Similar time-course of interleukin-1 beta production and extracellular-signal-regulated kinase (ERK) activation in permanent focal brain ischemic injury.
The present study investigated the activation of extracellular-signal-regulated kinase (ERK) and the potential role of interleukin-1 beta (IL-1beta) in the brain's response to focal brain ischemia in the permanent middle cerebral artery occlusion (pMCAO) model. Phosphorylated ERK p44 and p42 were increased time-dependently and significantly 18- and 28-fold, respectively, at 24-h post-pMCAO. Similarly, IL-1beta protein levels were significantly increased with the peak at 24 h in the lesioned core of the ischemic hemisphere compared to the contralateral side. Previous studies using various stimuli have shown ERK-dependent IL-1 induction. The results from our study suggest that this relation may also exist in vivo in ischemic brain tissue. Based on the progressive nature of IL-1 induction, we hypothetized that inhibition of interleukin-converting enzyme (ICE) could provide an extended time-window for neuroprotection. Therefore, we applied N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD x fmk), an ICE blocker 3 or 6 h after pMCAO. Reductions of infarct volume, however, were not observed. Taken together with previous results, where we showed protective activity of zVAD x fmk when given immediately after pMCAO, we conclude that the time window for zVAD x fmk is less than 3 h.
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D015151:Immunoblotting; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008026:Ligation; D048670:MAP Kinase Kinase 4; D008279:Magnetic Resonance Imaging; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D048051:p38 Mitogen-Activated Protein Kinases
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007375:Interleukin-1; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020170:Caspase 1