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: 9099753
• 负责人: Jian Wang
• 金额: $ 39.69万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099753
• 关键词: Address; Adverse effects; Affect; Aftercare; Age-Months; Aging; Animal Model; Animals; 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; Event; Exposure to; Female; Flavanol; Free Radicals; Future; General Population; Genes; Goals; Green tea; Health Personnel; Hemoglobin; 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; antioxidant enzyme; cerebral atrophy; clinical practice; clinically relevant; collagenase; design; dietary supplements; effective therapy; epicatechin; functional outcomes; gray matter; histological image; imaging genetics; improved; improved outcome; in vitro Model; in vivo; in vivo Model; insight; male; mouse model; neurobehavioral; neuroprotection; novel; oxidative damage; preclinical efficacy; preclinical study; preclinical trial; 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）：据报道，脑出血饮食多酚（如黄酮醇）在脑出血后的神经保护作用（ - ） - 据报道有助于预防心血管疾病和中枢神经系统疾病。可可和绿茶富含黄烷醇，包括（ - ） - 埃库汀。我们中风组的同事的最新研究表明，口服的黄烷醇（ - ） - epicatechin通过激活NRF2的激活来减少缺血性中风损伤，NRF2是一种调节大脑内源性抗氧化剂酶表达的转录因子。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）的脑损伤。另外，我们表明，NRF2基因敲除小鼠的脑损伤加剧与活性氧的产生增加有关。该R01的总体目的是解决黄酮醇（ - ） - epicatechin是否可以用作ICH中的神经保护疗法，如果是的，则可以生成临床前功效数据以供其使用并阐明基本机制。我们的工作假设是（ - ） - Epicatechin通过NRF2途径减少ICH损伤。我们设计了三个使用胶原酶诱导的ICH的自体血模型的特定目标。这项研究将在年轻小鼠和老年小鼠中进行，以增强临床相关性。 AIM 1将确定ICH后每天（ - ） - Epicatechin治疗是否可以改善年轻雄性小鼠的预后。 AIM 2将确定以（ - ） - epicatechin的最佳剂量对年轻女性和老年小鼠有效的治疗后处理后是否有效。 AIM 3将确定NRF2途径是否有助于ICH模型中（ - ） - epicatechin的神经保护作用以及血红蛋白诱导的毒性的体外模型。通过药理学，遗传，成像，组织学，分子和细胞生物学方法，我们将提供有关（ - ） - epicatechin在两个小鼠ICH模型以及基本机制中的疗效的新颖信息。需要此类信息来计划更详细的临床前试验，并可能影响有关黄酮醇使用的临床实践。最终，这些数据可能有助于公众和医疗保健提供者就是否可以接受（ - ） - Epicatechin作为ICH患者的辅助治疗做出明智的决定。