On average, one American has stroke every 40 seconds, and one dies every 4 minutes. Of the different types of stroke, acute ischemic stroke is the most common, and successful treatment of this medical condition remains very challenging. The clot busting drug tissue plasminogen activator (tPA) is the only drug approved for clinical use for acute ischemic stroke. However the drug must be initiated within 4.5 h of stroke onset or risk detrimental side effects including intracerebral hemorrhagic transformation (HT). Therefore, an important clinical problem is to develop methods that will extend the limited therapeutic time window of tPA or reduce complications associated with delayed treatment of tPA. The granulocyte-colony stimulating factor (G-CSF) has been shown to exert neuroprotective effects in animal models of ischemia. It is not yet known if the drug could attenuate detrimental side effects of delayed tPA treatment in ischemic stroke. Furthermore, we have shown in a rat model of traumatic brain injury (TBI) that G-CSF monotherapy reduced neuroinflammation in the gray and white matter areas and also ameliorated TBI-induced impairment in endogenous neurogenesis. These findings taken together with reported neuroprotective effects of G-CSF in animal models of ischemia led us to hypothesize that the treatment of G-CSF will also reduce HT associated with delayed treatment of tPA (Aim 1). Treatment with G-CSF mobilizes cells from the bone marrow to the peripheral blood including CD34+ bone marrow stem cells which contain endothelial progenitor cells (EPCs). Several studies suggested that beneficial effects of G-CSF in stroke (e.g. angiogenesis, vasculogenesis, etc.) are mediated by EPCs. Moreover, in a previous study, we have also shown that transplantation of human cerebral endothelial cells attenuated stroke-induced motor and neurological deficits in rats via enhancement of vasculogenesis. In light of these findings, we hypothesized that G-CSF mobilizes EPCs in the setting of tPA-induced HT in stroke, and EPCs attenuate HT via enhancement of vasculogenesis or angiogenesis, processes that preserve the cerebrovasculature (Aim 2). Delayed tPA-induced HT has been attributed to effects of tPA on the neurovascular unit and also via disruption of the blood brain barrier (BBB). We hypothesized that another mechanism underlying neuroprotective effects of G-CSF is via preservation of the integrity of the BBB through vasculogenic and angiogenic effects of recruited EPCs. The long-term goal of this study is to demonstrate that G-CSF in tandem with tPA will reduce delayed tPA-associated complications and also extend the thrombolytic efficacy of tPA. The overall impact is that at the completion of this study, the findings from this work will lay the foundation for the clinical evaluation of G-CSF in attenuating HT associated with delayed treatment of tPA.

Public Health Relevance

Successful treatment of acute ischemic stroke remains a major challenge in clinical medicine. Only 3% to 5% of patients receive tissue plasminogen (tPA) therapy for acute ischemic stroke and delayed treatment of tPA (i.e. beyond 4.5 h of stroke onset) has been associated with serious complications including hemorrhagic transformation (HT) and neurotoxicity. The goal of this study is to provide groundbreaking evidence that will advance the potential clinical application of G-CSF in reducing HT associated with delayed treatment of tPA. Our long-term goal is to demonstrate that G-CSF in combination with tPA will reduce the detrimental side effects of delayed tPA treatment and also extend the thrombolytic efficacy of tPA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS089851-02
Application #
8931096
Study Section
Drug Discovery for the Nervous System Study Section (DDNS)
Program Officer
Koenig, James I
Project Start
2014-09-30
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2017-08-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of South Florida
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
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Napoli, Eleonora; Borlongan, Cesar V (2017) Cell Therapy in Parkinson's Disease: Host Brain Repair Machinery Gets a Boost From Stem Cell Grafts. Stem Cells 35:1443-1445
Shojo, Hideki; Borlongan, Cesario V; Mabuchi, Tadashi (2017) Genetic and Histological Alterations Reveal Key Role of Prostaglandin Synthase and Cyclooxygenase 1 and 2 in Traumatic Brain Injury-Induced Neuroinflammation in the Cerebral Cortex of Rats Exposed to Moderate Fluid Percussion Injury. Cell Transplant 26:1301-1313
Liska, Michael G; Crowley, Marci G; Borlongan, Cesar V (2017) Regulated and Unregulated Clinical Trials of Stem Cell Therapies for Stroke. Transl Stroke Res 8:93-103

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