Hippocampal cellular stress responses after global brain ischemia and reperfusion

Brain ischemia and reperfusion (I/R) induce neuronal intracellular stress responses, including the heat-shock response (HSR) and the unfolded protein response (UPR), but the roles of each in neuronal survival or death are not well understood. We assessed the relative expression of UPR (ATF4, CHOP, GRP78, XBP-1) and HSR-related (HSP70 and HSC70) mRNAs and proteins after brain I/R. We evaluated these in hippocampal CA1 and CA3 after normothermic, transient global forebrain ischemia and up to 42 h of reperfusion. In CA1, chop and xbp-1 mRNA showed maximal 14- and 12-fold increases, and the only protein increase observed was for 30-kDa XBP-1. CA3 showed induction of only xbp-1. GRP78 protein declined in CA1, but increased twofold and then declined in CA3. Transcription of hsp70 was an order of magnitude greater than that of any UPR-induced transcript in either CA1 or CA3. HSP70 translation in CA1 lagged CA3 by approximately 24 h. We conclude that (a) in terms of functional end products, the ER stress response after brain ischemia and reperfusion more closely resembles the integrated stress response than the UPR; and (b) the HSR leads to quantitatively greater mRNA production in postischemic neurons, suggesting that cytoplasmic stress predominates over ER stress in reperfused neurons.