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

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 infarct...

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Autores principales: dela Peña, Ike C., Yang, Samuel, Shen, Guofang, Fang Liang, Hsiao, Solak, Sara, Borlongan, Cesar V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032420/
https://www.ncbi.nlm.nih.gov/pubmed/29857523
http://dx.doi.org/10.3390/ijms19061635
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author dela Peña, Ike C.
Yang, Samuel
Shen, Guofang
Fang Liang, Hsiao
Solak, Sara
Borlongan, Cesar V.
author_facet dela Peña, Ike C.
Yang, Samuel
Shen, Guofang
Fang Liang, Hsiao
Solak, Sara
Borlongan, Cesar V.
author_sort dela Peña, Ike C.
collection PubMed
description 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.
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spelling pubmed-60324202018-07-13 Extension of Tissue Plasminogen Activator Treatment Window by Granulocyte-Colony Stimulating Factor in a Thromboembolic Rat Model of Stroke dela Peña, Ike C. Yang, Samuel Shen, Guofang Fang Liang, Hsiao Solak, Sara Borlongan, Cesar V. Int J Mol Sci Article 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. MDPI 2018-05-31 /pmc/articles/PMC6032420/ /pubmed/29857523 http://dx.doi.org/10.3390/ijms19061635 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
dela Peña, Ike C.
Yang, Samuel
Shen, Guofang
Fang Liang, Hsiao
Solak, Sara
Borlongan, Cesar V.
Extension of Tissue Plasminogen Activator Treatment Window by Granulocyte-Colony Stimulating Factor in a Thromboembolic Rat Model of Stroke
title Extension of Tissue Plasminogen Activator Treatment Window by Granulocyte-Colony Stimulating Factor in a Thromboembolic Rat Model of Stroke
title_full Extension of Tissue Plasminogen Activator Treatment Window by Granulocyte-Colony Stimulating Factor in a Thromboembolic Rat Model of Stroke
title_fullStr Extension of Tissue Plasminogen Activator Treatment Window by Granulocyte-Colony Stimulating Factor in a Thromboembolic Rat Model of Stroke
title_full_unstemmed Extension of Tissue Plasminogen Activator Treatment Window by Granulocyte-Colony Stimulating Factor in a Thromboembolic Rat Model of Stroke
title_short Extension of Tissue Plasminogen Activator Treatment Window by Granulocyte-Colony Stimulating Factor in a Thromboembolic Rat Model of Stroke
title_sort extension of tissue plasminogen activator treatment window by granulocyte-colony stimulating factor in a thromboembolic rat model of stroke
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032420/
https://www.ncbi.nlm.nih.gov/pubmed/29857523
http://dx.doi.org/10.3390/ijms19061635
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