Stilbene's Contribution in Hemorrhagic Stroke

二苯乙烯在出血性中风中的作用

• 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
• 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

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(申请人提供)：二苯乙烯类化合物白藜芦醇天然存在于葡萄皮和种子中，在红葡萄酒中发现浓度特别高。流行病学研究表明，饮用红酒的人患血管疾病的风险降低，这一现象被称为法国悖论。在这里，我们记录了白藜芦醇的预治疗可以减少缺血性卒中损伤。神经退行性变条件下的神经细胞死亡被认为是由自由基损伤介导的。中枢神经系统中存在的内源性抗氧化酶，如过氧化氢酶、超氧化物歧化酶和血红素加氧酶，有望限制自由基介导的损伤。这些细胞保护蛋白的转录受Nrf2的控制，Nrf2在细胞氧化还原状态的调节中起着核心作用。例如，我们和其他人表明，血红素加氧酶是有保护作用的，它可以分解促氧化剂血红素，形成胆绿素/胆红素(抗氧化剂)。一个目标是诱导它，正如初步数据显示的那样，在我们测试的化合物中，白藜芦醇是最有效的诱导剂。我们的初步数据表明，白藜芦醇对神经元的预处理足以提供神经保护，这表明在氧化应激期间共同处理是不必要的。到目前为止的结果表明，Nrf2控制下的基因特异性诱导可能是白藜芦醇在中风中发挥神经保护作用的机制之一。我们将继续研究口服白藜芦醇预处理对出血性中风的益处，并确定它是否可以降低胶原酶和自体血液模型所致脑出血(ICH)小鼠的预后严重程度。我们将研究急性和慢性每日口服白藜芦醇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，并在Nrf2基因敲除小鼠中测试这些有益影响是否减弱。为了进一步确定白藜芦醇对神经元是否具有保护作用并阐明可能的细胞作用机制，来自Nrf2基因敲除幼鼠和匹配对照组的原代培养神经元将被白藜芦醇预处理，然后测试其对叔丁基氢过氧化氢诱导的自由基毒性和血红素的敏感性，后者也是一种促氧化剂。值得注意的是，在病理条件下，如在非物质文化遗产中，血红素的毒性水平很高；它不能再循环，必须被降解。然后，NRF2可以诱导各种抗氧化酶。这些结果将表明，初级神经元的预适应是否足以提供神经保护，以及这种作用是否受到Nrf2的调节。了解白藜芦醇等天然化合物对缺血性和出血性中风的有效性和局限性/安全性，可能有助于普通公众和医疗保健提供者做出明智的决定，决定白藜芦醇和类似的生物活性提取物作为辅助治疗此类破坏性神经疾病是否有效。这也将使我们能够解决口服二苯乙烯类白藜芦醇可能具有神经保护作用的可能机制，并可能具有为大脑提供细胞内源性抵抗衰弱神经退行性疾病的能力。 与公共健康相关：几十年来，二苯乙烯白藜芦醇和红酒一直被认为是增强心脏和大脑的预防药物，但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白藜芦醇上，并测试了导致转录因子Nrf2调节的途径可能参与白藜芦醇的神经保护功能的假设。利用临床前实验室小鼠模型，我们将确定预防性服用白藜芦醇是否可以防止出血性中风后的神经功能下降和脑损伤，从而为白藜芦醇提供抵抗急性神经疾病的新途径。