Induction of GRP78 by Ischemic Preconditioning Reduces Endoplasmic Reticulum Stress and Prevents Delayed Neuronal Cell Death

Abstract

Although the endoplasmic reticulum (ER) is implicated in neuronal degeneration in some situations, its role in delayed neuronal cell death (DND) after ischemia remains uncertain. The authors speculated that ER stress is involved in DND, that it is reduced by ischemic preconditioning, and that ER stress reduction by preconditioning is due to ER molecular chaperone induction. The phosphorylation status of eukaryotic initiation factor 2alpha (eIF2alpha) and RNA-dependent protein kinase-like ER eIF2alpha kinase (PERK) was investigated in the rat hippocampus after ischemia with and without preconditioning. PERK is phosphorylated by ER stress, which phosphorylates eIF2alpha. To investigate the role of ER molecular chaperones in preconditioning, the authors examined GRP78 and GRP94 expression, both of which are ER chaperones that inhibit PERK phosphorylation, and compared their induction and ischemic tolerance time windows. Phosphorylation of eIF2alpha and PERK was confirmed after severe ischemia but was inhibited by preconditioning. After preconditioning, GRP78 was increased in the brain with a peak at 2 days, which corresponded with the ischemic tolerance time window. Immunoprecipitation and double staining demonstrated involvement of GRP78 in prevention of PERK phosphorylation. These results suggest that GRP78 induced by preconditioning may reduce ER stress and eventual DND after ischemia.

The endoplasmic reticulum stress inhibitor salubrinal inhibits the activation of autophagy and neuroprotection induced by brain ischemic preconditioning

“…Recent research also implied that HSP70 might interact with the autophagy pathway to exert beneficial effects in neurodegenerative diseases [43,44] . In agreement with previous findings [8,[40][41][42] , our results showed that the expression of HSP70 was upregulated after ischemic preconditioning. However, SAL treatment significantly inhibited the IPC-induced increases in HSP70, suggesting that SAL treatment effectively inhibits the survival pathway induced by ischemic preconditioning.…”

“…The endoplasmic reticulum (ER) is an organelle in which secretory or membrane proteins are synthesized. Four main factors are known to cause ER stress: Gao B et al Acta Pharmacologica Sinica npg characterized by the upregulation of GRP78, is involved in preconditioning [8][9][10][11] , but the pathway through which ER stress promotes the neuroprotective effects of preconditioning remains to be elucidated.…”

Association of Multiple Cellular Stress Pathways With Accelerated Atherosclerosis in Hyperhomocysteinemic Apolipoprotein E-Deficient Mice

“…The inverse correlation between GRP78 and phospho-PERK immunostaining in macrophage foam cells is similar to that observed for ischemic hippocampal C 1 neurons 35 and suggests temporal differences in UPR activation. These findings are also consistent with previous studies indicating that PERK phosphorylation is an early response to ER stress that is required for the inhibition of translation (through the phosphorylation of eIF-2␣) and transcriptional induction of UPR genes, including GRP78 and GRP94.…”

Expression of two endoplasmic reticulum stress markers, GRP78 and GADD153, in rat retinal detachment model and its implication

“…Stresses like oxygen deficiency, low glucose, and low Ca 2 þ can lead to disruption of protein metabolism in cells; then accumulation of unfolded protein response (UPR) elevates GRP78 expression to maintain the ER homoeostasis by improving the synthesis and transportation of protein. 27,28 Recent studies revealed that UPR played an important role in neurodegenerative disorders, such as Alzheimer's disease, but few reported the role of UPR in retinal diseases. In our study, expression of GRP78 mRNA was observed on 0.5 d after RD and peaked on 1-2 d after RD.…”