects of SERMS on cognition are not known. We therefore used the rhesus monkey model to determine the effects of estradiol benzoate (EB), and the SERMs tamoxifen, DPN (a selective ER-beta agonist), and PPT (a selective ER-alpha agonist) on cognitive function. Animals were tested on a battery of cognitive tests that are presumed to be sensitive to sex hormones or ovarian status. Twenty-two monkeys were given memory and cognitive tasks including Delayed Non-Matching-To-Sample (DNMS) with mixed delays (1, 10 and 30s), and the object, face, and spatial versions of the Delayed Recognition Span Test (DRST). Following a baseline period, monkeys were randomly assigned to one of 3 treatment groups: estradiol benzoate (EB), selective ER-beta agonist (DPN) or selective ER modulator tamoxifen (TAM). In each treatment group, monkeys received oil vehicle for 2 weeks and the drug for 2 weeks, in a cross-over design. After a 4-week washout, a subset of 7 monkeys was re-tested on the battery for 2 weeks with oil vehicle and 2 weeks with a selective ER-alpha agonist (PPT). Overall, drug treatments had modest effects on performance. EB treatment, compared to placebo, was associated with better scores on the DNMS-mixed delays and faster response times at the 10 and 30s delays. Other tasks were unaffected by EB treatment. Monkeys treated with PPT had shorter response times on DNMS-mixed delays. Monkeys with TAM obtained relatively better scores at 30s delay and lower scores at 1s delay, and had increased response times with longer delays. DPN had no effect either on scores or response times on DNMS, but did result in increased response times on the DRST tasks. Overall, these results suggest that estrogen receptor specificity must be considered in evaluating endocrine effects on cognition.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 选择性雌激素受体调节剂 (SERM) 用于解决危及生命的临床问题，但 SERM 对认知的影响尚不清楚。因此，我们使用恒河猴模型来确定苯甲酸雌二醇 (EB) 和 SERM 他莫昔芬、DPN（选择性 ER-β 激动剂）和 PPT（选择性 ER-α 激动剂）对认知功能的影响。动物接受了一系列认知测试，这些测试被认为对性激素或卵巢状态敏感。 22 只猴子接受了记忆和认知任务，包括具有混合延迟（1、10 和 30 秒）的延迟不匹配样本 (DNMS)，以及延迟识别跨度测试 (DRST) 的对象、面部和空间版本）。基线期后，猴子被随机分配到 3 个治疗组之一：苯甲酸雌二醇 (EB)、选择性 ER-β 激动剂 (DPN) 或选择性 ER 调节剂他莫昔芬 (TAM)。在每个治疗组中，猴子采用交叉设计，接受两周的油载体治疗和两周的药物治疗。经过 4 周的清洗后，对 7 只猴子进行了 2 周的电池重新测试，使用油载体和选择性 ER-α 激动剂 (PPT) 进行 2 周。总体而言，药物治疗对表现的影响不大。与安慰剂相比，EB 治疗与 DNMS 混合延迟的更好得分以及 10 秒和 30 秒延迟的更快响应时间相关。其他任务不受 EB 治疗的影响。使用 PPT 治疗的猴子对 DNMS 混合延迟的反应时间较短。具有 TAM 的猴子在 30 秒延迟时获得相对较好的分数，在 1 秒延迟时获得较低分数，并且随着延迟时间较长，反应时间会增加。 DPN 对 DNMS 的分数或响应时间没有影响，但确实导致 DRST 任务的响应时间增加。 总的来说，这些结果表明在评估内分泌对认知的影响时必须考虑雌激素受体特异性。