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Department of Neurology
Jin Zhou, M.D., Ph.D.
Research Assistant Professor
Basic Research Laboratory in Cerebrovascular Disease
SUNY Downstate Medical Center, Brooklyn, NY
Post-Stroke Thrombopoietin Administration Reduces Brain Injury and Enhances Functional Recovery after Stroke
Recent studies have shown that hematopoietic growth factors (HGFs) can possess actions that extend beyond their haematopoietic properties. For example, erythropoietin (EPO) provides neuroprotection and promotes neurogenesis and angiogenesis following stroke. Although EPO has shown promise in preliminary stroke trials, negative cardiovascular and/or cerebrovascular events have occurred. Thrombopoietin (TPO), the primary HGF responsible for platelet production can enhance angiogenic responses and protection against ischemic injury in peripheral organs/tissues. However, no study has been performed to determine TPO’s cerebral protective effects. Thus, we conducted a study to determine the protective efficacy and mechanisms of TPO intervention in experimental focal stroke. Male rats underwent 2 hours of left middle cerebral artery occlusion (MCAO) followed by 22 hours of reperfusion. Vehicle or TPO (0.03 to 1.00 μg/kg) was administered intravenously immediately after reperfusion. Brain infarct and swelling, neurologic deficits, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), TPO and c-Mpl (TPO receptor) mRNA, MMP-9 enzyme activity and protein expression, and the integrity of the blood-brain barrier (BBB) were subsequently measured. MCAO reperfusion produced a large infarct and swelling after stroke. Thrombopoietin significantly reduced these in a dose-dependent manner. The most effective TPO dose, 0.10 μg/kg, when administrated immediately or 2 hours after reperfusion, significantly reduced infarct and swelling and ameliorated neurologic deficits after stroke. Stroke-induced increases in cortical MMP-9 mRNA, enzyme activity and protein expression, TIMP-1 mRNA, and Evans blue extravasation were reduced by TPO intervention. Thrombopoietin did not alter cortical TPO or c-Mpl mRNA expression, blood pressure, heart rate, blood hematocrit, or platelets. This is the first demonstration of TPO's efficacy in reducing ischemic brain injury and improving functional outcome, partly by inhibiting the stroke-induced increase in MMP-9 and the BBB dysfunction. Future research will investigate the effects of TPO in the embolic stroke model: (1) alone and in combination with tissue plasminogen activator (tPA) in the rat, and (2) in wild-type compared to TPO receptor knock-out (c-Mpl-/-) mice. This additional work will provide data on TPO brain protection in another stroke model and in a second species, will determine new potential applications for TPO (e.g., Can it extend the therapeutic window of tPA stroke intervention?), and will determine the on and off-target signaling pathways and mechanisms of TPO brain protection.
I was recently employed at the National Institutes of Mental Health (Section of Pharmacology; 2002-2008) and have been working in stroke now for over 2 years at SUNY DMC. I have significant research training/experience (i.e., skilled both in vivo and in vitro biology research; technical expertise in molecular biology, pharmacology, biochemistry, immunohistochemistry (IHC) and behavior. My background is in Brain Ischemia/Stress and the microvasculature/Angiotensin system. I was responsible for collecting all the data on TPO brain protection and anti-inflammatory mechanisms in rat middle cerebral artery ischemia-reperfusion stroke (e.g., all biochemistry including transcript expression measurements, Western Blots, gel zymography and blood brain barrier integrity). Also, I will carry out MMP-9 IHC, including celldouble-labeling work. I am currently developing the embolic stroke models in both rat and mouse for our future research. I am responsible for all data analysis/training in biochemistry and IHC data, and in neurological and cognitive testing; including blinded data collection, together with our research associate Jie Li, MD. I am also responsible (with Dr. Li) for all student research training in the laboratory. My goals are to help drive research on TPO brain protection, and to push our laboratory work into new areas of brain recovery from injury and models of vascular cognitive impairment.