Hypothermia differentially increases extracellular signal-regulated kinaseand stress-activated protein kinase/c-Jun terminal kinase activation in the hippocampus during reperfusion after asphyxial cardiac arrest

Mitogen-activated protein kinases are signal transduction mediators that ha ve been implicated in cell survival and cell death. This study characterize d the activation of pathways in the hippocampus during reperfusion after gl obal cerebral ischemia, as well as the influence of a regimen of hypothermi a that reduces ischemic cell death in the hippocampus. Circulatory arrest w as induced in rats by 8 min of asphyxia. Relative levels of phosphorylated and total extracellular signal-regulated kinase, stress-activated protein k inase/c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were measured in the hippocampus after 6, 12 or 24 h of reperfusion using immun oblotting. Asphyxia induced a progressive increase in phosphorylated extrac ellular signal-regulated kinase and stress-activated protein kinase/c-Jun N -terminal kinase, but no change in phosphorylated p38 mitogen-activated pro tein kinase. Induction of mild hypothermia (33 degrees C) during reperfusio n increased extracellular signal-regulated kinase phosphorylation and produ ced a smaller increase in stress-activated protein kinase/c-Jun N-terminal kinase phosphorylation at 24 h. Hypothermia did not alter extracellular sig nal-regulated kinase activation in rats not subjected to ischemia. Extracel lular signal-regulated kinase activation was associated with an increase in phosphorylation of the mitogen-activated protein kinase kinase 1/2, and wa s inhibited by administration of the specific mitogen-activated protein kin ase kinase 1/2 inhibitor SL327. Immunohistochemical staining showed an incr ease in active extracellular signal-regulated kinase in the CA1, CA2, CA3 a nd dentate gyrus regions of the hippocampus after ischemia and reperfusion. In contrast, active stress-activated protein kinase/c-Jun N-terminal kinas e immunoreactivity was most intense in the CA3 and dentate gyrus regions. These data demonstrate that both extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun N-terminal kinase pathways are activa ted during the first 24 h of reperfusion after global cerebral ischemia, an d that hypothermia increases the activation of extracellular signal-regulat ed kinase relative to stress-activated protein kinase/c-Jun N-terminal kina se. Thus, an increase in extracellular signal-regulated kinase activation m ay be associated with improved neuronal survival after ischemic injury. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.