Better Understanding of the Neuroprotective Mechanisms of Korean Ginseng in Strok

描述（由申请人提供）：更好地理解高丽人参在中风中的神经保护机制已经假定，在急性和慢性神经变性病症中神经元细胞死亡的决定因素由自由基损伤介导。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把注意力集中在高丽人参上，并检验转录因子Nrf 2可能参与人参整体神经保护功能的假设。HO切割血红素（促氧化剂）以形成胆绿素/胆红素（抗氧化剂）、一氧化碳（血管扩张剂）和铁（促氧化剂），已显示在氧化应激、缺血、炎症和高血压中起保护作用。虽然HO 2是组成型表达的，但HO 1是诱导型的。因此，增加HO水平以实现神经保护的可能方法可能是诱导HO 1。在我们在原代神经元培养物中的初步实验中测试的化合物中，人参是最有效的HO 1诱导剂之一。我们的研究结果还表明，用人参预处理神经元足以提供神经保护，这表明在氧化应激期间的共同治疗是不必要的。这种神经保护作用被蛋白质合成抑制剂所消除，并且被HO抑制剂大大降低。这些初步结果表明，特异性诱导HO 1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HO 1诱导和血红素降解的相关有益作用来介导。最近，我们和其他人已经描述了Nrf 2作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（急性或慢性）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年龄的增长而持续，并测试这些效果是否在Nrf 2敲除小鼠中减弱。在目标2中，我们将确定人参是否诱导脑细胞的特征变化，并开始解决这些Nrf 2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，以及哪些细胞可能与人参预防性脑机制途径最相关，人参将通过该途径为细胞/大脑提供对急性衰弱性神经退行性疾病的抵抗力。

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.