Potential Neuroprotective Mechanism of Korean Ginseng use in Global Ischemia

描述（由申请人提供）：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。我们的初步研究结果促使我们将注意力集中在高丽人参上，并验证血红素加氧酶（HO）活性可能参与人参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，HO 1的特异性诱导可能是人参发挥其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以通过HO 1诱导和血红素降解的相关有益作用来介导。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（WT）小鼠在全脑缺血后的神经元细胞死亡和行为结果，并测试这些作用是否在敲除小鼠中减弱。在目标2中，我们将确定人参诱导的HO 1表达的变化是否导致来自WT和敲除小鼠的神经元培养物中血红素加氧酶活性和细胞存活的变化。总之，这些结果将帮助我们确定食用人参提取物是否有益，以及人参可以为大脑提供对急性和/或慢性衰弱性神经退行性疾病的抵抗力的途径。几个世纪以来，人参一直被报道为加强神经系统的预防性药物，但其潜在的细胞机制仍不清楚。我们的初步研究结果促使我们将注意力集中在高丽人参上，并验证血红素加氧酶（HO）可能参与人参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，已显示在氧化应激、缺血、炎症和高血压中起保护作用。使用临床前模型，我们将确定人参是否可以防止神经功能衰退和神经元细胞死亡后，全球缺血事件;从而提供新的途径，人参可以提供大脑抵抗急性和/或慢性衰弱性神经退行性疾病。

DESCRIPTION (provided by applicant): 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 heme oxygenase (HO) activity could participate in 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 HO1inducers. 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 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. In Aim 1, we will determine neuronal cell death and behavioral outcomes following global ischemia in wildtype (WT) mice pre-treated (acutely or chronically) with Ginseng and test whether these effects are attenuated in knockout mice. In Aim 2, we will determine whether changes in HO1 expression induced by Ginseng result in changes in heme oxygenase activity and cell survival in neuronal cultures derived from WT and knockout mice. Together, these results will help us determine whether consumption of Ginseng extracts could be beneficial and the pathways by which Ginseng could provide the brain with resistance to acute and/or chronic debilitating neurodegenerative conditions. For centuries, Ginseng has been reported as preventive medicine to strengthen the nervous system, 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 heme oxygenase (HO) enzyme could participate in Ginseng's neuroprotective function. HO, which cleaves heme (a prooxidant) to form biliverdin/bilirubin (antioxidants), carbon monoxide (a vasodilator), and iron, has been shown to play a protective role in oxidative stress, ischemia, inflammation, and hypertension. Using pre-clinical models, we will determine whether Ginseng can prevent neurological decline and neuronal cell death following global ischemic events; thus providing new pathways by which Ginseng could provide the brain with resistance against acute and/or chronic debilitating neurodegenerative conditions.