Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Xu, Hao-Liang, Pelligrino, Dale A, Paisansathan, Chanannait, Testai, Fernando D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
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
_version_ 1782356735261933568
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
work_keys_str_mv AT xuhaoliang protectiveroleoffingolimodfty720inratssubjectedtosubarachnoidhemorrhage
AT pelligrinodalea protectiveroleoffingolimodfty720inratssubjectedtosubarachnoidhemorrhage
AT paisansathanchanannait protectiveroleoffingolimodfty720inratssubjectedtosubarachnoidhemorrhage
AT testaifernandod protectiveroleoffingolimodfty720inratssubjectedtosubarachnoidhemorrhage