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Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage
BACKGROUND: Subarachnoid hemorrhage (SAH) is a neurological emergency with limited pharmacological treatment options. Inflammation is increasingly recognized as a key pathogenic contributor to brain injury in this condition. In the present study, we examined the neuroprotective effects of the immuno...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324852/ https://www.ncbi.nlm.nih.gov/pubmed/25622980 http://dx.doi.org/10.1186/s12974-015-0234-7 |
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author | Xu, Hao-Liang Pelligrino, Dale A Paisansathan, Chanannait Testai, Fernando D |
author_facet | Xu, Hao-Liang Pelligrino, Dale A Paisansathan, Chanannait Testai, Fernando D |
author_sort | Xu, Hao-Liang |
collection | PubMed |
description | BACKGROUND: Subarachnoid hemorrhage (SAH) is a neurological emergency with limited pharmacological treatment options. Inflammation is increasingly recognized as a key pathogenic contributor to brain injury in this condition. In the present study, we examined the neuroprotective effects of the immunomodulatory agent, fingolimod, in rats subjected to SAH. METHODS: We utilized an endovascular rat perforation model of SAH. Animals were divided into four groups: (1) sham-vehicle; (2) sham-fingolimod; (3) SAH-vehicle; and (4) SAH-fingolimod. Rats received either vehicle solution or fingolimod (0.5 mg/kg) intraperitoneally 3 hours after sham surgery or SAH. A closed cranial window and intravital microscope system was used at 48 hours to assess neuroinflammation, which was represented by rhodamine-6G-labeled leukocyte trafficking in pial venules, and pial arteriolar dilating responses to a variety of vasodilators, including hypercapnia, and topically-applied acetylcholine, adenosine, and S-nitroso-N-acetyl penicillamine. In addition, motor-sensory function was evaluated. RESULTS: Compared to sham-vehicle rats, SAH-vehicle animals displayed a four-times greater increase in pial venular intraluminal leukocyte adhesion. Treatment with fingolimod largely reduced the intravascular leukocyte adhesion. Vehicle-treated SAH animals displayed a significant decrease in pial arteriolar responses to all the vasodilators tested and vascular reactivity was preserved, to a significant degree, in the presence of fingolimod. In addition, neurological scores obtained at 48 hours post-SAH indicated significant neurological deficits in the vehicle-treated group (versus sham-vehicle surgical control). Those deficiencies were partially reduced by fingolimod (P < 0.0001 compared to the vehicle-treated SAH group). CONCLUSIONS: Treatment of rats with fingolimod was associated with a marked limitation in the intravascular adhesion of leukocytes to pial venules, preserved pial arteriolar dilating function, and improved neurological outcome in rats subjected to SAH. |
format | Online Article Text |
id | pubmed-4324852 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-43248522015-02-12 Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage Xu, Hao-Liang Pelligrino, Dale A Paisansathan, Chanannait Testai, Fernando D J Neuroinflammation Research BACKGROUND: Subarachnoid hemorrhage (SAH) is a neurological emergency with limited pharmacological treatment options. Inflammation is increasingly recognized as a key pathogenic contributor to brain injury in this condition. In the present study, we examined the neuroprotective effects of the immunomodulatory agent, fingolimod, in rats subjected to SAH. METHODS: We utilized an endovascular rat perforation model of SAH. Animals were divided into four groups: (1) sham-vehicle; (2) sham-fingolimod; (3) SAH-vehicle; and (4) SAH-fingolimod. Rats received either vehicle solution or fingolimod (0.5 mg/kg) intraperitoneally 3 hours after sham surgery or SAH. A closed cranial window and intravital microscope system was used at 48 hours to assess neuroinflammation, which was represented by rhodamine-6G-labeled leukocyte trafficking in pial venules, and pial arteriolar dilating responses to a variety of vasodilators, including hypercapnia, and topically-applied acetylcholine, adenosine, and S-nitroso-N-acetyl penicillamine. In addition, motor-sensory function was evaluated. RESULTS: Compared to sham-vehicle rats, SAH-vehicle animals displayed a four-times greater increase in pial venular intraluminal leukocyte adhesion. Treatment with fingolimod largely reduced the intravascular leukocyte adhesion. Vehicle-treated SAH animals displayed a significant decrease in pial arteriolar responses to all the vasodilators tested and vascular reactivity was preserved, to a significant degree, in the presence of fingolimod. In addition, neurological scores obtained at 48 hours post-SAH indicated significant neurological deficits in the vehicle-treated group (versus sham-vehicle surgical control). Those deficiencies were partially reduced by fingolimod (P < 0.0001 compared to the vehicle-treated SAH group). CONCLUSIONS: Treatment of rats with fingolimod was associated with a marked limitation in the intravascular adhesion of leukocytes to pial venules, preserved pial arteriolar dilating function, and improved neurological outcome in rats subjected to SAH. BioMed Central 2015-01-27 /pmc/articles/PMC4324852/ /pubmed/25622980 http://dx.doi.org/10.1186/s12974-015-0234-7 Text en © Xu et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Xu, Hao-Liang Pelligrino, Dale A Paisansathan, Chanannait Testai, Fernando D Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage |
title | Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage |
title_full | Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage |
title_fullStr | Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage |
title_full_unstemmed | Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage |
title_short | Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage |
title_sort | protective role of fingolimod (fty720) in rats subjected to subarachnoid hemorrhage |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324852/ https://www.ncbi.nlm.nih.gov/pubmed/25622980 http://dx.doi.org/10.1186/s12974-015-0234-7 |
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