Effect of Flavanol-Rich Cocoa Extract in Acute Neurodegenerative Conditions

富含黄烷醇的可可提取物对急性神经退行性疾病的作用

基本信息

批准号：
7989678
负责人：
Sylvain DORE
金额：
$ 0.53万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7989678
关键词：
Acute Address Affect Anti-Inflammatory Agents Anti-inflammatory Antioxidants Attention Attenuated Be++ element Behavioral Beryllium Bilateral Bilirubin Biliverdine Biological Brain Brain Injuries Bypass Cacao Plant Carbon Monoxide Carotid Arteries Cell Survival Cells Cerebral Ischemia Cessation of life Chronic Civilization Cleaved cell Cocoa Powder Cognitive Consumption Data Enzyme Induction Enzymes Extended Family Family Ferritin Flavanol Flavonoids Food Free Radicals Glucose Goals Green tea Heart Arrest Heme Hippocampus (Brain)Housing Hypertension Impaired cognition Inflammation Iron Ischemia Ischemic Stroke Isoenzymes Knock-out Knockout Mice Laboratory mice Mediating Methods Modality Modeling Multi-Infarct Dementia Mus Nerve Degeneration Nervous system structure Neurologic Neurons Nutrient Operative Surgical Procedures Organ Outcome Oxidative Stress Oxygen Oxygenases Pathway interactions Physiological Play Pre-Clinical Model Predisposition Preventive Preventive Medicine Property Prosencephalon Proteins Reactive Oxygen Species Reperfusion Therapy Reporting Research Resistance Resuscitation Role Simulate Stroke Structure Symptoms System Testing Therapeutic Effect Time Toxic effect Transcriptional Regulation Transgenic Mice Traumatic Brain Injury Vasodilator Agents Work artery occlusion base cell injury deprivation design epicatechin heme a heme oxygenase-1 in vivo inhibitor/antagonist mouse model nervous system disorder neuron loss neuroprotection overexpression polyphenol pre-clinical prevent promoter prophylactic protective effect public health relevance red wine research study

项目摘要

DESCRIPTION (provided by applicant): It has been postulated that the determinants of neuronal cell death in acute and chronic neurodegenerative conditions are mediated by free radical damage. Epicatechin and cocoa (Theobroma cacao), has been reported to be neuroprotective and a potential preventive medicine, but the underlying cellular mechanisms are still unclear. Our preliminary results prompted us to focus our attention on (-)-epicatechin and flavanol-rich cocoa extract and test the hypothesis that heme oxygenase (HO) activity could participate in cocoa extract neuroprotective function. HO, which cleaves heme (a prooxidant) to form biliverdin/bilirubin (antioxidants), carbon monoxide (a vasodilator), and iron (which by increasing ferritin would be protective) has been shown to play a protective role in oxidative stress, ischemia, inflammation, and hypertension. Although HO2 is constitutively expressed, HO1 is inducible. Consequently, an increase in the activity of this endogenous antioxidant system via an increase in HO1 levels, could be a way to achieve neuroprotection both at a cellular and organ levels. Of the compounds tested in our preliminary experiments using primary neuronal cultures, epicatechin was one of the most potent HO1 inducers. Our results using stroke models also suggest that epicatechin given orally significantly prevented ischemic-reperfusion brain damage. Together, our results indicate that pretreatment with the single compound epicatechin which is the flavanol most enriched in cocoa extract - and likely to cocoa extract itself - is sufficient to provide endogenous neuroprotection, suggesting that co-treatment during oxidative stress is not necessary. These preliminary results implied that specific induction of HO1 could be a mechanism by which cocoa extract exerts its neuroprotective actions and motivated us to propose that some of the neuroprotective effects attributed to Cocoa extract could be mediated through a pathway leading to stimulation of an endogenous antioxidant pathway. In Aim 1, we will determine neuronal cell death and behavioral outcomes following global ischemia in wildtype (WT) mice pre-treated (acutely or chronically) with epicatechin and/or flavanol-rich cocoa extract and test whether these effects are attenuated in knockout mice. In Aim 2, we will determine whether changes in HO1 expression induced by epicatechin and/or flavanol-rich cocoa extract result in changes in cell survival in neuronal cultures derived from WT and knockout mice. Together, these results will help us determine whether consumption of a standardized cocoa extract could be beneficial and the pathways by which cocoa extract could provide the brain with resistance to acute debilitating neurodegenerative conditions. PUBLIC HEALTH RELEVANCE: For centuries, cocoa (Theobroma cacao) has been reported as preventive medicine to strengthen the nervous system, but the underlying cellular mechanisms are still unclear. Our preliminary results prompted us to focus our attention on epicatechin and cocoa extract and test the hypothesis that the pathway leading to heme oxygenase (HO) enzyme induction could participate in cocoa's neuroprotective function. HO, which cleaves heme (a pro-oxidant) to form biliverdin/bilirubin (anti-oxidants) has been shown to play a protective role in oxidative stress, ischemia, inflammation, and hypertension. Using pre-clinical laboratory mouse models, we will determine whether prophylactic consumption of a standardized flavanol-rich cocoa extract can prevent neurological decline and neuronal cell death following global ischemia; thus providing new pathways by which cocoa could provide brain resistance against acute neurological disorders.

描述（由申请人提供）：已经假定急性和慢性神经退行性疾病中神经元细胞死亡的决定因素是由自由基损害介导的。据报道，epicatechin和可可（可可可可）是神经保护作用和潜在的预防医学，但潜在的细胞机制尚不清楚。我们的初步结果促使我们将注意力集中在（ - ） - 富含黄烷醇的可可提取物上，并检验了血红素氧合酶（HO）活性可以参与可可提取物神经保护功能的假设。 Ho裂解血红素（一种促氧化剂）以形成双脂蛋白/胆红素（抗氧化剂），一氧化碳（一种加速剂）和铁（通过提高铁蛋白的保护性可以保护性具有保护性）在氧化应激，缺血，炎症，炎症和高血压中起保护作用。尽管HO2是组成型表达的，但HO1是可诱导的。因此，这种内源性抗氧化剂系统的活性通过HO1水平的升高增加，这可能是在细胞和器官水平上实现神经保护的一种方法。在我们使用原发性神经元培养物的初步实验中测试的化合物中，epicatechin是最有效的HO1诱导剂之一。我们使用中风模型的结果还表明，口头上的epicatechin显着阻止了缺血性再灌注脑损伤。总之，我们的结果表明，对单个化合物epicatechin进行了预处理，该复合性epicatechin是可可提取物中最富集的黄酮醇（可能是可可提取物本身）足以提供内源性神经保护作用，这表明不需要在氧化应激期间的共同处理。这些初步结果暗示，HO1的特定诱导可能是一种机制，可可提取物发挥其神经保护作用，并激励我们提出，提出归因于可可提取物的某些神经保护作用可以通过A途径介导，从而导致刺激内源性抗氧化途径。在AIM 1中，我们将在野生型（WT）小鼠中（急性或长期）用epicatechin和/或富含黄酮醇的可可提取物进行预处理（急性或慢性）的全局缺血后，确定神经元细胞死亡和行为结果，并测试这些作用是否在淘汰小鼠中减弱。在AIM 2中，我们将确定由epicatechin和/或富含黄酮醇的可可提取物引起的HO1表达的变化是否会导致源自WT和敲除小鼠的神经元培养物的细胞存活变化。总之，这些结果将有助于我们确定标准化可可提取物的消耗是否可能是有益的，并且可可提取物可以为大脑提供抗急性衰弱的神经退行性疾病的途径。公共卫生相关性：数百年来，可可（Theobroma cacao）被报道为预防医学以增强神经系统，但基本的细胞机制仍不清楚。我们的初步结果促使我们将注意力集中在epicatechin和Cocoa提取物上，并测试了导致血红素氧酶（HO）酶诱导的途径可以参与可可的神经保护功能。 Ho已裂解血红素（一种促氧化剂）形成双脂蛋白/胆红素（抗氧化剂），已显示出在氧化应激，缺血，炎症和高血压中起保护作用。使用临床前实验室小鼠模型，我们将确定标准化富含黄酮醇的可可提取物的预防性消耗是否可以防止全局缺血后神经系统下降和神经元细胞死亡；因此，可可提供了可可对急性神经系统疾病的大脑耐药性的新途径。