Variations in Hormone Therapy: Effects on Cognition and Markers of Brain Aging

激素疗法的变化：对认知和大脑衰老标志的影响

基本信息

批准号：
7487343
负责人：
HEATHER A. BIMONTE-NELSON
金额：
$ 26.96万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7487343
关键词：
Acetylcholine Address Affect Age Aging Agonist Alzheimer&apos s Disease Alzheimer&apos s disease risk Animal Experimentation Animals Attenuated Basic Science Brain Brain region Clinic Clinical Research Clinical Trials Cognition Cognitive Cognitive aging Combined Modality Therapy Conjugated Equine Estrogens Conjugated Estrogens Controlled Clinical Trials Data Dendritic Spines Deterioration Dose Drug Formulations Endometrial Carcinoma Estradiol Estriol Estrogen Replacements Estrogen Therapy Estrogens Evaluation Event Female Goals Growth Factor Health Hippocampus (Brain)Hormone replacement therapy Hormones Impaired cognition In Vitro Learning Life Link Mediating Medroxyprogesterone Memory Menopausal Symptom Menopause Modeling Negative Finding Neuraxis Neurobiology Norethisterone Acetate Outcome Ovarian hormone Prempro Preparation Progesterone Progestins Pyramidal Cells Rattus Replacement Therapy Research Research Personnel Risk Risk Factors Rodent Rodent Model Staging Sum Supplementation Synaptic plasticity System Testing Treatment Protocols Uterus Variant Woman Women&apos s Health Work age related aged aging brain animal data attenuation base clinically relevant cognitive function evaluation/testing gamma-Aminobutyric Acid hormone therapy human study middle age neuropathology neurotrophic factor pre-clinical programs receptor research study

项目摘要

DESCRIPTION (provided by applicant): The broad goal of this application is to determine which variables influence whether hormone therapy acts as a protectant or a risk factor for cognitive functioning and brain aging. Ovarian hormone loss due to menopause has been linked with cognitive decline and increased risk of Alzheimer's disease. While there is evidence that hormone replacement decreases such effects, recent clinical trials failed to find positive effects, and some found detrimental effects. However, abundant basic science evidence suggests that estrogens exert beneficial effects on cognition and neurobiological variables related to memory. Hence, despite the null and negative findings in some clinical trials, the numerous animal and clinical studies showing positive effects of hormone treatment begs the question of what factors determine whether hormone therapy acts as a protectant or a risk factor for brain functioning and brain aging. We will use the rat model to systematically evaluate variations in current hormone therapies, testing whether they are beneficial or detrimental to cognition, neurotrophins, and markers of synaptic plasticity. Based on prior research, what factors might influence the outcome of estrogen replacement? 1. Dose and type of estrogen. Specific Aim I compares the dose-specific effects of three estrogen preparations: the most commonly used estrogen in animal studies (estradiol), the most commonly used estrogen therapy in the clinic (Premarin, or conjugated equine estrogens), and a promising estrogen therapy that has positive effects on menopausal symptoms (estriol). Neither Premarin nor estriol have been tested for cognitive effects in the rodent. 2. Unopposed vs. opposed estrogen treatment. We recently found that progesterone, given alone, is detrimental to spatial memory, and that tonic estradiol replacement enhances memory and alters neurotrophins in cognitive brain regions in aged rats. When progesterone was added to estradiol treatment, the cognitive and neurotrophin alterations due to estradiol were completely reversed. Specific Aim 2 tests whether the three most common clinically-used progestins alter cognition and the brain when given alone, and counteract estrogen-induced alterations when given as part of combination hormone therapy. Further, we will also test a mechanism of progesterone's effects on cognition. Some metabolites of progesterone have effects on the GABAA receptor. We hypothesize that progesterone is impairing memory by increasing GABAA stimulation, in turn resulting in greater hippocampal inhibition thereby impairing memory. By using GABAA antagonists and agonists as well as metabolites of progesterone that mediate the actions of GAB A on the GABAA receptor, Specific Aim 3 will test whether progesterone's negative effects on cognition, when given alone and concurrently with estradiol, are due to effects mediated by the GABAA system. In each study, rats will be tested on a battery of spatial and non-spatial working and reference memory tests, followed by evaluations of neurotrophin levels and markers of synaptic plasticity in cognitive brain regions. These studies will help elucidate which variations in hormone therapy attenuate or exacerbate age-related changes in cognition and the brain, as well as the mechanism of progesterone's effects when given alone and with estrogen.

描述（由申请人提供）：本申请的主要目标是确定哪些变量影响激素疗法是否充当认知功能和大脑衰老的保护剂或危险因素。更年期导致的卵巢激素减少与认知能力下降和阿尔茨海默病风险增加有关。虽然有证据表明激素替代疗法可以减少这种影响，但最近的临床试验未能发现积极的影响，有些还发现了有害的影响。然而，大量的基础科学证据表明，雌激素对与记忆相关的认知和神经生物学变量产生有益的影响。因此，尽管一些临床试验中存在无效和阴性结果，但大量动物和临床研究显示激素治疗具有积极作用，这引出了一个问题：哪些因素决定激素治疗是否充当大脑功能和大脑老化的保护剂或危险因素。我们将使用大鼠模型来系统地评估当前激素疗法的变化，测试它们对认知、神经营养素和突触可塑性标志物是否有益或有害。根据先前的研究，哪些因素可能会影响雌激素替代的结果？ 1.雌激素的剂量和类型。具体目标 I 比较了三种雌激素制剂的剂量特异性效应：动物研究中最常用的雌激素（雌二醇）、临床中最常用的雌激素疗法（倍力马或结合马雌激素）以及一种有前途的雌激素疗法，对更年期症状（雌三醇）有积极作用。倍美力和雌三醇都没有测试过对啮齿动物的认知影响。 2. 不反对与反对雌激素治疗。我们最近发现，单独给予黄体酮对空间记忆有害，而补品雌二醇替代品可增强记忆并改变老年大鼠认知脑区域的神经营养素。当在雌二醇治疗中添加黄体酮时，雌二醇引起的认知和神经营养素改变被完全逆转。具体目标 2 测试临床上最常用的三种孕激素在单独使用时是否会改变认知和大脑，以及在作为联合激素治疗的一部分使用时是否会抵消雌激素引起的改变。此外，我们还将测试黄体酮对认知的影响机制。黄体酮的一些代谢物对 GABAA 受体有影响。我们假设黄体酮通过增加 GABAA 刺激来损害记忆，进而导致更大的海马抑制，从而损害记忆。通过使用 GABAA 拮抗剂和激动剂以及黄体酮代谢物来介导 GABAA 对 GABAA 受体的作用，Specific Aim 3 将测试黄体酮单独给药或与雌二醇同时给药时对认知的负面影响是否是由GABAA系统。在每项研究中，将对大鼠进行一系列空间和非空间工作和参考记忆测试，然后评估神经营养蛋白水平和认知大脑区域突触可塑性标记。这些研究将有助于阐明激素疗法的哪些变化会减弱或加剧与年龄相关的认知和大脑变化，以及黄体酮单独使用和与雌激素一起使用时的作用机制。