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，饮食中低剂量（0.5％）的年轻（1个月大的）卵巢切除型自发性高血压大鼠（OVX-SHR）在饮食中喂养低剂量（0.5％）的葡萄种子提取物（GSE），具有增强的认知能力，暗示了哺乳动物大脑中GSE的有益作用。先前的研究表明，饮食中的GSE以高（5％）但无毒的浓度改变了正常成年雌性大鼠的脑蛋白。这些蛋白质包括许多先前证明在阿尔茨海默氏病患者的大脑和痴呆转基因模型中受到影响的许多蛋白质。受影响的大脑蛋白的大部分变化方向都被认为是有益的。最近，我们表明GSE摄入导致痴呆的转基因小鼠模型中脑蛋白氧化的减少，暗示GSE在啮齿动物大脑中的抗氧化作用，并与我们和其他人的数据一致，显示出在其他慢性疾病中显示GSE的健康益处。尽管GSE和类似的制剂已经进行了许多实验，但尚未完成对GES的有效剂量范围以及GSE摄入的最佳时机的系统分析。这种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，需要严格理解饮食饮食施用的生物活性化合物的作用和机制。拟议的研究将利用OVX-SHR，这是一种加速绝经后高血压的模型，并测试了低剂量的葡萄种子提取物可预防卵巢切除术引起的晚期认知障碍的假设。 OVX-SHR对从OVX时给予的GSE的系统剂量响应分析将确定GSE有效剂量的最低剂量。然后，以这种剂量进行后续实验将检查GSE给药时间较短是否可以具有行为益处。一旦确定了有益的GSE剂量，我们将通过2D凝胶蛋白质组学识别，将接近SHR脑中雌激素剥夺引起的蛋白质差异，其中哪些被GSE在保护性剂量下会减弱。这些将是理解认知功能中雌激素丧失的后果的初步步骤，以及GESE诸如GSE等多酚物质如何抵消雌激素剥夺。在研究过程中，基于HPLC-MAS光谱法的方法将通过HPLC-MAS光谱法监测GSE制剂和饮食供应。我们的目标是定义人类慢性病模型中GSE和相关补充剂的实验参数，这将为严格研究这种机制奠定基础，从而对这种机制和其他基于植物学的饮食补充剂保护免受衰老和更年期相关的认知能力下降。 公共卫生相关性：我们将在大鼠中确定最低剂量的葡萄种子提取物（GSE），以防止因去除卵巢（卵巢切除术或OVX）引起的雌激素剥夺引起的晚期认知下降。生化实验将鉴定OVX诱导的脑蛋白变化，并确定在最低剂量的GSE中阻止了哪种脑蛋白变化，这些gse仍可以防止OVX引起的认知障碍，以开始鉴定蛋白质变化，这是OVX诱导的认知能力下降的机制。由于蛋白质氧化被认为与年龄相关的脑功能障碍涉及，因此我们还将研究OVX后发生的蛋白质氧化，哪些蛋白质氧化是由GSE保护性剂量预防的。这些研究将定义用于未来研究的实验参数，用于GSE和相关饮食补充剂，以评估人类慢性疾病模型中的作用机理。