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Extension of Tissue Plasminogen Activator Treatment Window by Granulocyte-Colony Stimulating Factor in a Thromboembolic Rat Model of Stroke

1
Department of Pharmaceutical and Administrative Sciences, Loma Linda University, Loma Linda, CA 92350, USA
2
Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(6), 1635; https://doi.org/10.3390/ijms19061635
Received: 18 May 2018 / Revised: 27 May 2018 / Accepted: 29 May 2018 / Published: 31 May 2018
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases)
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Abstract

When given beyond 4.5 h of stroke onset, tissue plasminogen activator (tPA) induces deleterious side effects in the ischemic brain, notably, hemorrhagic transformation (HT). We examined the efficacy of granulocyte-colony stimulating factor (G-CSF) in reducing delayed tPA-induced HT, cerebral infarction, and neurological deficits in a thromboembolic (TE) stroke model, and whether the effects of G-CSF were sustained for longer periods of recovery. After stroke induction, rats were given intravenous saline (control), tPA (10 mg/kg), or G-CSF (300 μg/kg) + tPA 6 h after stroke. We found that G-CSF reduced delayed tPA-associated HT by 47%, decreased infarct volumes by 33%, and improved motor and neurological deficits by 15% and 25%, respectively. It also prevented delayed tPA treatment-induced mortality by 46%. Immunohistochemistry showed 1.5- and 1.8-fold enrichment of the endothelial progenitor cell (EPC) markers CD34+ and VEGFR2 in the ischemic cortex and striatum, respectively, and 1.7- and 2.8-fold increases in the expression of the vasculogenesis marker von Willebrand factor (vWF) in the ischemic cortex and striatum, respectively, in G-CSF-treated rats compared with tPA-treated animals. Flow cytometry revealed increased mobilization of CD34+ cells in the peripheral blood of rats given G-CSF. These results corroborate the efficacy of G-CSF in enhancing the therapeutic time window of tPA for stroke treatment via EPC mobilization and enhancement of vasculogenesis. View Full-Text
Keywords: G-CSF; thromboembolic model; tPA; hemorrhagic transformation; vasculogenesis G-CSF; thromboembolic model; tPA; hemorrhagic transformation; vasculogenesis
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Dela Peña, I.C.; Yang, S.; Shen, G.; Fang Liang, H.; Solak, S.; Borlongan, C.V. Extension of Tissue Plasminogen Activator Treatment Window by Granulocyte-Colony Stimulating Factor in a Thromboembolic Rat Model of Stroke. Int. J. Mol. Sci. 2018, 19, 1635.

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