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：
7899898
负责人：
HEATHER A. BIMONTE-NELSON
金额：
$ 26.66万
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/7899898
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 Human 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 Regimen Replacement Therapy Research Research Personnel Risk Risk Factors Rodent Rodent Model Staging Sum Supplementation Synaptic plasticity System Testing 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 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）：本申请的广泛目标是确定哪些变量会影响激素治疗是否充当保护剂或认知功能和大脑衰老的危险因素。由于更年期导致的卵巢激素损失与认知下降和阿尔茨海默氏病风险增加有关。虽然有证据表明激素替代降低了这种影响，但最近的临床试验未能发现积极作用，有些临床试验发现有害影响。但是，大量的基本科学证据表明，雌激素对与记忆有关的认知和神经生物学变量产生有益的影响。因此，尽管在某些临床试验中发现了无效的发现，但众多的动物和临床研究表明，激素治疗的积极作用引发了哪些因素确定激素治疗是确定激素治疗是保护剂还是大脑功能和大脑衰老的危险因素。我们将使用大鼠模型系统地评估当前激素疗法的变化，测试它们是否对认知，神经营养蛋白和突触可塑性的标志物有益或有害。基于先前的研究，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。具体目的我比较了三种雌激素制剂的剂量特异性作用：动物研究中最常用的雌激素（雌二醇），是临床中最常用的雌激素疗法（premarin或premarin或结合的马雌激素），以及有希望的雌激素疗法，对中期症状具有积极作用（cantriol）。在啮齿动物中，未测试了预氨林和雌二醇的认知作用。 2。无反对与相反的雌激素治疗。我们最近发现，单独给出的孕酮对空间记忆有害，而补品雌二醇替代可以增强记忆力并改变老年大鼠认知大脑区域的神经营养蛋白。当将孕激素添加到雌二醇治疗中时，雌二醇引起的认知和神经营养蛋白改变被完全逆转。特定的目标2测试三种最常见的临床孕激素是否在单独给予时是否会改变认知和大脑，并在作为组合激素治疗的一部分时抵消雌激素诱导的改变。此外，我们还将测试孕激素对认知作用的机制。一些孕酮的代谢产物对GABAA受体有影响。我们假设孕酮通过增加GABAA刺激会损害记忆，进而导致海马抑制更大，从而损害了记忆。通过使用GABAA拮抗剂和激动剂以及介导GAB A对GABAA受体的作用的孕酮的代谢产物，具体AIM 3将测试孕酮对认知的负面影响（与雌二醇单独给出并同时给出），这是由于GABAA系统介导的影响。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的测试，然后对认知大脑区域的神经营养蛋白水平和突触可塑性标记进行评估。这些研究将有助于阐明激素治疗的哪些变化减弱或加剧了与年龄相关的认知和大脑变化，以及单独和雌激素时孕激素作用的机制。