Persistent phosphorylation of cyclic AMP responsive element-binding protein and activating transcription factor-2 transcription factors following transient cerebral ischemia in rat brain

The transcription factors cyclic AMP responsive element-binding protein (CR EB) and activating transcription factor-2 were studied in rat brains subjec ted to 15 min ischemia followed by varied periods of reperfusion using west ern blot and immunocytochemical analyses. The total amounts of both CREB an d activating transcription factor-2 were not altered in the hippocampus aft er ischemia. In contrast, levels of the phosphorylated forms of both transc ription factors decreased during ischemia but rebounded following reperfusi on. The phospho-forms of CREB and activating transcription factor-2 showed regional and temporal differences in their expression. Phospho-CREB was inc reased relative to control levels at 30 min, and continued to increase for at least three days postischemia, mainly in dentate granule cells. The leve l of phospho-activating transcription factor-2 appeared to be higher in CA1 pyramidal cells than in dentate granule cells after ischemia. The present findings suggest that the signaling pathways for phosphorylatio n of CREB may be neuroprotective for dentate cells, which are relatively re sistant to ischemic insults. The increased phospho-activating transcription factor-2 may reflect increased stresses in these neurons. The more modest activation of CREB pathways in CA1 neurons may not be enough to overcome th e increased stresses in these neurons, contributing to delayed neuronal dea th. (C) 1998 IBRO. Published by Elsevier Science Ltd.