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：
8117138
负责人：
Sylvain DORE
金额：
$ 21.76万
依托单位：
UNIVERSITY OF FLORIDA
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 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8117138
关键词：
Acute Address Affect Anti-Inflammatory Agents Anti-inflammatory Antioxidants Attention Attenuated 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）：据推测，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伤介导的。据报道，表儿茶素和可可（Theobroma cacao）具有神经保护作用和潜在的预防药物，但其潜在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富含 (-)-表儿茶素和黄烷醇的可可提取物上，并检验血红素加氧酶 (HO) 活性可能参与可可提取物神经保护功能的假设。 H2O 能裂解血红素（一种促氧化剂），形成胆绿素/胆红素（抗氧化剂）、一氧化碳（一种血管扩张剂）和铁（通过增加铁蛋白起到保护作用），已被证明在氧化应激、缺血、炎症、高血压。尽管 HO2 是组成型表达，但 HO1 是诱导型表达。因此，通过增加 HO1 水平来增加这种内源性抗氧化系统的活性，可能是在细胞和器官水平上实现神经保护的一种方法。在我们使用原代神经元培养物进行的初步实验中测试的化合物中，表儿茶素是最有效的 HO1 诱导剂之一。我们使用中风模型的结果还表明，口服表儿茶素可显着预防缺血再灌注脑损伤。总之，我们的结果表明，用单一化合物表儿茶素（可可提取物中最丰富的黄烷醇）（并且可能是可可提取物本身）进行预处理足以提供内源性神经保护，这表明氧化应激期间没有必要进行共同治疗。这些初步结果表明，HO1 的特异性诱导可能是可可提取物发挥其神经保护作用的机制，并促使我们提出，可可提取物的一些神经保护作用可能是通过刺激内源性抗氧化途径的途径介导的。在目标 1 中，我们将确定用表儿茶素和/或富含黄烷醇的可可提取物预处理（急性或慢性）的野生型 (WT) 小鼠整体缺血后的神经细胞死亡和行为结果，并测试这些效应在基因敲除小鼠中是否减弱。在目标 2 中，我们将确定表儿茶素和/或富含黄烷醇的可可提取物诱导的 HO1 表达变化是否会导致 WT 和基因敲除小鼠神经元培养物中细胞存活率的变化。总之，这些结果将帮助我们确定食用标准化可可提取物是否有益，以及可可提取物可以为大脑提供对急性衰弱性神经退行性疾病的抵抗力的途径。公共卫生相关性：几个世纪以来，可可（Theobroma cacao）一直被报道为增强神经系统的预防药物，但其潜在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表儿茶素和可可提取物上，并测试导致血红素加氧酶 (HO) 酶诱导的途径可能参与可可的神经保护功能的假设。 H2O 可裂解血红素（促氧化剂）形成胆绿素/胆红素（抗氧化剂），已被证明在氧化应激、缺血、炎症和高血压中发挥保护作用。使用临床前实验室小鼠模型，我们将确定预防性食用富含黄烷醇的标准化可可提取物是否可以预防全身缺血后的神经功能衰退和神经元细胞死亡；因此，可可提供了新的途径，使大脑能够抵抗急性神经系统疾病。