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

最近的数据表明，与年龄相关的认知和运动障碍可以通过摄入 水果和蔬菜引发了人们对多酚的兴趣，这些化学物质被认为是 对于这些作用，可能对帕金森氏病(PD)有效。使用同一年龄的动物进行的研究通常 用于帕金森病研究(3-4个月大)的研究表明，多酚/多酚混合物可以保护 各种帕金森病动物模型。然而，帕金森病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，大脑会经历许多变化，这些变化不仅会影响大脑的 它不仅易受损害，而且对保护性/恢复性治疗的反应也是如此。我们观察到 蓝莓汁(BBJ)和葡萄(GP)喂饲老年大鼠可增加行为缺陷和对 多巴胺能神经毒素诱导的黑质纹状体通路与氧化应激增加相一致。不是 在年龄较小的老鼠身上也观察到了这种影响。更多的石榴汁本身最近显示出增加 氧化应激、炎症和caspase-3的激活以及加强鱼藤酮诱导的这些的激活 在老鼠身上也有同样的因素。我们推测，这些食物/果汁中含有的多酚类物质参与了这些过程。 效果。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，以及可能残留的除草剂和杀虫剂。 因此，目前我们还不能肯定地将多酚与BBJ和GPS观察到的效果联系起来。至 围绕这一问题，我们计划探索以下目标：目标1：制定合成BBJ并评估 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， 酚酸和二苯乙烯类化合物)将使用高效液相色谱结合 高分辨率质谱仪(LCMS)。然后将使用从LCMS分析中获得的数据来准备 合成的BBJ。合成的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 与商业化产品的浓度相同。这些关键酚类化合物的分布 和/或它们的结合物将在幼年和老年大鼠的脑组织中进行评估，这些大鼠维持在两种形式的 BBJ锻炼1-4周。血浆水平也将在这些时间点进行评估。目标2：比较两种方法的效果 用幼年大鼠和老年大鼠建立帕金森病动物模型的两种补肾合剂。BBJ混合液对人体健康的影响 黑质纹状体多巴胺神经元的脆弱性将被评估。一系列感觉运动行为测试将 评估维持大鼠对两种果汁混合物作用前后的功能影响 用6-OHDA挑战。纹状体和黑质偶联的常规免疫组织化学分析 密度测量和细胞计数将评估黑质纹状体通路的损害程度。

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.