Neuroprotective effect of flavanol (-) epicatechin after intracerebral hemorrhage

黄烷醇(-)表儿茶素对脑出血后的神经保护作用

• 批准号: 8700323
• 负责人: Jian Wang
• 金额: $ 38.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700323
• 关键词: Address; Adverse effects; Affect; Aftercare; Age-Months; Aging; Animal Model; Animals; Antioxidants; Attention; Attenuated; Autologous; Biological Assay; Blood; Brain; Brain Edema; Brain Injuries; Cardiovascular Diseases; Cerebral hemisphere hemorrhage; Cerebrum; Clinical; Clinical Trials; Cocoa Powder; Coupled; Data; Dietary Polyphenol; Disease; Dose; Enzymes; Event; Exposure to; Female; Flavanol; Free Radicals; Future; General Population; Genes; Genetic; Goals; Green tea; Health Personnel; Hemoglobin; Histologic; Image; In Vitro; Inflammatory Response; Injury; Ischemic Stroke; Knockout Mice; Magnetic Resonance Imaging; Mammals; Measures; Modeling; Molecular; Mus; Neuraxis; Neurologic; Neurologic Deficit; Neurons; Oral; Outcome; Pathway interactions; Patients; Pilot Projects; Production; Proteins; Quality of life; Reactive Oxygen Species; Reporting; Research; Risk; Sex Characteristics; Stroke; System; Testing; Therapeutic; Toxic effect; Treatment Protocols; Validation; Whole Blood; Work; age difference; aged; cerebral atrophy; clinical practice; clinically relevant; collagenase; design; dietary supplements; effective therapy; epicatechin; functional outcomes; gray matter; improved; in vitro Model; in vivo; in vivo Model; insight; male; mouse model; neurobehavioral; neuroprotection; novel; oxidative damage; preclinical efficacy; preclinical study; prevent; tert-Butylhydroperoxide; transcription factor; treatment duration; white matter injury

DESCRIPTION (provided by applicant): Neuroprotective effect of flavanol (-)-epicatechin after intracerebral hemorrhage Dietary polyphenols such as flavanols have been reported to help prevent diseases of the cardiovascular and central nervous systems. Cocoa and green tea are rich in flavanols, including (-)-epicatechin. A recent study from colleagues in our stroke group demonstrated that the flavanol (-)-epicatechin given orally reduces ischemic stroke damage through activation of Nrf2, a transcription factor that regulates the expression of endogenous antioxidant enzymes in the brain. We have demonstrated that mice lacking Nrf2 are more susceptible than wild-type control mice to brain damage from intracerebral hemorrhage (ICH). Additionally we showed that the exacerbation of brain injury in Nrf2 knockout mice was associated with increases in production of reactive oxygen species. The overall objective of this R01 is to address whether the flavanol (-)-epicatechin can be used as neuroprotective therapy in ICH, and if so, to generate preclinical efficacy data for its use and elucidate the underlying mechanisms. Our working hypothesis is that (-)-epicatechin reduces ICH injury through the Nrf2 pathway. We have designed three specific aims that utilize the collagenase-induced and autologous blood models of ICH. This research will be carried out in young and aged mice to enhance the clinical relevance. Aim 1 will determine whether daily (-)-epicatechin treatment after ICH improves outcomes in young male mice. Aim 2 will determine whether post-treatment with the optimal dose of (-)-epicatechin is effective in young female and aged mice. Aim 3 will determine whether the Nrf2 pathway contributes to the neuroprotective effect of (-)- epicatechin in ICH models and in in vitro models of hemoglobin-induced toxicity. Through pharmacologic, genetic, imaging, histologic, molecular, and cellular biologic approaches, we will provide novel information about the efficacy of (-)-epicatechin in the two mouse ICH models and about the underlying mechanisms. Such information is required to plan more detailed preclinical trials and could influence clinical practices regarding flavanol use. Ultimately, the data may help the general public and healthcare providers make informed decisions on whether (-)-epicatechin could be accepted as an adjunct treatment in patients with ICH.

描述（由申请人提供）：黄烷醇（-）-表儿茶素对脑出血后的神经保护作用 据报道，膳食多酚如黄烷醇有助于预防心血管和中枢神经系统疾病。可可和绿茶富含黄烷醇，包括(-)-表儿茶素。我们中风小组同事最近的一项研究表明，口服黄烷醇 (-)-表儿茶素可通过激活 Nrf2（一种调节大脑内源性抗氧化酶表达的转录因子）来减少缺血性中风损伤。我们已经证明，缺乏 Nrf2 的小鼠比野生型对照小鼠更容易受到脑出血 (ICH) 造成的脑损伤。此外，我们发现 Nrf2 敲除小鼠脑损伤的加剧与活性氧产生的增加有关。该 R01 的总体目标是解决黄烷醇 (-)-表儿茶素是否可以用作 ICH 的神经保护疗法，如果可以，则生成其使用的临床前疗效数据并阐明其潜在机制。我们的工作假设是 (-)-表儿茶素通过 Nrf2 途径减少 ICH 损伤。我们设计了三个具体目标，利用胶原酶诱导的 ICH 和自体血液模型。这项研究将在年轻和老年小鼠中进行，以增强临床相关性。目标 1 将确定 ICH 后每日 (-)-表儿茶素治疗是否可以改善年轻雄性小鼠的结果。目标 2 将确定最佳剂量的 (-)-表儿茶素后处理对年轻雌性和老年小鼠是否有效。目标 3 将确定 Nrf2 通路是否有助于 (-)-表儿茶素在 ICH 模型和血红蛋白诱导毒性体外模型中的神经保护作用。通过药理学、遗传学、成像、组织学、分子和细胞生物学方法，我们将提供有关 (-)-表儿茶素在两种小鼠 ICH 模型中的功效及其潜在机制的新信息。需要这些信息来计划更详细的临床前试验，并可能影响有关黄烷醇使用的临床实践。最终，这些数据可以帮助公众和医疗保健提供者就是否可以接受 (-)-表儿茶素作为 ICH 患者的辅助治疗做出明智的决定。