U0126 prevents ERK pathway phosphorylation and interleukin-1beta mRNA production after cerebral ischemia.
OBJECTIVE
To 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.


METHODS
Mice 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.


RESULTS
Phosphorylated 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.


CONCLUSIONS
Intravenous 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.
Wang
Zhi-qiu
ZQ
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040. zhiqiuwang@yahoo.com
Chen
Xian-cheng
XC
Yang
Guo-yuan
GY
Zhou
Liang-fu
LF
D000818:Animals; D002070:Butadienes / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism*; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D050807:ets-Domain Protein Elk-1
D002070:Butadienes; D004268:DNA-Binding Proteins; C494113:Elk1 protein, mouse; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C113580:U 0126; D050807:ets-Domain Protein Elk-1; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases