Cognitive Effects of Grape Seed Extract-Brain Protein Targets

葡萄籽提取物的认知影响——脑蛋白靶标

• 批准号: 7589469
• 负责人: HELEN KIM
• 金额: $ 21.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589469
• 关键词: Address; Adult; Affect; Age; Age-Months; Aging; Alzheimer' s Disease; Animal Disease Models; Animals; Antioxidants; Attenuated; Behavioral; Biochemical; Brain; Chronic Disease; Classification; Cognitive; Data; Dementia; Diet; Dietary Supplementation; Dose; Dyes; Elderly; Electrophoresis; Estrogens; Excision; Exhibits; Fingerprint; Foundations; Functional disorder; Future; Gel; Gene Proteins; Health Benefit; Human; Hypertension; Image; Impaired cognition; Inbred SHR Rats; Ingestion; Intake; Label; Learning; Left; MALDI-TOF Mass Spectrometry; Mass Spectrum Analysis; Mediating; Memory impairment; Menopause; Methods; Modeling; Modification; Molecular Weight; Monitor; Mus; Nature; Nerve Degeneration; Ovariectomy; Ovary; Patients; Peptides; Positioning Attribute; Postmenopause; Preparation; Proanthocyanidins; Process; Protein Isoforms; Proteins; Proteome; Proteomics; Radial; Rattus; Relative (related person); Rodent; Rodent Model; Role; Running; Sampling; Spottings; Staining method; Stains; Testing; Time; Transgenic Mice; Transgenic Model; Upper arm; Western Blotting; age related; attenuation; base; behavior test; cognitive function; deprivation; dietary supplements; dinitrophenyl; dinitrophenylhydrazine; feeding; follow-up; gel electrophoresis; grape seed extract; morris water maze; mouse model; oxidation; prevent; public health relevance; rat female protein; research study; response; young adult

DESCRIPTION (provided by applicant): We recently showed that young (1 month old) ovariectomized spontaneously hypertensive rats (OVX-SHR) fed a low dose (0.5%) of grape seed extract (GSE) in the diet exhibited enhanced cognitive abilities, suggestive of beneficial actions of the GSE in mammalian brain. Previous studies had shown that dietary administration of the GSE at a high (5%) but nontoxic concentration altered brain proteins in normal young adult female rats; these proteins included many previously shown to be affected in the brains of Alzheimer's disease patients and in transgenic models of dementia. The majority of the directions of change for the affected brain proteins were in those considered beneficial. More recently, we showed that GSE intake resulted in a reduction in brain protein oxidations in a transgenic mouse model of dementia, suggestive of anti-oxidant actions of GSE in rodent brain, and consistent with our and others' data showing health benefits of GSE in other models of chronic disease. While much experimentation has been carried out with GSE and similar preparations, systematic analysis of the effective dose range of GSE, and the optimal timing of GSE intake, have not been done. Such experimental parameters, as well as an understanding of compositional variability or stability of the preparations during the course of the experiment, are required for rigorous understanding of the actions and mechanisms of action of dietarily administered bioactive compounds. The proposed studies will utilize OVX- SHR, a model of accelerated postmenopausal hypertension, and test the hypothesis that low doses of grape seed extract protect against ovariectomy-induced late-life cognitive impairment. A systematic dose response analysis of OVX-SHR to GSE administered from the time of OVX will determine the lowest effective dose of GSE. Follow up experiments at this dose will then examine whether shorter times of administration of GSE can have behavioral benefit. Once a beneficial dose of GSE is identified, we will identify by 2D gel proteomics approaches protein differences induced by estrogen-deprivation in the SHR brain, and which of these are attenuated by GSE at the protective dose. These will be initial steps in understanding the consequences of the loss of estrogen in cognitive function, and how polyphenolic substances such as GSE counteract estrogen- deprivation. GSE preparations and diet-supplemented with GSE will be monitored by HPLC-mass spectrometry-based methods for composition and stability during the course of the study. Our objective is to define experimental parameters for the study of GSE and related supplements in models of human chronic disease that will lay a foundation for rigorous studies on the mechanisms by which this and other botanically- based dietary supplements protect from aging- and menopause-related cognitive decline. PUBLIC HEALTH RELEVANCE: We will determine in rats the lowest effective dose of grape seed extract (GSE) that protects against late life cognitive decline induced by estrogen deprivation, caused by removal of the ovaries (ovariectomy or OVX). Biochemical experiments will identify the brain protein changes induced by the OVX, and determine which of these are prevented by the GSE at the lowest dose of GSE that still protects against the OVX-induced cognitive impairment, to begin to identify protein changes that are the mechanism of OVX-induced cognitive decline. Because protein oxidations are thought to be involved in age-related brain dysfunction, we will also study what protein oxidations occur following OVX, and which are prevented by protective doses of GSE. The studies will define experimental parameters for future studies with GSE and related dietary supplements to assess mechanisms of action in models of human chronic disease.

描述（由申请人提供）：我们最近表明，在饮食中喂食低剂量（0.5％）葡萄籽提取物（GSE）的年轻（1个月大）卵巢切除自发性高血压大鼠（OVX-SHR）表现出认知能力增强，提示GSE 在哺乳动物大脑中的有益作用。先前的研究表明，饮食中给予高浓度（5%）但无毒的 GSE 会改变正常年轻成年雌性大鼠的脑蛋白；这些蛋白质包括许多先前显示在阿尔茨海默氏病患者大脑和痴呆症转基因模型中受到影响的蛋白质。受影响的大脑蛋白质的大部分变化方向被认为是有益的。最近，我们发现 GSE 摄入导致痴呆转基因小鼠模型中脑蛋白氧化减少，这表明 GSE 在啮齿类动物大脑中具有抗氧化作用，并且与我们和其他人的数据一致，显示 GSE 对健康的益处其他慢性疾病模型。虽然已经对GSE和类似制剂进行了大量实验，但尚未对GSE的有效剂量范围和GSE摄入的最佳时机进行系统分析。为了严格理解饮食施用的生物活性化合物的作用和作用机制，需要这样的实验参数以及对实验过程中制剂的组成变异性或稳定性的理解。拟议的研究将利用 OVX-SHR（一种加速绝经后高血压的模型）并测试低剂量葡萄籽提取物可预防卵巢切除术引起的晚年认知障碍的假设。对 OVX-SHR 对从 OVX 开始施用的 GSE 进行系统剂量反应分析将确定 GSE 的最低有效剂量。该剂量的后续实验将检查较短的 GSE 给药时间是否可以带来行为益处。一旦确定了 GSE 的有益剂量，我们将通过 2D 凝胶蛋白质组学方法识别 SHR 大脑中雌激素剥夺引起的蛋白质差异，以及其中哪些在保护剂量下被 GSE 减弱。这些将是了解雌激素丧失对认知功能的影响以及 GSE 等多酚物质如何抵消雌激素剥夺的初步步骤。在研究过程中，将通过基于 HPLC 质谱的方法监测 GSE 制剂和添加 GSE 的饮食的组成和稳定性。我们的目标是确定人类慢性病模型中 GSE 和相关补充剂研究的实验参数，这将为严格研究 GSE 和其他植物性膳食补充剂预防衰老和更年期相关的机制奠定基础。认知能力下降。 公共健康相关性：我们将在大鼠中确定葡萄籽提取物 (GSE) 的最低有效剂量，以防止由于卵巢切除（卵巢切除术或 OVX）引起的雌激素剥夺引起的晚年认知能力下降。生化实验将识别 OVX 引起的大脑蛋白质变化，并确定 GSE 在最低剂量的 GSE 下可以预防哪些变化，但仍能防止 OVX 引起的认知障碍，从而开始识别蛋白质变化的机制OVX 引起的认知能力下降。由于蛋白质氧化被认为与年龄相关的脑功能障碍有关，因此我们还将研究 OVX 后会发生哪些蛋白质氧化，以及哪些蛋白质氧化可以通过保护剂量的 GSE 来预防。这些研究将为 GSE 和相关膳食补充剂的未来研究确定实验参数，以评估人类慢性疾病模型的作用机制。