title: Different mechanisms account for extracellular-signal regulated kinase activation in distinct brain regions following global ischemia and reperfusion.
abstract: Oxidative stress after cerebral ischemia and reperfusion activates extracellular signal-regulated kinases (ERK) in brain. However, the mechanism of this activation has not been elucidated. We have previously reported that in an in vitro model of oxidative stress in immature cortical neuronal cultures, the inhibition of ERK phosphatase activity contributes to ERK1/2 activation and subsequent neuronal toxicity. This study examined whether ERK activation was associated with altered activity of ERK phosphatases in a rat cardiac arrest model. Rats in experimental groups were subjected to asphyxial cardiac arrest for 8 min and then resuscitated for 30 min. Significant ERK activation was detected in both cortex and hippocampus following ischemia/reperfusion by immunoblotting. ERK phosphatase activity was reversibly inhibited in cerebral cortex but not affected in hippocampus following ischemia/reperfusion. MEK1/2 was activated in both cerebral cortex and hippocampus following ischemia/reperfusion. Using a specific inhibitor of protein phosphatase 2A (PP2A), okadaic acid (OA), we have identified PP2A to be the major ERK phosphatase that is responsible for regulating ERK activation in ischemic brain tissues. Orthovanadate inhibited ERK phosphatase activity in brain tissues, suggesting that tyrosine phosphatases and dual specificity phosphatases may also contribute to the ERK phosphatase activity in brain tissues. Together, these data implicate ERK phosphatase in the regulation of ERK activation in distinct brain regions following global ischemia.
authors.affiliation: Center for Neuroscience, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ho
authors.forename: E
authors.initials: E
authors.lastname: Logue
authors.forename: C W
authors.initials: CW
authors.lastname: Callaway
authors.forename: D B
authors.initials: DB
authors.lastname: DeFranco
mesh_terms: D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D007511:Ischemia / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D019319:Okadaic Acid / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion
chemical_list: D004791:Enzyme Inhibitors; D019319:Okadaic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D010744:Phosphoric Monoester Hydrolases