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Early and Sustained Increases in Leukotriene B(4) Levels Are Associated with Poor Clinical Outcome in Ischemic Stroke Patients
Leukotriene B(4) (LTB(4)) has been implicated in ischemic stroke pathology. We examined the prognostic significance of LTB(4) levels in patients with acute middle cerebral artery (MCA) infarction and their mechanisms in rat stroke models. In ischemic stroke patients with middle cerebral artery infar...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007445/ https://www.ncbi.nlm.nih.gov/pubmed/31520306 http://dx.doi.org/10.1007/s13311-019-00787-4 |
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author | Chan, Su Jing Ng, Mary P. E. Zhao, Hui Ng, Geelyn J. L. De Foo, Chuan Wong, Peter T.-H. Seet, Raymond C. S. |
author_facet | Chan, Su Jing Ng, Mary P. E. Zhao, Hui Ng, Geelyn J. L. De Foo, Chuan Wong, Peter T.-H. Seet, Raymond C. S. |
author_sort | Chan, Su Jing |
collection | PubMed |
description | Leukotriene B(4) (LTB(4)) has been implicated in ischemic stroke pathology. We examined the prognostic significance of LTB(4) levels in patients with acute middle cerebral artery (MCA) infarction and their mechanisms in rat stroke models. In ischemic stroke patients with middle cerebral artery infarction, plasma LTB(4) levels were found to increase rapidly, roughly doubling within 24 h when compared to initial post-stroke levels. Further analyses indicate that poor functional recovery is associated with early and more sustained increase in LTB(4) rather than the peak levels. Results from studies using a rat embolic stroke model showed increased 5-lipoxygenase (5-LOX) expression in the ipsilateral infarcted cortex compared with sham control or respective contralateral regions at 24 h post-stroke with a concomitant increase in LTB(4) levels. In addition, neutrophil influx was also observed in the infarcted cortex. Double immunostaining indicated that neutrophils express 5-LOX and leukotriene A(4) hydrolase (LTA(4)H), highlighting the pivotal contributions of neutrophils as a source of LTB(4). Importantly, rise in plasma LTB(4) levels corresponded with an increase in LTB(4) amount in the infarcted cortex, thereby supporting the use of plasma as a surrogate for brain LTB(4) levels. Pre-stroke LTB(4) loading increased brain infarct volume in tMCAO rats. Conversely, administration of the 5-LOX-activating protein (FLAP) inhibitor BAY-X1005 or B-leukotriene receptor (BLTR) antagonist LY255283 decreased the infarct volume by a similar extent. To conclude, targeted interruption of the LTB(4) pathway might be a viable treatment strategy for acute ischemic stroke. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00787-4) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-7007445 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-70074452020-02-24 Early and Sustained Increases in Leukotriene B(4) Levels Are Associated with Poor Clinical Outcome in Ischemic Stroke Patients Chan, Su Jing Ng, Mary P. E. Zhao, Hui Ng, Geelyn J. L. De Foo, Chuan Wong, Peter T.-H. Seet, Raymond C. S. Neurotherapeutics Original Article Leukotriene B(4) (LTB(4)) has been implicated in ischemic stroke pathology. We examined the prognostic significance of LTB(4) levels in patients with acute middle cerebral artery (MCA) infarction and their mechanisms in rat stroke models. In ischemic stroke patients with middle cerebral artery infarction, plasma LTB(4) levels were found to increase rapidly, roughly doubling within 24 h when compared to initial post-stroke levels. Further analyses indicate that poor functional recovery is associated with early and more sustained increase in LTB(4) rather than the peak levels. Results from studies using a rat embolic stroke model showed increased 5-lipoxygenase (5-LOX) expression in the ipsilateral infarcted cortex compared with sham control or respective contralateral regions at 24 h post-stroke with a concomitant increase in LTB(4) levels. In addition, neutrophil influx was also observed in the infarcted cortex. Double immunostaining indicated that neutrophils express 5-LOX and leukotriene A(4) hydrolase (LTA(4)H), highlighting the pivotal contributions of neutrophils as a source of LTB(4). Importantly, rise in plasma LTB(4) levels corresponded with an increase in LTB(4) amount in the infarcted cortex, thereby supporting the use of plasma as a surrogate for brain LTB(4) levels. Pre-stroke LTB(4) loading increased brain infarct volume in tMCAO rats. Conversely, administration of the 5-LOX-activating protein (FLAP) inhibitor BAY-X1005 or B-leukotriene receptor (BLTR) antagonist LY255283 decreased the infarct volume by a similar extent. To conclude, targeted interruption of the LTB(4) pathway might be a viable treatment strategy for acute ischemic stroke. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00787-4) contains supplementary material, which is available to authorized users. Springer International Publishing 2019-09-13 2020-01 /pmc/articles/PMC7007445/ /pubmed/31520306 http://dx.doi.org/10.1007/s13311-019-00787-4 Text en © The Author(s) 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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. |
spellingShingle | Original Article Chan, Su Jing Ng, Mary P. E. Zhao, Hui Ng, Geelyn J. L. De Foo, Chuan Wong, Peter T.-H. Seet, Raymond C. S. Early and Sustained Increases in Leukotriene B(4) Levels Are Associated with Poor Clinical Outcome in Ischemic Stroke Patients |
title | Early and Sustained Increases in Leukotriene B(4) Levels Are Associated with Poor Clinical Outcome in Ischemic Stroke Patients |
title_full | Early and Sustained Increases in Leukotriene B(4) Levels Are Associated with Poor Clinical Outcome in Ischemic Stroke Patients |
title_fullStr | Early and Sustained Increases in Leukotriene B(4) Levels Are Associated with Poor Clinical Outcome in Ischemic Stroke Patients |
title_full_unstemmed | Early and Sustained Increases in Leukotriene B(4) Levels Are Associated with Poor Clinical Outcome in Ischemic Stroke Patients |
title_short | Early and Sustained Increases in Leukotriene B(4) Levels Are Associated with Poor Clinical Outcome in Ischemic Stroke Patients |
title_sort | early and sustained increases in leukotriene b(4) levels are associated with poor clinical outcome in ischemic stroke patients |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007445/ https://www.ncbi.nlm.nih.gov/pubmed/31520306 http://dx.doi.org/10.1007/s13311-019-00787-4 |
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