Potential Neuroprotective Mechanism of Korean Ginseng use in Global Ischemia

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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.