U0126 prevents ERK pathway phosphorylation and interleukin-1beta mRNA production after cerebral ischemia.
- Author:
Zhi-qiu WANG
1
;
Xian-cheng CHEN
;
Guo-yuan YANG
;
Liang-fu ZHOU
Author Information
- Publication Type:Journal Article
- MeSH: Animals; Butadienes; pharmacology; DNA-Binding Proteins; metabolism; Enzyme Inhibitors; pharmacology; Infarction, Middle Cerebral Artery; metabolism; Interleukin-1; biosynthesis; genetics; Male; Mice; Mitogen-Activated Protein Kinase 1; metabolism; Mitogen-Activated Protein Kinase Kinases; antagonists & inhibitors; metabolism; Nitriles; pharmacology; Phosphorylation; Proto-Oncogene Proteins; metabolism; RNA, Messenger; biosynthesis; genetics; Signal Transduction; Transcription Factors; metabolism; ets-Domain Protein Elk-1
- From: Chinese Medical Sciences Journal 2004;19(4):270-275
- CountryChina
- Language:English
-
Abstract:
OBJECTIVETo study the role of extracellular signal-regulated kinase (ERK) in cerebral ischemia and the mechanism of protective effects of U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene) on ischemic brain.
METHODSMice underwent left middle cerebral artery occlusion (MCAO) by introducing a suture in the lumen. U0126 was injected intravenously through the internal jugular vein. The immuno-activity of phosphorylated ERK1/2 (pERK1/2), phosphorylated mitogen activated protein kinase kinase (pMEK), and phosphorylated Elk-1 (pElk-1) was assessed by Western blot analysis and immunohistochemistry. Interleukin (IL)-1beta mRNA level was measured by ribonuclease protection assay.
RESULTSPhosphorylated ERK1/2 in 2 hours MCAO mice was down-regulated after intravenous injection of U0126. The inhibition was dose dependent and treatment time related. pMEK and pElk-1 were also reduced in a similar fashion after U0126 treatment. IL-1beta mRNA increased after 1 and 2 hours of MCAO. After injection of U0126, it was down-regulated during 1 to 4 hours after MCAO.
CONCLUSIONIntravenous administration of the MEK inhibitor U0126 inhibits pMEK, pERK1/2, and pElk-1 up-regulation induced by cerebral ischemia. The protective effect of U0126 against ischemic injury is probably resulted from the reduction of IL-1beta mRNA via the inhibition of ERK pathway.
