Better Understanding of the Neuroprotective Mechanisms of Korean Ginseng in Strok

描述(申请人提供)：更好地了解韩国人参在中风中的神经保护机制据推测，在急性和慢性神经退行性疾病中，神经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作用，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韩国人参上，并测试了转录因子Nrf2可能参与人参整体神经保护功能的假设。HO分解血红素(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。虽然HO2是结构性表达的，但HO1是可以诱导表达的。因此，增加HO水平以实现神经保护的一种可能方法可能是诱导HO1。在我们在原代神经元培养的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，人参对神经元的预处理足以提供神经保护，这表明氧化应激期间的共同处理是不必要的。这种神经保护作用被蛋白质合成抑制剂消除，并被HO抑制剂大大减弱。这些初步结果表明，HO1的特异性诱导可能是人参发挥预防性神经保护作用的一种机制，并促使我们提出人参的一些神经保护作用可能是通过HO1诱导和与之相关的血红素降解的有益作用来介导的。最近，我们和其他人将Nrf2描述为炎症和氧化还原动态平衡的关键调节因子。在目标1中，我们将确定人参预先(急性或慢性)处理的野生型小鼠缺血后的解剖学和行为结果，确定这种有益作用是否随着年龄的增长而持续，并在Nrf2基因敲除小鼠中测试这些影响是否减弱。在目标2中，我们将确定人参是否诱导了脑细胞的特征变化，并开始研究这些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脑机制途径最相关，人参通过这些途径为细胞/大脑提供对急性衰弱神经退行性疾病的抵抗。

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.