Neuroprotective effect of flavanol (-) epicatechin after intracerebral hemorrhage

描述(由申请人提供)：黄烷醇(-)-表儿茶素在脑出血后的神经保护作用据报道，黄烷醇等饮食多酚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。我们中风组的同事最近的一项研究表明，口服黄烷醇(-)-表儿茶素通过激活Nrf2来减少缺血性中风的损害，Nrf2是一种转录因子，调节大脑中内源性抗氧化酶的表达。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，我们还发现，Nrf2基因敲除小鼠脑损伤的加重与活性氧产生的增加有关。该R01的总体目标是解决黄烷醇(-)-表儿茶素是否可用于脑出血的神经保护治疗，如果可以，则为其使用产生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途径减轻脑出血损伤。我们利用胶原酶诱导的和自体的脑出血血液模型设计了三个特定的目标。这项研究将在年轻和老年小鼠身上进行，以增强临床意义。目的1将确定脑出血后每日(-)-表儿茶素治疗是否能改善年轻雄性小鼠的预后。目的2将确定(-)-表儿茶素的最佳剂量的后处理是否对年轻雌性和老年小鼠有效。目的3确定Nrf2通路是否参与了(-)-表儿茶素在脑出血模型和体外血红蛋白毒性模型中的神经保护作用。通过药理学、遗传学、成像学、组织学、分子生物学和细胞生物学的方法，我们将提供关于(-)-表儿茶素在两种小鼠脑出血模型中的疗效及其潜在机制的新信息。这些信息是计划更详细的临床前试验所必需的，并可能影响有关黄烷醇使用的临床实践。最终，这些数据可能会帮助普通公众和医疗保健提供者做出明智的决定，决定(-)-表儿茶素是否可以被接受为脑出血患者的辅助治疗。

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.