Impact of food-derived polyphenols on dopamine neurons in the aged brain

食物源多酚对老年大脑多巴胺神经元的影响

基本信息

批准号：
9761990
负责人：
AMANDA D SMITH
金额：
$ 16.4万
依托单位：
VETERANS HEALTH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761990
关键词：
3-nitrotyrosine Affect Age Age-Months Age-associated memory impairment Aging Animal Model Animals Antioxidants Applications Grants Attenuated Behavioral Beverages Blueberries Brain Brain region CASP3 gene Carbohydrates Cell Count Cell Culture Techniques Cell Death Chemicals Chemistry Collaborations Communities Complex Mixtures Consumption Corpus striatum structure Coupled Data Data Reporting Deposition Dietary Supplementation Disease Dopamine Drug Kinetics Elderly Environmental Pollution Flavonoids Food Fruit Grapes Health Health Benefit Herbicides High Pressure Liquid Chromatography Hour Hydroxydopamines Incidence Inflammation Ingestion Juice Laboratories Link Mass Spectrum Analysis Measures Mediating Minerals Modeling Motor Neurons Nervous system structure Neurodegenerative Disorders Neurotoxins Oxidative Stress Parkinson Disease Pesticides Phenols Phytochemical Plasma Pomegranate Juice Property Protocols documentation Rattus Reactive Oxygen Species Reporting Research Research Personnel Residual state Resolution Resources Risk Factors Rotenone Stilbenes Substantia nigra structure Testing Time Toxic Environmental Substances Toxic effect Transition Elements Universities Vitamins Work age related aged aging brain behavior test brain tissue cell age design dopaminergic neuron fluorescence imaging food consumption fruits and vegetables heme oxygenase-1 in vivo interest juvenile animal liquid chromatography mass spectrometry motor deficit motor disorder nigrostriatal dopaminergic pathway nigrostriatal pathway phenolic acid polyphenol

项目摘要

Recent data indicating that age-related cognitive and motor deficits can be attenuated with the consumption of fruits and vegetables has sparked interest in to whether polyphenols, the chemicals thought to be responsible for these effects, might be effective against Parkinson's disease (PD). Studies using animals of an age typically used in PD research (3-4 months old) have shown that polyphenols/polyphenolic mixtures can protect in various animals models of PD. However, PD is a progressive neurodegenerative disease that predominantly affects the elderly. The brain undergoes a number of changes with aging that may not only affect its vulnerability to damage but also its responsiveness to protective/restorative therapy. We observed that blueberry juice (BBJ) and grapes (GPs) fed to aged rats increased behavioral deficits and damage to the nigrostriatal pathway induced by a dopaminergic neurotoxin coincident with an increase in oxidative stress. No such effects were observed in younger rats. Further pomegranate juice per se was recently shown to increase oxidative stress, inflammation and caspase-3 activation and to potentiate rotenone-induced activation of these same factors in rats. We hypothesize that polyphenols contained within these foods/juices mediate these effects. However, BBJ, GPs and pomegranate juice are all complex mixtures, which in addition to polyphenols contain carbohydrates, vitamins, minerals, and potentially residual levels of herbicides and pesticides as well. Therefore, at present we cannot conclusively link polyphenols to our effects observed with BBJ and GPs. To circumvent this problem, we plan to explore the following aims: Aim 1: Formulate synthetic BBJ and assess the distribution of key phenolic compounds in brain tissue. Key components of the commercial BBJ (i.e. flavonoids, phenolic acids and stilbenes) will be assessed using high performance liquid chromatography coupled with high-resolution mass spectrometry (LCMS). Data attained from the LCMS analysis will then be used to prepare the synthetic BBJ. The synthetic BBJ will contain 2-3 key phenolic compounds from each major chemical class at the same concentrations as the commercial product. The distribution of these key phenolic compounds and/or their conjugates will be assessed in brain tissue of young and old rats maintained on the two forms of BBJ for 1-4 wks. Plasma levels will also be assessed at these time points. Aim 2: Compare the effect of the two BBJ mixtures in an animal model of PD using young and old rats. The effect of the BBJ mixtures on the vulnerability of nigrostriatal dopamine neurons will be assessed. A battery of sensorimotor behavioral tests will assess the functional effects of maintaining the rats on the two juice mixtures both before and after being challenged with 6-OHDA. Routine immunohistochemical analysis of the striatum and SN coupled with densitometric measures and cell counting will assess the extent of damage to the nigrostriatal pathway.

最近的数据表明，与年龄相关的认知和运动缺陷可以通过食用水果和蔬菜引起了人们对多酚（被认为是造成这种现象的化学物质）的兴趣。由于这些作用，可能对帕金森病（PD）有效。通常使用某个年龄的动物进行研究用于 PD 研究（3-4 个月）表明，多酚/多酚混合物可以保护 PD的各种动物模型。然而，PD 是一种进行性神经退行性疾病，主要表现为影响老年人。随着年龄的增长，大脑会发生许多变化，这些变化可能不仅会影响其功能易受损害的程度以及对保护性/恢复性治疗的反应性。我们观察到给老年老鼠喂食蓝莓汁（BBJ）和葡萄（GP）会增加行为缺陷和对大脑的损害由多巴胺能神经毒素诱导的黑质纹状体通路与氧化应激的增加同时发生。不在较年轻的大鼠中观察到了这种效应。最近显示石榴汁本身会增加氧化应激、炎症和 caspase-3 激活，并增强鱼藤酮诱导的这些激活大鼠身上也有同样的因素。我们假设这些食物/果汁中含有的多酚介导这些影响。然而，BBJ、GPs和石榴汁都是复杂的混合物，除了多酚之外含有碳水化合物、维生素、矿物质以及潜在残留的除草剂和杀虫剂。因此，目前我们还不能最终将多酚与我们用 BBJ 和 GP 观察到的效果联系起来。到为了规避这个问题，我们计划探索以下目标：目标 1：配制合成 BBJ 并评估脑组织中关键酚类化合物的分布。商业 BBJ 的关键成分（即类黄酮、酚酸和二苯乙烯）将使用高效液相色谱法和高分辨率质谱（LCMS）。从 LCMS 分析中获得的数据将用于制备合成BBJ。合成 BBJ 将包含每个主要化学类别的 2-3 种关键酚类化合物与商业产品的浓度相同。这些关键酚类化合物的分布和/或它们的缀合物将在维持两种形式的年轻和年老大鼠的脑组织中进行评估 BBJ 1-4 周。还将在这些时间点评估血浆水平。目标 2：比较效果使用年轻和年老大鼠的 PD 动物模型中使用两种 BBJ 混合物。 BBJ 混合物对将评估黑质纹状体多巴胺神经元的脆弱性。一系列感觉运动行为测试将评估在喂食之前和之后让大鼠继续饮用两种果汁混合物的功能影响用 6-OHDA 进行挑战。纹状体和 SN 的常规免疫组织化学分析光密度测量和细胞计数将评估黑质纹状体通路的损伤程度。