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.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Transition Award (R00)
Project #
5R00AT004197-05
Application #
8223212
Study Section
Special Emphasis Panel (NSS)
Program Officer
Alekel, D Lee
Project Start
2008-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$242,165
Indirect Cost
$80,506
Name
University of Toledo
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Tulsulkar, Jatin; Nada, Shadia E; Slotterbeck, Brandon D et al. (2016) Obesity and hyperglycemia lead to impaired post-ischemic recovery after permanent ischemia in mice. Obesity (Silver Spring) 24:417-23
Jain, Sudhir; Tulsulkar, Jatin; Rana, Anita et al. (2016) Transgenic Mice Overexpressing Human Angiotensin I Receptor Gene Are Susceptible to Stroke Injury. Mol Neurobiol 53:1533-9
Tulsulkar, Jatin; Glueck, Bryan; Hinds Jr, Terry D et al. (2016) Ginkgo biloba Extract Prevents Female Mice from Ischemic Brain Damage and the Mechanism Is Independent of the HO1/Wnt Pathway. Transl Stroke Res 7:120-31
Nada, Shadia E; Williams, Frederick E; Shah, Zahoor A (2016) Development of a Novel and Robust Pharmacological Model of Okadaic Acid-induced Alzheimer's Disease in Zebrafish. CNS Neurol Disord Drug Targets 15:86-94
Madineni, Anusha; Alhadidi, Qasim; Shah, Zahoor A (2016) Cofilin Inhibition Restores Neuronal Cell Death in Oxygen-Glucose Deprivation Model of Ischemia. Mol Neurobiol 53:867-78
Nash, Kevin M; Shah, Zahoor A (2015) Current Perspectives on the Beneficial Role of Ginkgo biloba in Neurological and Cerebrovascular Disorders. Integr Med Insights 10:1-9
Raghavan, Aparna; Shah, Zahoor A (2015) Withania somnifera Improves Ischemic Stroke Outcomes by Attenuating PARP1-AIF-Mediated Caspase-Independent Apoptosis. Mol Neurobiol 52:1093-105
Raghavan, Aparna; Shah, Zahoor A (2014) Repair and regeneration properties of Ginkgo biloba after ischemic brain injury. Neural Regen Res 9:1104-1107
Orbán-Gyapai, Orsolya; Raghavan, Aparna; Vasas, Andrea et al. (2014) Flavonoids isolated from Rumex aquaticus exhibit neuroprotective and neurorestorative properties by enhancing neurite outgrowth and synaptophysin. CNS Neurol Disord Drug Targets 13:1458-64
Nada, Shadia E; Tulsulkar, Jatin; Shah, Zahoor A (2014) Heme oxygenase 1-mediated neurogenesis is enhanced by Ginkgo biloba (EGb 761ýý) after permanent ischemic stroke in mice. Mol Neurobiol 49:945-56

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