Blockade of the MEK/ERK pathway with a raf inhibitor prevents activation of pro-inflammatory mediators in cerebral arteries and reduction in cerebral blood flow after subarachnoid hemorrhage in a rat model.
(2011) In Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism May 4. p.144-154- Abstract
- Cerebral ischemia that develops after subarachnoid hemorrhage (SAH) carries high morbidity and mortality. Inflammatory mediators are involved in the development of cerebral ischemia through activation of the mitogen-activated protein kinase pathway. We hypothesized that blockade of the MAPkinase/ERK (MEK)/extracellular signal-regulated kinase (ERK) pathway upstream with a specific raf inhibitor would prevent SAH-induced activation of the cerebrovascular inflammatory response. The raf inhibitor SB-386023-b was injected intracisternally in our rat model at 0, 6, or 12 hours after the SAH. After 48 hours, cerebral arteries were harvested, and iNOS, interleukin (IL)-6, IL-1beta, matrix metalloproteinase (MMP)-9, tissue inhibitors of... (More)
- Cerebral ischemia that develops after subarachnoid hemorrhage (SAH) carries high morbidity and mortality. Inflammatory mediators are involved in the development of cerebral ischemia through activation of the mitogen-activated protein kinase pathway. We hypothesized that blockade of the MAPkinase/ERK (MEK)/extracellular signal-regulated kinase (ERK) pathway upstream with a specific raf inhibitor would prevent SAH-induced activation of the cerebrovascular inflammatory response. The raf inhibitor SB-386023-b was injected intracisternally in our rat model at 0, 6, or 12 hours after the SAH. After 48 hours, cerebral arteries were harvested, and iNOS, interleukin (IL)-6, IL-1beta, matrix metalloproteinase (MMP)-9, tissue inhibitors of metalloproteinase (TIMP)-1, and phosphorylated ERK1/2 were investigated by immunofluorescence, real-time polymerase chain reaction (PCR), and Western blot analysis. Cerebral blood flow (CBF) was measured using autoradiography. Protein levels of MMP-9, TIMP-1, iNOS, IL-6, and IL-1beta were increased after SAH, as were mRNA levels of IL-6, MMP-9, and TIMP-1. After SAH, pERK1/2 was increased, but CBF was reduced. Treatment with SB-386023-b at 0 or 6 hours after SAH normalized CBF and prevented SAH-induced upregulation of MMPs, pro-inflammatory cytokines, and pERK1/2 proteins. These results suggested that inhibition of MEK/ERK signal transduction by a specific raf inhibitor administered up to 6 hours after SAH normalized the expression of pro-inflammatory mediators and extracellular matrix-related genes.Journal of Cerebral Blood Flow & Metabolism advance online publication, 28 April 2010; doi:10.1038/jcbfm.2010.62. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1594721
- author
- Maddahi, Aida LU ; Ansar, Saema LU ; Chen, Qingwen LU and Edvinsson, Lars LU
- organization
- publishing date
- 2011
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
- volume
- May 4
- pages
- 144 - 154
- publisher
- Nature Publishing Group
- external identifiers
-
- wos:000285870700017
- pmid:20424636
- scopus:78650891600
- pmid:20424636
- ISSN
- 1559-7016
- DOI
- 10.1038/jcbfm.2010.62
- language
- English
- LU publication?
- yes
- id
- 3c212d5b-6cd9-48e3-94bb-3d3a5fcbe13c (old id 1594721)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/20424636?dopt=Abstract
- date added to LUP
- 2016-04-04 09:22:37
- date last changed
- 2024-01-12 12:39:57
@article{3c212d5b-6cd9-48e3-94bb-3d3a5fcbe13c,
abstract = {{Cerebral ischemia that develops after subarachnoid hemorrhage (SAH) carries high morbidity and mortality. Inflammatory mediators are involved in the development of cerebral ischemia through activation of the mitogen-activated protein kinase pathway. We hypothesized that blockade of the MAPkinase/ERK (MEK)/extracellular signal-regulated kinase (ERK) pathway upstream with a specific raf inhibitor would prevent SAH-induced activation of the cerebrovascular inflammatory response. The raf inhibitor SB-386023-b was injected intracisternally in our rat model at 0, 6, or 12 hours after the SAH. After 48 hours, cerebral arteries were harvested, and iNOS, interleukin (IL)-6, IL-1beta, matrix metalloproteinase (MMP)-9, tissue inhibitors of metalloproteinase (TIMP)-1, and phosphorylated ERK1/2 were investigated by immunofluorescence, real-time polymerase chain reaction (PCR), and Western blot analysis. Cerebral blood flow (CBF) was measured using autoradiography. Protein levels of MMP-9, TIMP-1, iNOS, IL-6, and IL-1beta were increased after SAH, as were mRNA levels of IL-6, MMP-9, and TIMP-1. After SAH, pERK1/2 was increased, but CBF was reduced. Treatment with SB-386023-b at 0 or 6 hours after SAH normalized CBF and prevented SAH-induced upregulation of MMPs, pro-inflammatory cytokines, and pERK1/2 proteins. These results suggested that inhibition of MEK/ERK signal transduction by a specific raf inhibitor administered up to 6 hours after SAH normalized the expression of pro-inflammatory mediators and extracellular matrix-related genes.Journal of Cerebral Blood Flow & Metabolism advance online publication, 28 April 2010; doi:10.1038/jcbfm.2010.62.}},
author = {{Maddahi, Aida and Ansar, Saema and Chen, Qingwen and Edvinsson, Lars}},
issn = {{1559-7016}},
language = {{eng}},
pages = {{144--154}},
publisher = {{Nature Publishing Group}},
series = {{Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}},
title = {{Blockade of the MEK/ERK pathway with a raf inhibitor prevents activation of pro-inflammatory mediators in cerebral arteries and reduction in cerebral blood flow after subarachnoid hemorrhage in a rat model.}},
url = {{http://dx.doi.org/10.1038/jcbfm.2010.62}},
doi = {{10.1038/jcbfm.2010.62}},
volume = {{May 4}},
year = {{2011}},
}