Potential Neuroprotective Mechanism of Korean Ginseng use in Global Ischemia

描述(由申请人提供)：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，并检验了血红素加氧酶(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。在我们的初步神经元培养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神经保护作用的机制之一，并促使我们提出人参的一些神经保护作用可能是通过HO1诱导和相关的血红素降解的有益作用来介导的。在目标1中，我们将确定野生型(WT)小鼠经人参预处理(急性或长期)后的神经细胞死亡和行为结果，并在基因敲除小鼠中测试这些影响是否减弱。在目标2中，我们将确定人参诱导的HO1表达的变化是否会导致WT和基因敲除小鼠来源的神经元培养中血红素加氧酶活性和细胞存活率的变化。总之，这些结果将帮助我们确定食用人参提取物是否有益，以及人参可以通过哪些途径为大脑提供对急性和/或慢性衰弱神经退行性疾病的抵抗力。几个世纪以来，人参一直被报道为加强神经系统的预防药物，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韩国人参上，并验证了血红素加氧酶(HO)酶可能参与人参神经保护功能的假说。HO能分解血红素(一种氧化剂)，形成胆绿素/胆红素(抗氧化剂)、一氧化碳(血管扩张剂)和铁，已被证明在氧化应激、缺血、炎症和高血压方面起到保护作用。利用临床前模型，我们将确定人参是否可以防止全球缺血事件后的神经功能衰退和神经细胞死亡，从而提供新的途径，使人参能够为大脑提供对急性和/或慢性衰弱神经退行性疾病的抵抗。

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.