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

• 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
• 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

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的兴趣，多酚是一种被认为是导致 对于这些效果，可能对帕金森病（PD）有效。研究使用的动物年龄通常 用于PD研究（3-4个月大）的研究表明，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， 影响老年人。随着年龄的增长，大脑会发生一些变化，这些变化不仅会影响大脑的功能， 对损伤的脆弱性以及对保护/恢复治疗的反应性。我们观察到 蓝莓汁（BBJ）和葡萄（GPs）喂养老年大鼠增加了行为缺陷和损害， 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一致。没有 在较年轻的大鼠中观察到这种效应。此外，石榴汁本身最近显示， 氧化应激、炎症和半胱天冬酶-3活化，并增强鱼藤酮诱导的这些活化 同样的因素在老鼠身上。我们假设这些食物/果汁中含有的多酚介导了这些 方面的影响.然而，BBJ，GPs和石榴汁都是复杂的混合物，除了多酚外， 含有碳水化合物，维生素，矿物质，以及潜在的残留水平的除草剂和杀虫剂。 因此，目前我们不能最终将多酚与我们观察到的BBJ和GP的效果联系起来。到 为了解决这个问题，我们计划探索以下目标：目标1：配制合成BBJ并评估其生物相容性。 关键酚类化合物在脑组织中的分布。商业BBJ的关键成分（即黄酮类化合物， 酚酸类和芪类）将使用高效液相色谱法进行评估， 高分辨率质谱（LCMS）。然后将从LCMS分析获得的数据用于制备 合成BBJ合成BBJ将包含来自每个主要化学类别的2-3种关键酚类化合物 浓度与市售产品相同。这些关键酚类化合物的分布 和/或它们的缀合物将在维持在两种形式的 还将在这些时间点评估血浆水平。目标2：比较 两种BBJ混合物在PD动物模型中使用年轻和老年大鼠。BBJ混合物的效果， 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 评估维持大鼠在两种果汁混合物之前和之后的功能效果， 用6-OHDA攻击。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。