Possible mechanisms of protein synthesis inhibition in CNS during postischemic reperfusion

Alterations in protein synthesis during ischemia and subsequent reperfusion may be evaluated in terms of the capacity for protein synthesis or the int egrity of the protein synthesising machinery, namely the ribosomes, initiat ion and elongation factors. Although ischemia per se produces relatively mo derate changes which are dependent on the model and duration of the ischemi a and intraischemic temperature, generates background for profound protein synthesis alterations occurring during subsequent reperfusion. First minute s of postischemic reperfusion are characterised by a nearly complete block of translation, focused on the inhibition of initiation, which is manifeste d by the disaggregation of polyribosomes to monosomes and ribosomal subunit s. This acute inhibition of protein synthesis, which call be seen in all re gions of CNS, seems to be caused by a phosphorylation of alpha-subunit of i nitiation factor 2 (eIF-2 alpha) and a decreased activity of initiation fac tor 2B (eIF-2B). After the common transient inhibition of initiation, most brain regions recover their protein synthesis capability. However, inhibiti on in selectively vulnerable regions is persistent. The persistent inhibiti on of translation in selective vulnerable brain regions is presumably cause d by an inhibition of ternary complex formation which could be partly indep endent on the phosphorylation status of eIF2 alpha. Moreover, the massive r elease of glutamate, responsible for an increase in cytosolic Ca+2 which is able to originate phosphorylation of eukaryotic elongation factor 2 (eEF-2 ) by a Ca+2/calmoduline-dependent enzyme eEF-2 kinase, could be involved si multaneously in this process.