Better Understanding of the Neuroprotective Mechanisms of Korean Ginseng in Strok

描述（由申请人提供）：更好地了解高丽人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和潜在的预防药物，但其潜在的细胞机制尚不清楚。我们的初步结果促使我们将注意力集中在高丽人参上，并验证转录因子Nrf2可能参与人参整体神经保护功能的假设。HO可以裂解血红素（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、炎症和高血压中起保护作用。虽然HO2是组成性表达，但HO1是诱导性的。因此，增加HO水平以达到神经保护的一种可能方法是诱导HO1。在我们的初步神经细胞培养实验中，人参是最有效的HO1诱导剂之一。我们的研究结果还表明，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的联合治疗是不必要的。这种神经保护作用被蛋白质合成抑制剂所消除，并被HO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能是通过HO1的诱导和血红素降解的相关有益作用介导的。最近，我们和其他人已经将Nrf2描述为炎症和氧化还原稳态的关键调节因子。在Aim 1中，我们将确定人参预处理（急性或慢性）野生型小鼠缺血后的解剖和行为结果，确定有益效果是否随年龄增长而持续，并测试这些效果是否在Nrf2敲除小鼠中减弱。在Aim 2中，我们将确定人参是否诱导了脑细胞的特征变化，并开始确定这些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人参提取物是否有益，以及哪些细胞与人参预防脑机制途径最相关，人参可以通过这些途径为细胞/大脑提供抗急性衰弱性神经退行性疾病的能力。

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.