期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 31, 期 1, 页码 144-154出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2010.62
关键词
extracellular signal-regulated kinase 1/2 (ERK1/2); matrix metalloproteinase; pro-inflammatory cytokines; subarachnoid hemorrhage (SAH); tissue inhibitor of metalloproteinase 1 (TIMP-1)
资金
- Swedish Research Council
- Heart and Lung Foundation, Sweden
- Royal Physiographic Society, Sweden
- Danish Research Council
- Lundbeck Foundation, Denmark
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-1 beta, 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-1 beta 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 (2011) 31, 144-154; doi:10.1038/jcbfm.2010.62; published online 28 April 2010
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