Impact of Estrogens and Menopause on Interacting Monoamine Neurotransmitters in t

雌激素和更年期对相互作用的单胺神经递质的影响

• 批准号: 8582597
• 负责人: ROBERT B GIBBS
• 金额: $ 22.89万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582597
• 关键词: Accounting; Affect; Age-associated memory impairment; Aging; Agonist; Amino Acid Neurotransmitters; Amino Acids; Animal Model; Binding; Biochemical Pathway; Biological; Blood capillaries; Brain; Brain region; Choline O-Acetyltransferase; Clinical; Cognitive; Corpus striatum structure; Coupled; Critical Pathways; DNA; Data; Diestrus; Disease; Dopamine; Electrodes; Estradiol; Estrogen Receptors; Estrogen Therapy; Estrogens; Flame Ionization; G-Protein-Coupled Receptors; Gas Chromatography; Genetic Transcription; Goals; Heart Arrest; High Pressure Liquid Chromatography; Hippocampus (Brain); Hormone replacement therapy; Hormones; Individual; Laboratories; Lead; Mediating; Membrane; Menopause; Metabolic; Modeling; Molecular Weight; Neurons; Neurotransmitters; Nuclear Receptors; Operative Surgical Procedures; Outcome; Ovarian; Ovariectomy; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Performance; Play; Proestrus; Rattus; Relative (related person); Role; Selective Estrogen Receptor Modulators; Serotonin; Stroke; Surgical Models; System; Technology; Testing; Tissues; Woman; capillary; cholinergic neuron; clinically relevant; cognitive function; detector; frontal lobe; improved; interest; metabolomics; middle age; monoamine; neurochemistry; neuroprotection; prevent; public health relevance; receptor; response; young adult

DESCRIPTION (provided by applicant): Our goal is to understand mechanisms by which estrogens affect the brain and cognitive performance. Estrogens have many beneficial effects in the brain; however, the mechanisms by which estrogens mediate these effects are in many ways unknown. We hypothesize that these effects reflect in large part effects on multiple interacting neurotransmitter pathways in specific brain regions. In particular, we hypothesize that loss of ovarian function results in multiple and simultaneous decreases in specific monoaminergic pathways in the brain, and that selective agonists acting at specific estrogen receptors can reverse these effects and restore the neurotransmitter pathways to a physiologically normal state. Over the past decade, Dr. Yao's (co-PI) laboratory has focused on developing technologies to quantify multiple low-molecular weight redox-active compounds (e.g., monoamines, monoamine metabolites, amino acids, markers of oxidative stress, etc...) in biological tissues. This is accomplished using state-of-the-art high-pressure liquid chromatography coupled with a 16-channel Coulometric Multi-Electrode Array System (HPLC-CMEAS) and capillary gas chromatography with a flame-ionization detector (GC-FID). The power of this technology is the ability to assess multiple metabolites from different biochemical pathways simultaneously in the picomol range. Using animal models of both surgical and natural menopause, we will apply this technology to evaluate the effects of 'menopause' and treatment with selective estrogen receptor agonists on multiple neurotransmitter pathways within specific brain regions. Models of menopause will include ovariectomy (a model of surgical menopause), and treatment with 4-vinylcyclohexene diepoxide (VCD; a model of natural menopause). Estrogen treatments will include 17ss-estradiol (E2), G-1 (a selective GPR30 agonist), PPT (a selective ER¿ agonist) and DPN (a selective ERss agonist) administered continuously sc. at 5 ¿g/day for 1 week or six weeks following loss of ovarian function. Tissues from the hippocampus, frontal cortex, and striatum will be dissected and analyzed for levels of monoamines, monoamine metabolites, amino acid neurotransmitters, and choline acetyltransferase (a marker of cholinergic neurons). This study will provide a detailed description of the changes in neurochemically relevant compounds that occur in specific regions of the brain, in two models of menopause, in response to selective hormone treatments. The studies also will be the first to evaluate the effects of a selective GPR30 agonist on these targets and to compare them with the effects of selective ER¿ and ERss agonists. The findings will provide a much clearer understanding of the neurochemical changes associated with different types of menopause and will lead to better strategies for approaching estrogen therapy in women.

描述（适用提供）：我们的目标是了解演变影响大脑和认知表现的机制。雌激素对大脑具有许多有益的作用。但是，进化介导这些作用的机制在许多方面都是未知的。我们假设这些影响在很大程度上反映了特定大脑区域中多个相互作用的神经递质途径的影响。特别是，我们假设卵巢功能的丧失会导致大脑中特定的单胺能途径的多重和简单降低，并且作用于特定雌激素受体的选择性激动剂可以逆转这些作用，并恢复神经递质途径至物理状态。在过去的十年中，Yao博士（CO-PI）实验室致力于开发技术，以量化生物组织组织中多种低分子氧化还原活性化合物（例如，单胺，单胺，单胺代谢产物，氨基酸，氨基酸，氧化应激标志等）。这是使用最先进的高压液相色谱和16通道库米多电极阵列系统（HPLC-肺部）和带有火焰离子检测器（GC-FID）的毛细血管色谱法（GC-FID）来完成的。该技术的功能是能够仅在Picomol范围内的不同生化途径中评估多个代谢产物。使用手术和天然更年期的动物模型，我们将应用这项技术来评估“更年期”的影响，并使用选择性雌激素受体激动剂对特定大脑区域内多个神经递质途径进行治疗。更年期的模型将包括卵巢切除术（手术绝经的模型），以及4-乙烯基环己烯二氧化碳（VCD；一种天然绝经模型）进行处理。雌激素治疗将包括17s-雌二醇（E2），G-1（选择性的GPR30激动剂），PPT（选择性ER？激动剂）和DPN（一种选择性的ERSS激动剂）连续施用。卵巢功能丧失后，在5 g/day持续1周或六周。将解剖和分析来自海马，额叶皮质和纹状体的组织，并分析单胺，单胺代谢产物，氨基酸神经递质和胆碱乙酰基转移酶（胆碱能神经元的标记）的水平。这项研究将详细描述在对选择性骑马酮治疗的响应中，在两种模型中，在大脑特定区域中发生的神经化学相关化合物的变化。这些研究还将是第一个评估选择性GPR30激动剂对这些靶标的影响，并将其与选择性ER�和ERSS激动剂的影响进行比较的研究。这些发现将为与不同类型的更年期相关的神经化学变化提供更清晰的理解，并为接近女性雌激素治疗的策略提供更好的策略。