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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.

Maddahi, Aida LU ; Ansar, Saema LU ; Chen, Qingwen LU and Edvinsson, Lars LU (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)
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Contribution to journal
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published
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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
ISSN
1559-7016
DOI
10.1038/jcbfm.2010.62
language
English
LU publication?
yes
id
3c212d5b-6cd9-48e3-94bb-3d3a5fcbe13c (old id 1594721)
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http://www.ncbi.nlm.nih.gov/pubmed/20424636?dopt=Abstract
date added to LUP
2010-05-04 23:11:25
date last changed
2017-01-15 04:27:24
@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},
  volume       = {May 4},
  year         = {2011},
}