Neuroprotective Effect of Ginkgo Biloba and its Bioactive Components Ischemia

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My expertise and skill in neurosurgery, particularly in small animal models, together with my knowledge of herbal drugs and proteomics are essential to the advancement of research in the field of stroke and ischemic brain damage. Because stroke is the third most common cause of death in the US, research in this field is of great importance. I have made a number of contributions to this clinically relevant problem. For example, I have recently published an optimized method for producing transient stroke in mice, and have been optimizing a permanent model of ischemia also. I have used both of these methods to test the beneficial properties of other well standardized herbal plant extracts and their bioactive components against stroke. My long term goals involve researching natural products, such as Ginkgo biloba (EGb 761), to find novel mechanisms for preventing and treating stroke and ischemia-related brain injury. While starting my fifth year of postdoctoral training, my immediate goal is to become an independent researcher in the cutting-edge research of neuronal damage associated with ischemia. In addition to my experience in stroke and herbal medicine, this proposal will allow me to complete my training in behavioral science and molecular biology which is necessary to reach my independent career goals. I will work with my mentor, Dr. Dore, who has extensive expertise in neuronal dysfunction associated with stroke and other neurodegenerative diseases and has a proven record of training fellows. The training environment also involves a team of top researchers in behavioral neuroscience, stroke, and aging at the Johns Hopkins School of Medicine. The K99/ROO award will allow me the time and support necessary to work toward my research goals. The main goal of the proposed project is to determine the neuroprotective effect and mechanism of actions of EGb in ischemic brain injury by using permanent, transient, and global models of ischemia. We have accumulated evidence that heme oxygenase 1 (HO1) activity reduces ischemic brain injury, and we hypothesize that EGb provides neuroprotection by inducing HO1. To determine the role of HO1 in EGb neuroprotection, we will subject wildtype mice and mice with targeted deletion of HO1 (HOT'") to models of ischemia and compare the effect of EGb pre- and post-treatment on injury size. We will also optimize the therapeutic dose and window. We will address possible mechanisms of protection by measuring cerebral blood flow, hippocampal cell death, HO1 expression, and functional outcomes in various in vitro and in vivo ischemia models. This research proposal will have direct pre-clinical relevance by 1) determining the efficacy of EGb in treating or preventing stroke-related injury, 2) determining the optimal dose and time frame for EGb use, and 3) providing information for clinicians and their patients regarding the prophylactic use of Ginkgo extract, EGb.