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Critical Care↗
Biomedical subjects
J E Pittman
Publications and source records attributed to J E Pittman.
Eukaryotic initiation factor 2alpha kinase and phosphatase activity during postischemic brain reperfusion.
When ischemic brain is reperfused, there is in vulnerable neurons immediate inhibition of protein synthesis associated with a large increase in phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 [eIF2alpha, phosphorylated form eIF2alpha(P)]. We examined eIF2alpha kinase and eIF2alpha(P) phosphatase activity in brain homogenate postmitochondrial supernatants obtained from rats after 3 to 30 min of global brain ischemia (cardiac arrest), after 5 min of ischemia and 5 min of reperfusion (5R), and after 10 min of ischemia and 90 min reperfusion (90R). Because it has been suggested that PKR might be specifically responsible for producing eIF2alpha(P) during reperfusion, we also examined in brain homogenates from wild-type and PKR0/0 C57BL/6J x 129/SV mice the effect of 5 min of ischemia and 5 min of reperfusion on eIF2alpha(P). Cytosolic brain eIF2alpha(P) in the 5R and 90R rats was 18- and 23-fold that of nonischemic controls without any change in the rate of eIF2alpha(P) dephosphorylation. There was no change in eIF2alpha kinase activity between 3 and 30 min of ischemia but an 85% decrease in the 5R group; the 90R group was similar to controls. In wild-type and PKR0/0 mice total eIF2alpha was identical, and there was an identical 16-fold increase in eIF2alpha(P) at 5 min of reperfusion. Our observations contradict hypotheses that PKR activation, loss of eIF2alpha(P) phosphatase activity, or any general increase in eIF2alpha kinase activity are responsible for reperfusion-induced phosphorylation of eIF2alpha, and we suggest that the mechanism may involve regulation of the availability of eIF2alpha to a kinase.
Animals↗
Comparison of the effects of propofol and pentobarbital on neurologic outcome and cerebral infarct size after temporary focal ischemia in the rat.
BACKGROUND: Although propofol is known to have effects on cerebral physiology similar to the barbiturates, a direct comparison of the relative effects of these drugs on outcome from cerebral ischemia has not been performed. The authors postulated that pentobarbital or propofol would yield similar effects on neurologic and histologic outcome from temporary focal ischemia in the rat. METHODS: Wistar rats were anesthetized with sufficient doses of pentobarbital (n = 20) or propofol (n = 20) to cause electroencephalographic burst suppression. The middle cerebral artery was then occluded for 75 min. Animals were awakened 4-6 h after onset of reperfusion and allowed to recover for 1 week. Neurologic function and infarct size were then assessed. RESULTS: Relevant physiologic values were similar between groups during ischemia and early reperfusion. No difference between groups was observed for severity of hemiparesis (P = 0.10). Total cerebral infarct volumes (median +/- quartile deviation) were similar for the two groups (pentobarbital = 190 +/- 36 mm3; propofol = 200 +/- 24 mm3, P = 0.35). CONCLUSION: Neurologic and histologic outcome were similar in pentobarbital or propofol anesthetized rats undergoing temporary focal cerebral ischemia and a 1-week recovery interval.
Anesthetics, Intravenous↗
Effect of brain ischemia and reperfusion on the localization of phosphorylated eukaryotic initiation factor 2 alpha.
Postischemic brain reperfusion is associated with a substantial and long-lasting reduction of protein synthesis in selectively vulnerable neurons. Because the overall translation initiation rate is typically regulated by altering the phosphorylation of serine 51 on the alpha-subunit of eukaryotic initiation factor 2 (eIF-2 alpha), we used an antibody specific to phosphorylated eIF-2 alpha [eIF-2(alpha P)] to study the regional and cellular distribution of eIF-2(alpha P) in normal, ischemic, and reperfused rat brains. Western blots of brain postmitochondrial supernatants revealed that approximately 1% of all eIF-2 alpha is phosphorylated in controls, eIF-2(alpha P) is not reduced by up to 30 minutes of ischemia, and eIF-2(alpha P) is increased approximately 20-fold after 10 and 90 minutes of reperfusion. Immunohistochemistry shows localization of eIF-2(alpha P) to astrocytes in normal brains, a massive increase in eIF-2(alpha P) in the cytoplasm of neurons within the first 10 minutes of reperfusion, accumulation of eIF-2(alpha P) in the nuclei of selectively vulnerable neurons after 1 hour of reperfusion, and morphology suggesting pyknosis or apoptosis in neuronal nuclei that continue to display eIF-2(alpha P) after 4 hours of reperfusion. These observations, together with the fact that eIF-2(alpha P) inhibits translation initiation, make a compelling case that eIF-2(alpha P) is responsible for reperfusion-induced inhibition of protein synthesis in vulnerable neurons.
Animals↗