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A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke

Alteration of the extracellular matrix (ECM) is one of the major events in the pathogenesis of brain lesions following ischemic stroke. Heparan sulfate mimetics (HSm) are synthetic pharmacologically active polysaccharides that promote ECM remodeling and tissue regeneration in various types of lesion...

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Autores principales: Khelif, Yacine, Toutain, Jérôme, Quittet, Marie-Sophie, Chantepie, Sandrine, Laffray, Xavier, Valable, Samuel, Divoux, Didier, Sineriz, Fernando, Pascolo-Rebouillat, Emanuelle, Papy-Garcia, Dulce, Barritault, Denis, Touzani, Omar, Bernaudin, Myriam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299437/
https://www.ncbi.nlm.nih.gov/pubmed/30613264
http://dx.doi.org/10.7150/thno.28252
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author Khelif, Yacine
Toutain, Jérôme
Quittet, Marie-Sophie
Chantepie, Sandrine
Laffray, Xavier
Valable, Samuel
Divoux, Didier
Sineriz, Fernando
Pascolo-Rebouillat, Emanuelle
Papy-Garcia, Dulce
Barritault, Denis
Touzani, Omar
Bernaudin, Myriam
author_facet Khelif, Yacine
Toutain, Jérôme
Quittet, Marie-Sophie
Chantepie, Sandrine
Laffray, Xavier
Valable, Samuel
Divoux, Didier
Sineriz, Fernando
Pascolo-Rebouillat, Emanuelle
Papy-Garcia, Dulce
Barritault, Denis
Touzani, Omar
Bernaudin, Myriam
author_sort Khelif, Yacine
collection PubMed
description Alteration of the extracellular matrix (ECM) is one of the major events in the pathogenesis of brain lesions following ischemic stroke. Heparan sulfate mimetics (HSm) are synthetic pharmacologically active polysaccharides that promote ECM remodeling and tissue regeneration in various types of lesions. HSm bind to growth factors, protect them from enzymatic degradation and increase their bioavailability, which promotes tissue repair. As the ECM is altered during stroke and HSm have been shown to restore the ECM, we investigated the potential of HSm4131 (also named RGTA-4131®) to protect brain tissue and promote regeneration and plasticity after a stroke. Methods: Ischemic stroke was induced in rats using transient (1 h) intraluminal middle cerebral artery occlusion (MCAo). Animals were assigned to the treatment (HSm4131; 0.1, 0.5, 1.5, or 5 mg/kg) or vehicle control (saline) groups at different times (1, 2.5 or 6 h) after MCAo. Brain damage was assessed by MRI for the acute (2 days) and chronic (14 days) phases post-occlusion. Functional deficits were evaluated with a battery of sensorimotor behavioral tests. HSm4131-(99m)Tc biodistribution in the ischemic brain was analyzed between 5 min and 3 h following middle cerebral artery reperfusion. Heparan sulfate distribution and cellular reactions, including angiogenesis and neurogenesis, were evaluated by immunohistochemistry, and growth factor gene expression (VEGF-A, Ang-2) was quantified by RT-PCR. Results: HSm4131, administered intravenously after stroke induction, located and remained in the ischemic hemisphere. HSm4131 conferred long-lasting neuroprotection, and significantly reduced functional deficits with no alteration of physiological parameters. It also restored the ECM, and increased brain plasticity processes, i.e., angiogenesis and neurogenesis, in the affected brain hemisphere. Conclusion: HSm represent a promising ECM-based therapeutic strategy to protect and repair the brain after a stroke and favor functional recovery.
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spelling pubmed-62994372019-01-04 A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke Khelif, Yacine Toutain, Jérôme Quittet, Marie-Sophie Chantepie, Sandrine Laffray, Xavier Valable, Samuel Divoux, Didier Sineriz, Fernando Pascolo-Rebouillat, Emanuelle Papy-Garcia, Dulce Barritault, Denis Touzani, Omar Bernaudin, Myriam Theranostics Research Paper Alteration of the extracellular matrix (ECM) is one of the major events in the pathogenesis of brain lesions following ischemic stroke. Heparan sulfate mimetics (HSm) are synthetic pharmacologically active polysaccharides that promote ECM remodeling and tissue regeneration in various types of lesions. HSm bind to growth factors, protect them from enzymatic degradation and increase their bioavailability, which promotes tissue repair. As the ECM is altered during stroke and HSm have been shown to restore the ECM, we investigated the potential of HSm4131 (also named RGTA-4131®) to protect brain tissue and promote regeneration and plasticity after a stroke. Methods: Ischemic stroke was induced in rats using transient (1 h) intraluminal middle cerebral artery occlusion (MCAo). Animals were assigned to the treatment (HSm4131; 0.1, 0.5, 1.5, or 5 mg/kg) or vehicle control (saline) groups at different times (1, 2.5 or 6 h) after MCAo. Brain damage was assessed by MRI for the acute (2 days) and chronic (14 days) phases post-occlusion. Functional deficits were evaluated with a battery of sensorimotor behavioral tests. HSm4131-(99m)Tc biodistribution in the ischemic brain was analyzed between 5 min and 3 h following middle cerebral artery reperfusion. Heparan sulfate distribution and cellular reactions, including angiogenesis and neurogenesis, were evaluated by immunohistochemistry, and growth factor gene expression (VEGF-A, Ang-2) was quantified by RT-PCR. Results: HSm4131, administered intravenously after stroke induction, located and remained in the ischemic hemisphere. HSm4131 conferred long-lasting neuroprotection, and significantly reduced functional deficits with no alteration of physiological parameters. It also restored the ECM, and increased brain plasticity processes, i.e., angiogenesis and neurogenesis, in the affected brain hemisphere. Conclusion: HSm represent a promising ECM-based therapeutic strategy to protect and repair the brain after a stroke and favor functional recovery. Ivyspring International Publisher 2018-11-12 /pmc/articles/PMC6299437/ /pubmed/30613264 http://dx.doi.org/10.7150/thno.28252 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Khelif, Yacine
Toutain, Jérôme
Quittet, Marie-Sophie
Chantepie, Sandrine
Laffray, Xavier
Valable, Samuel
Divoux, Didier
Sineriz, Fernando
Pascolo-Rebouillat, Emanuelle
Papy-Garcia, Dulce
Barritault, Denis
Touzani, Omar
Bernaudin, Myriam
A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke
title A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke
title_full A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke
title_fullStr A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke
title_full_unstemmed A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke
title_short A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke
title_sort heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299437/
https://www.ncbi.nlm.nih.gov/pubmed/30613264
http://dx.doi.org/10.7150/thno.28252
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