Stilbene's Contribution in Hemorrhagic Stroke

二苯乙烯在出血性中风中的作用

基本信息

批准号：
8059681
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：
2010-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8059681
关键词：
Acute Address Affect Anti-Inflammatory Agents Anti-inflammatory Antioxidants Attention Attenuated Autologous Bilirubin Biliverdine Blood Brain Brain Edema Brain Injuries Brain hemorrhage Brain region C57BL/6 Mouse Carbon Monoxide Cells Cerebral hemisphere hemorrhage Chronic Cleaved cell Consumption Corpus striatum structure Cytoprotection Data Dose Elements Enzymes Epidemiologic Studies Ferritin Financial Support Free Radicals General Population Generations Genetic Transcription Goals Grapes Health Benefit Health Personnel Heart Heme Hemorrhage Hippocampus (Brain)Injury Iron Ischemic Stroke Knock-out Knockout Mice Laboratory mice Mediating Methods Modeling Mus Nerve Degeneration Neuraxis Neurologic Neurons Oral Oral Administration Outcome Oxidation-Reduction Oxidative Stress Oxygenases Pathologic Pathway interactions Play Positioning Attribute Predisposition Preventive Medicine Property Prosencephalon Proteins Reactive Oxygen Species Recycling Regulation Resistance Resveratrol Risk Role Safety Seeds Severities Skin Stilbenes Stroke Superoxide Dismutase Techniques Testing Time Toxic effect Traditional Medicine Transcriptional Regulation Vascular Diseases Vasodilator Agents Work brain cell catalase cell growth regulation collagenase gene induction heme oxygenase-1 inhibitor/antagonist interest mature animal mouse model nervous system disorder neurobehavioral neuron loss neuroprotection postnatal pre-clinical preconditioning prevent promoter prophylactic public health relevance pup recombinase red wine research study response tert-Butylhydroperoxide tool trans-resveratrol

项目摘要

DESCRIPTION (provided by applicant): The stilbene compound resveratrol is naturally present in grape skin and seeds and is found in particularly high concentrations in red wine. Epidemiological studies have shown that those who consume red wine have a reduced risk of vascular diseases, a phenomenon known as the French Paradox. Here, we document that pretreatment with resveratrol decreases ischemic stroke damage. Neuronal cell death in neurodegenerative conditions has been postulated to be mediated by free radical damage. Promising candidates to limit free radical-mediated damage are the endogenous antioxidant enzymes present in the central nervous system, such as catalase, superoxide dismutases, and heme oxygenases. Transcription of these cytoprotective proteins is under control of Nrf2, which plays a central role in the regulation of the cellular redox status. For example, we and other showed that heme oxygenase enzyme, which cleaves the prooxidant heme to form biliverdin/bilirubin (antioxidants), is protective. One goal would be to induce it, and of the compounds we tested, as shown in the preliminary data, resveratrol was a most potent inducer. Our preliminary data indicate that pretreatment of neurons with resveratrol was sufficient to provide neuroprotection, suggesting that cotreatment during oxidative stress is not necessary. The results so far imply that specific induction of genes under the control of Nrf2 could be a mechanism by which resveratrol exerts its neuroprotective actions in stroke. We will extend our ongoing inquiry into the beneficial effects of oral pretreatment with resveratrol against hemorrhagic stroke and determine whether it can reduce the severity of outcomes in mice subjected to the collagenase and autologous blood models of intracerebral hemorrhage (ICH). We will investigate the effect of acute and chronic daily oral administration of resveratrol on brain injury volume, brain edema, and neurobehavioral outcome deficits at different time points following hemorrhage and test whether these beneficial effects are attenuated in Nrf2 knockout mice. To further determine if resveratrol of protective in neurons and address possible cellular mechanisms of action, primary postnatal cultured neurons derived from Nrf2 knockout pups and matched controls will be pretreated with resveratrol and then tested for susceptibility to tert- butylhydroperoxide-induced free radical toxicity and heme, which is also a pro-oxidant. Notably, under pathologic conditions such as in ICH, heme reaches high toxic levels; it cannot be recycled and has to be degraded. Nrf2 can then induce various antioxidant enzymes. These results will indicate whether preconditioning of primary neurons is sufficient to afford neuroprotection and whether the effect is modulated by Nrf2. Understanding the efficacy and limitations/safety of natural compounds such as resveratrol in ischemic and hemorrhagic stroke may help the general public and healthcare providers to make informed decisions on whether resveratrol and similar bioactive extracts are efficacious as adjunct treatments for such devastating neurological diseases. It will also allow us to address possible mechanisms by which the oral consumption of the stilbene resveratrol could be neuroprotective and have the putative ability to provide the brain with cellular endogenous resistance to debilitating neurodegenerative conditions. PUBLIC HEALTH RELEVANCE: For decades, the stilbene resveratrol and red wine have been suggested as preventive medicine to strengthen the heart and the brain, but the underlying cellular mechanisms are still unclear. Our preliminary results prompted us to focus our attention on resveratrol and test the hypothesis that the pathway leading to the regulation of the transcriptional factor Nrf2 could participate in resveratrol's neuroprotective function. Using preclinical laboratory mouse models, we will determine whether prophylactic consumption of resveratrol can prevent neurological decline and brain damage following hemorrhagic stroke, thus providing new pathways by which resveratrol could provide resistance to acute neurological disorders.

描述（由申请人提供）：Stilbene化合物白藜芦醇自然存在于葡萄皮和种子中，并且在红酒中特别浓缩。流行病学研究表明，食用红酒的人患血管疾病的风险降低，这是一种称为法国悖论的现象。在这里，我们记录了白藜芦醇预处理会减少缺血性中风损伤。假定神经退行性疾病中的神经元细胞死亡是由自由基损伤介导的。有希望限制自由基介导的损害的有前途的候选者是中枢神经系统中存在的内源性抗氧化剂酶，例如过氧化氢酶，超氧化物歧化酶和血红素氧酶。这些细胞保护蛋白的转录受NRF2的控制，该蛋白在调节细胞氧化还原状态中起着核心作用。例如，我们和其他表明血红素氧酶酶（裂解）促氧化剂血红素形成双脂蛋白/胆红素（抗氧化剂）具有保护性。一个目标是诱导它，在我们测试的化合物中，如初步数据所示，白藜芦醇是最有效的诱导剂。我们的初步数据表明，用白藜芦醇对神经元进行预处理足以提供神经保护作用，这表明无需在氧化应激过程中进行共同治疗。迄今为止的结果表明，在NRF2控制下基因的特定诱导可能是白藜芦醇在中风中施加神经保护作用的机制。我们将持续询问对毒s中风的口服预处理的有益作用，并确定它是否可以减少经受胶原酶和自体血液模型的小鼠的结局严重程度（ICH）。我们将研究白藜芦醇的急性和慢性每日口服给药对出血后不同时间点的脑损伤体积，脑水肿和神经行为结果缺陷的影响，并测试在NRF2敲除小鼠中这些有益效应是否会减弱。为了进一步确定神经元中保护性的白藜芦醇是否解决了可能的细胞作用机制，从NRF2敲除幼崽和匹配的对照组中得出的主要产后培养神经元将用白藜芦醇预处理，然后测试，以易于易于诱发的自由氧化氢诱导的自由氧诱导的自由氧诱导的自由基诱导的自由基毒性。值得注意的是，在ICH等病理状况下，血红素达到高毒性水平。它不能回收，必须降级。然后，NRF2可以诱导各种抗氧化剂酶。这些结果将表明原发性神经元的预处理是否足以负担神经保护作用，以及该效果是否由NRF2调节。了解自然化合物（例如白藜芦醇）在缺血性和出血性中风等天然化合物的效果和局限性/安全性可能有助于公共和医疗保健提供者就白藜芦醇和类似的生物活性提取物做出明智的决定，是否有效地是对这种破坏性神经疾病的辅助治疗方法。它还将使我们能够解决可能具有神经保护性的细曲替氏菌的口服消耗的可能机制，并具有为大脑提供细胞内源性抗性神经退行性疾病的推定能力。公共卫生相关性：数十年来，Stilbene白藜芦醇和红酒被认为是预防医学来增强心脏和大脑的预防医学，但是基本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白藜芦醇上，并检验了导致转录因子NRF2调节的途径可以参与白藜芦醇的神经保护功能。使用临床前实验室小鼠模型，我们将确定白藜芦醇的预防性消耗是否可以防止出血性中风后神经系统下降和脑损伤，从而提供新的途径，而白藜芦醇可以通过这些途径可以提供对急性神经系统疾病的抗性。