Possible mechanisms involved in the down-regulation of translation during transient global ischaemia in the rat brain

The striking correlation between neuronal vulnerability and down-regulation of translation suggests that this cellular process plays a critical part i n the cascade of pathogenetic events leading to ischaemic cell death. There is compelling evidence supporting the idea that inhibition of translation is exerted at the polypeptide chain initiation step, and the present study explores the possible mechanism/s implicated. Incomplete forebrain ischaemi a (30 min) was induced in rats by using the four-vessel occlusion model. Eu karyotic initiation factor (eIF)2, eIF4E and eIF4E-binding protein (4E-BP1) phosphorylation levels, eIF4F complex formation, as well as eIF2B and ribo somal protein S6 kinase (p70(S6K)) activities, were determined in different subcellular fractions from the cortex and the hippocampus [the CA1-subfiel d and the remaining hippocampus (RH)], at several post-ischaemic times. Inc reased phosphorylation of the alpha subunit of eIF2 (eIF2 alpha) and eIF2B inhibition paralleled the inhibition of translation in the hippocampus, but they normalized to control values, including the CA1-subfield, after 4-6 h of reperfusion. eIF4E and 4E-BP1 were significantly dephosphorylated durin g ischaemia and total eIF4E levels decreased during reperfusion both in the cortex and hippocampus, with values normalizing after 4 h of reperfusion o nly in the cortex. Conversely, p70(S6K) activity, which was inhibited in bo th regions during ischaemia, recovered to control values earlier in the hip pocampus than in the cortex. eIF4F complex formation diminished both in the cortex and the hippocampus during ischaemia and reperfusion, and it was lo wer in the CAI-subfield than in the RH, roughly paralleling the observed de crease in eIF4E and eIF4G levels. Our findings are consistent with a potent ial role for eIF4E, 4E-BP1 and eIF4G in the down-regulation of translation during ischaemia. eIF2 alpha, eIF2B, eIF4G and p70(S6K) are positively impl icated in the translational inhibition induced at early reperfusion, wherea s eIF4F complex formation is likely to contribute to the persistent inhibit ion of translation observed at longer reperfusion times.