Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation (phosphorylation) and the possible mechanism of extracellular signal-regulated kinase 5 (ERK5) were evaluated after cerebral ischemia-reperfusion (I/R) in the hippocampus in a four-vessel occlusion model of Sprague-Dawley rats. Western blotting showed that ERK5 was strongly activated from 10 min to 1 day and peaked at 30 min of reperfusion after 15 min ischemia. Pretreatment with N-acetylcysteine, a free radical scavenger, effectively inhibited ERK5 activation in a dose-dependent manner. Consistently, ERK5 activation was significantly suppressed by genistein (protein-tyrosine kinase inhibitor), PP2 (specific inhibitor of Src family kinases), nifedipine (L-VGCC blocker) and dextromethorphan (NMDA receptor antagonist), but not 6,7-dinitroquinoxaline-2, 3(1H, 4H)-dione (AMPA receptor antagonist). These results suggested that ERK5 could be significantly activated by I/R, which might be mediated by NMDA receptor and L-VGCC through Src kinase pathway involving oxidative stress in rat hippocampus.
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PMID:Activation of ERK5 is mediated by N-methyl-D-aspartate receptor and L-type voltage-gated calcium channel via Src involving oxidative stress after cerebral ischemia in rat hippocampus. 1503 2

Extracellular signal-regulated kinase 5 (ERK5), the newest member of the mitogen-activated protein (MAP) kinase family of proteins, is widely expressed in many tissues, including the brain. Here we investigated the activation and subcellular localization of ERK5 by immunoblotting and immunohistochemistry as well as its potential role following cerebral ischemia in rat hippocampus. Transient cerebral ischemia was induced by the four-vessel occlusion method in Sprague-Dawley rats. Our results first indicated that the strongly activated ERK5 immunoreactivity was seen in the CA3/DG region but not in the CA1 pyramidal cell of rat hippocampus following reperfusion. In cytosol extracts, ERK5 activation was rapidly increased, with a peak at 30 min, and then gradually decreased to basal level at 3 days of reperfusion. In nucleus extracts, both phospho-ERK5 and its protein expression were persistently enhanced during the later reperfusion period (from 6 hr to 3 days). To elucidate further the possible role of ERK5 activation and subcellular localization in ischemic insult, rats were intraperitoneally administrated with nifedipine (ND) and dextromethorphan (DM), inhibitors of two types of calcium channels, 20 min prior to ischemia. Our findings showed that ND or DM significantly reduced activated ERK5 immunoreactivity in the nucleus and that most of the CA3/DG neurons were lost 3 days later. Most importantly, intracerebroventricular infusion of ERK5 antisense oligonucleotides (AS; every 24 hr for 3 days before ischemia), but not sense oligonucleotides or vehicle, not only markedly decreased the level of ERK5 and p-ERK5 but also largely caused neuronal loss in the CA3/DG region at 3 days of reperfusion. Taken together, the results strongly suggest that ERK5 was selectively activated in the hippocampal CA3/DG region and subsequently translocated from the cytosol to the nucleus through activation of N-methyl-D-aspartate receptor and L-type voltage-gated calcium channel, which might act as an important survival signal in ischemia-induced neuronal cell damage of the CA3/DG region.
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PMID:Activation of extracellular signal-regulated kinase 5 may play a neuroprotective role in hippocampal CA3/DG region after cerebral ischemia. 1578 69

The purpose of the present study was to investigate the role of myocyte enhancer binding factor 2C (MEF2C), a common substrate of p38 kinase and extracellular signal-regulated kinase 5 (ERK5) in the hippocampal CA1 region following cerebral ischemia preconditioning (CIP) and without CIP. In animals that did not undergo preconditioning, MEF2C was significantly activated with an early peak at 30 min of reperfusion, which was followed by a pronounced decrease of MEF2C protein levels in the late phase of reperfusion (3-5 d). Co-immunoprecipitation studies failed to show an interaction between ERK5 and MEF2C, and ERK5-antisense oligonucleotide (ERK5-AS) had no effect on MEF2C activation, suggesting that the MEF2C activation is mediated by a kinase other than ERK5. Following preconditioning (3 min ischemia), MEF2C was strongly activated during the late stage of reperfusion (6 h-5 d). Co-immunoprecipitation studies showed that the interaction of ERK5 and MEF2C significantly increased at 3 d of reperfusion, and this increase was markedly inhibited by ERK5-AS. Inhibition of the ERK5-MEF2C pathway resulted in a significant increase in the number of TUNEL-positive apoptotic cells compared with CIP groups in the hippocampal CA1 region, and abolished the neuroprotective effect induced by CIP. Taken together, these results demonstrate that ERK5-MEF2C signaling is significantly enhanced in the hippocampus CA1 following CIP, and that ERK5-MEF2C signaling plays a critical role in the mediation of the anti-apoptotic and neuroprotective actions of ischemic preconditioning.
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PMID:The ERK5-MEF2C transcription factor pathway contributes to anti-apoptotic effect of cerebral ischemia preconditioning in the hippocampal CA1 region of rats. 1910 77