Better Understanding of the Neuroprotective Mechanisms of Korean Ginseng in Strok

更好地了解高丽参对中风的神经保护机制

基本信息

批准号：
8543642
负责人：
Sylvain DORE
金额：
$ 45.58万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8543642
关键词：
Acute Address Age Aging Alzheimer&apos s Disease American Anti-Inflammatory Agents Anti-inflammatory Antioxidants Attention Attenuated Behavioral Bilirubin Biliverdine Binding Biological Assay Blood Vessels Brain Brain Injuries Carbon Monoxide Cell Nucleus Cells Cerebral Atheroscleroses Cerebral Edema Characteristics Chronic Cleaved cell Cognition Disorders Consumption Drug Metabolic Detoxication Elements Enzymes Ferritin Free Radicals Genes Ginseng Preparation Goals Heme Homeostasis Hypertension Impairment In Vitro Inflammation Iron Ischemia Knock-out Knockout Mice Koreans Mediating Modeling Multi-Infarct Dementia Mus Names Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurologic Neurologic Dysfunctions Neurons Oral Outcome Oxidation-Reduction Oxidative Stress Oxygenases Panax ginseng Pathway interactions Play Preventive Preventive Medicine Property Protein Isoforms Protein Synthesis Inhibitors Reporting Resistance Response Elements Role Saponin Saponins Stroke Testing Therapeutic Effect Time Transgenic Mice Traumatic Brain Injury Vascular Dementia Vasodilator Agents Wild Type Mouse Work age related brain cell cell type heme a heme oxygenase-1 in vivo in vivo Model inhibitor/antagonist neuron loss neuroprotection novel overexpression oxidative damage pre-clinical premature prevent promoter protective effect protein expression public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): Better Understanding of the Neuroprotective Mechanisms of Korean Ginseng in Stroke It has been postulated that the determinants of neuronal cell death in acute and chronic neurodegenerative conditions are mediated by free radical damage. Ginseng has been reported to be neuroprotective and a potential preventive medicine, but the underlying cellular mechanisms are still unclear. Our preliminary results prompted us to focus our attention on Korean Ginseng and test the hypothesis that the transcriptional factor Nrf2 could participate in the overall Ginseng's neuroprotective function. HO, which cleaves heme (a prooxidant) to form biliverdin/bilirubin (antioxidants), carbon monoxide (a vasodilator), and iron (a prooxidant) has been shown to play a protective role in oxidative stress, ischemia, inflammation, and hypertension. Although HO2 is constitutively expressed, HO1 is inducible. Consequently, a possible way to increase HO levels to achieve neuroprotection may be to induce HO1. Of the compounds tested in our preliminary experiments in primary neuronal cultures, Ginseng was one of the most potent HO1 inducers. Our results also indicate that pretreatment of neurons with Ginseng is sufficient to provide neuroprotection, suggesting that co-treatment during oxidative stress is not necessary. This neuroprotective effect was abolished by a protein synthesis inhibitor, and was greatly reduced by an HO inhibitor. These preliminary results implied that specific induction of HO1 could be a mechanism by which Ginseng exerts its preventive neuroprotective actions and motivated us to propose that some of the neuroprotective effects attributed to Ginseng could be mediated through HO1 induction and the associated beneficial actions of heme degradation. Recently, we and others have described Nrf2 has as a key regulator of inflammation and redox homeostasis. In Aim 1, we will determine anatomical and behavioral outcomes following ischemia in wild type mice pre-treated (acutely or chronically) with Ginseng, determine whether the beneficial effect is sustained with aging, and test whether these effects are attenuated in Nrf2 knockout mice. In Aim 2, we will determine whether Ginseng induced characteristic changes in brain cells, and start addressing in which cell types these Nrf2 changes occurs. Together, these in vivo results will help us determine whether oral consumption of a standardized Ginseng extract could be beneficial, and which cells can be most associated with the Ginseng preventive brain mechanistic pathways by which Ginseng would provide the cell/brain with resistance to acute debilitating neurodegenerative conditions.

描述（由申请人提供）：更好地理解高丽参在中风中的神经保护机制据推测，急性和慢性神经退行性疾病中神经元细胞死亡的决定因素是由自由基损伤介导的。据报道，人参具有神经保护作用，是一种潜在的预防药物，但其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高丽参上，并检验转录因子 Nrf2 可以参与人参整体神经保护功能的假设。 H2O 可裂解血红素（一种促氧化剂），形成胆绿素/胆红素（抗氧化剂）、一氧化碳（一种血管扩张剂）和铁（一种促氧化剂），已被证明在氧化应激、缺血、炎症和高血压中发挥保护作用。尽管 HO2 是组成型表达，但 HO1 是诱导型表达。因此，增加 HO 水平以实现神经保护的一种可能方法是诱导 HO1。在我们的原代神经元培养物初步实验中测试的化合物中，人参是最有效的 HO1 诱导剂之一。我们的结果还表明，用人参预处理神经元足以提供神经保护，这表明氧化应激期间没有必要进行共同治疗。这种神经保护作用被蛋白质合成抑制剂消除，并被 H2O 抑制剂大大降低。这些初步结果表明，HO1 的特异性诱导可能是人参发挥其预防性神经保护作用的机制，并促使我们提出人参的一些神经保护作用可以通过 HO1 诱导和血红素降解的相关有益作用来介导。最近，我们和其他人将 Nrf2 描述为炎症和氧化还原稳态的关键调节因子。在目标 1 中，我们将确定用人参预处理（急性或长期）的野生型小鼠缺血后的解剖学和行为结果，确定有益效果是否随着衰老而持续，并测试这些效果在 Nrf2 敲除小鼠中是否减弱。在目标 2 中，我们将确定人参是否诱导脑细胞发生特征性变化，并开始解决这些 Nrf2 变化发生在哪些细胞类型中。总之，这些体内结果将帮助我们确定口服标准化人参提取物是否有益，以及哪些细胞与人参预防性大脑机制途径最相关，通过这些途径人参可以为细胞/大脑提供对急性衰弱的抵抗力。神经退行性疾病。