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Keywords:

  • eukaryotic initiation factor 2;
  • RNA-dependent protein kinase-like endoplasmic reticulum kinase;
  • transgenic mice;
  • transient cerebral ischemia;
  • translation initiation factors

Abstract

Reperfusion after global brain ischemia results initially in a widespread suppression of protein synthesis in neurons that is due to inhibition of translation initiation as a result of the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2). To address the role of the eIF2α kinase RNA-dependent protein kinase-like endoplasmic reticulum kinase (PERK) in the reperfused brain, transgenic mice with a targeted disruption of the Perk gene were subjected to 20 min of forebrain ischemia followed by 10 min of reperfusion. In wild-type mice, phosphorylated eIF2α was detected in the non-ischemic brain and its levels were elevated threefold after 10 min of reperfusion. Conversely, there was no phosphorylated eIF2α detected in the non-ischemic transgenic mice and there was no sizeable rise in phosphorylated eIF2α levels in the forebrain after ischemia and reperfusion. Moreover, there was a substantial rescue of protein translation in the reperfused transgenic mice. Neither group showed any change in total eIF2α, phosphorylated eukaryotic elongation factor 2 or total eukaryotic elongation factor 2 levels. These data demonstrate that PERK is responsible for the large increase in phosphorylated eIF2α and the suppression of translation early in reperfusion after transient global brain ischemia.