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膳食多酚如黄烷醇已被报道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（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）引起的脑损伤。此外，我们发现Nrf2基因敲除小鼠脑损伤的加重与活性氧产生的增加有关。本R01的总体目标是确定黄烷醇(-)-表儿茶素是否可用于脑出血的神经保护治疗，如果可以，为其使用提供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途径减少脑出血损伤。我们设计了三个特定的目标，利用胶原酶诱导和自体血模型脑出血。本研究将在年轻和老年小鼠中进行，以增强临床相关性。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将确定最佳剂量的(-)-表儿茶素治疗后是否对年轻雌性和老年小鼠有效。目的3将确定Nrf2通路是否有助于(-)-表儿茶素在脑出血模型和体外血红蛋白诱导毒性模型中的神经保护作用。通过药理学、遗传学、影像学、组织学、分子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。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做出明智的决定，是否可以接受(-)-表儿茶素作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.