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Role of the S1P pathway and inhibition by fingolimod in preventing hemorrhagic transformation after stroke

Hemorrhagic transformation (HT) is a complication of severe ischemic stroke after revascularization. Patients with low platelet counts do not receive reperfusion therapies due to high risk of HT. The immunomodulatory drug fingolimod attenuated HT after tissue plasminogen activator in a thromboemboli...

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Autores principales: Salas-Perdomo, Angélica, Miró-Mur, Francesc, Gallizioli, Mattia, Brait, Vanessa H., Justicia, Carles, Meissner, Anja, Urra, Xabier, Chamorro, Angel, Planas, Anna M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549179/
https://www.ncbi.nlm.nih.gov/pubmed/31165772
http://dx.doi.org/10.1038/s41598-019-44845-5
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author Salas-Perdomo, Angélica
Miró-Mur, Francesc
Gallizioli, Mattia
Brait, Vanessa H.
Justicia, Carles
Meissner, Anja
Urra, Xabier
Chamorro, Angel
Planas, Anna M.
author_facet Salas-Perdomo, Angélica
Miró-Mur, Francesc
Gallizioli, Mattia
Brait, Vanessa H.
Justicia, Carles
Meissner, Anja
Urra, Xabier
Chamorro, Angel
Planas, Anna M.
author_sort Salas-Perdomo, Angélica
collection PubMed
description Hemorrhagic transformation (HT) is a complication of severe ischemic stroke after revascularization. Patients with low platelet counts do not receive reperfusion therapies due to high risk of HT. The immunomodulatory drug fingolimod attenuated HT after tissue plasminogen activator in a thromboembolic stroke model, but the underlying mechanism is unknown. Fingolimod acts on several sphingosine-1-phosphate (S1P) receptors, prevents lymphocyte trafficking to inflamed tissues, and affects brain and vascular cells. This study aimed to investigate changes in S1P-signaling in response to brain ischemia/reperfusion and the effects of the S1P receptor modulator fingolimod on HT. We studied brain expression of S1P signaling components, S1P concentration, and immune cell infiltration after ischemia/reperfusion in mice. We administered fingolimod after ischemia to wild-type mice, lymphocyte-deficient Rag2(−/−) mice, and mice with low platelet counts. Ischemia increased S1P-generating enzyme SphK1 mRNA, S1P concentration, and S1P receptor-1 (S1P1)(+) T-cells in the brain. Fingolimod prevented lymphocyte infiltration, and attenuated the severity of HT in Rag2(−/−) mice but it was ineffective under thrombocytopenia. Fingolimod prevented β-catenin degradation but not Evans blue extravasation. Ischemia/reperfusion upregulates brain S1P signaling pathway, and fingolimod exerts local effects that attenuate HT. Although fingolimod seems to act on the brain tissue, it did not prevent blood-brain barrier leakage.
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spelling pubmed-65491792019-06-12 Role of the S1P pathway and inhibition by fingolimod in preventing hemorrhagic transformation after stroke Salas-Perdomo, Angélica Miró-Mur, Francesc Gallizioli, Mattia Brait, Vanessa H. Justicia, Carles Meissner, Anja Urra, Xabier Chamorro, Angel Planas, Anna M. Sci Rep Article Hemorrhagic transformation (HT) is a complication of severe ischemic stroke after revascularization. Patients with low platelet counts do not receive reperfusion therapies due to high risk of HT. The immunomodulatory drug fingolimod attenuated HT after tissue plasminogen activator in a thromboembolic stroke model, but the underlying mechanism is unknown. Fingolimod acts on several sphingosine-1-phosphate (S1P) receptors, prevents lymphocyte trafficking to inflamed tissues, and affects brain and vascular cells. This study aimed to investigate changes in S1P-signaling in response to brain ischemia/reperfusion and the effects of the S1P receptor modulator fingolimod on HT. We studied brain expression of S1P signaling components, S1P concentration, and immune cell infiltration after ischemia/reperfusion in mice. We administered fingolimod after ischemia to wild-type mice, lymphocyte-deficient Rag2(−/−) mice, and mice with low platelet counts. Ischemia increased S1P-generating enzyme SphK1 mRNA, S1P concentration, and S1P receptor-1 (S1P1)(+) T-cells in the brain. Fingolimod prevented lymphocyte infiltration, and attenuated the severity of HT in Rag2(−/−) mice but it was ineffective under thrombocytopenia. Fingolimod prevented β-catenin degradation but not Evans blue extravasation. Ischemia/reperfusion upregulates brain S1P signaling pathway, and fingolimod exerts local effects that attenuate HT. Although fingolimod seems to act on the brain tissue, it did not prevent blood-brain barrier leakage. Nature Publishing Group UK 2019-06-05 /pmc/articles/PMC6549179/ /pubmed/31165772 http://dx.doi.org/10.1038/s41598-019-44845-5 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Salas-Perdomo, Angélica
Miró-Mur, Francesc
Gallizioli, Mattia
Brait, Vanessa H.
Justicia, Carles
Meissner, Anja
Urra, Xabier
Chamorro, Angel
Planas, Anna M.
Role of the S1P pathway and inhibition by fingolimod in preventing hemorrhagic transformation after stroke
title Role of the S1P pathway and inhibition by fingolimod in preventing hemorrhagic transformation after stroke
title_full Role of the S1P pathway and inhibition by fingolimod in preventing hemorrhagic transformation after stroke
title_fullStr Role of the S1P pathway and inhibition by fingolimod in preventing hemorrhagic transformation after stroke
title_full_unstemmed Role of the S1P pathway and inhibition by fingolimod in preventing hemorrhagic transformation after stroke
title_short Role of the S1P pathway and inhibition by fingolimod in preventing hemorrhagic transformation after stroke
title_sort role of the s1p pathway and inhibition by fingolimod in preventing hemorrhagic transformation after stroke
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549179/
https://www.ncbi.nlm.nih.gov/pubmed/31165772
http://dx.doi.org/10.1038/s41598-019-44845-5
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