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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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（一种选择性ER-β激动剂）和PPT（一种选择性ER-α激动剂）对认知功能的影响。对动物进行了一系列认知测试，这些测试被认为对性激素或卵巢状态敏感。22只猴子被给予记忆和认知任务，包括延迟非匹配样本（DNMS）与混合延迟（1，10和30秒），以及对象，面部和空间版本的延迟识别广度测试（DRST）。基线期后，将猴随机分配至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）。在每个处理组中，猴以交叉设计接受油溶剂2周和药物2周。经过4周的洗脱后，对7只猴子的子集进行了重新测试，使用油性溶剂进行2周，使用选择性ER-α激动剂（PPT）进行2周。总体而言，药物治疗对性能的影响不大。与安慰剂相比，EB治疗与DNMS混合延迟的更好评分以及10和30秒延迟的更快反应时间相关。其他任务不受EB治疗的影响。用PPT处理的猴子对DNMS混合延迟的反应时间较短。接受TAM的猴子在30 s延迟时获得了相对较好的分数，在1 s延迟时获得了较低的分数，并且随着延迟时间的延长而增加了反应时间。DPN对DNMS的分数或反应时间没有影响，但确实导致DRST任务的反应时间增加。 总之，这些结果表明，雌激素受体的特异性，必须考虑在评估内分泌对认知的影响。