Proteins are required for cell survival. Normally, GRP78 binds PERK, IRE1 and ATF6 and inhibits their activation in non-stressed cells [33]. When unfolded proteins in the ER lumen reach a critical level, GRP78 disassociates from PERK, IRE1aand ATF6 to bind the unfolded protein to prevent its aggregation [34], [35]. In this study, we showed that the mRNA and protein expression level of GRP78 increased at 1 day, peaked at 4 days, and decreased atdays after SPS. The increase in GRP78 expression at the early time points after SPS indicates GRP78 accumulation in the ER, which is the initial event to buy Dimethylenastron protect against SPS-induced apoptosis. The increase in GRP78 expression is beneficial because GRP78 binds unfolded proteins in order to eliminate denatured proteins and to re-establish cellular homeostasis. At 7 days after SPS, we observed a decrease in GRP78 expression and an increase in the number of TUNEL-positive cells, suggesting that SPS compromised ER function in the hippocampus and that ER-stress cannot be resolved through increased GRP78 expression, consequently leading to cell death. These data also confirm that an increase in GRP78 expression protects against ER stress-induced apoptosis. Recently, GRP78 has been intensively studied as the master regulator of ER stress. Prolonged ER stress leads to cell death and is linked to the pathogenesis of some neurodegenerative disorders including ischemia, Alzheimer’s and Parkinson’s diseases [36]. For example, following ischemic injury, the mRNA and protein expression of GRP78 in the hippocampus increased immediatelyER- Pathway is Involved in PTSD-Induced Apoptosisafter the injury, but then decreased at a later time [37]. However, it remains to be determined what the exact role of GRP78 in ameliorating PTSD. Our results suggest that understanding GRP78 function in the context of PTSD may reveal the mechanisms underlying PTSD pathogenesis. Caspase-12 is localized to the ER and activated by ER stress, which includes disruption of calcium homeostasis and accumulation of unfolded proteins in the ER. It is not activated, however, by membrane- or mitochondrial-targeted apoptotic signals [17]. This suggests that caspase-12 is specific to ER-related pathways. Shibata and colleagues have found that concomitant to the temporal increase in GRP78 expression is the increase in the level of activated caspase-12 when the ER is stressed [38]. Interestingly, mice deficient in caspase-12 are resistant to ER stress-induced apoptosis [17]. In our study, caspase-12 mRNA expression level was unchanged in the MedChemExpress HIF-2��-IN-1 control group. However, it increased in rats examined 1 day after SPS, remained at a high level at 4 days, but then disappeared at 7 days. It has been suggested that ER stressdependent apoptotic cell death is caused through the activation of ER-specific caspase-12. The stimuli that induce ER stress also induce the recruitment of IRE1, which results in the disassociation of IRE1 from procaspase-12 and consequently, the oligomerization and activation of caspase-12. Thus the signaling pathway that initiates ER stress-induced apoptosis appears to depend on the ER-associated caspase-12 [17]. 23977191 Several lines of evidence support the view that alterations in intracellular Ca2+ homeostasis are important in the apoptotic process [18], [39]. Some stress stimuli damage Ca2+ homeostasis. This can lead to either Ca2+ overload or deprivation, which can compromise ER function and protein synthesis, translation, and folding. The.Proteins are required for cell survival. Normally, GRP78 binds PERK, IRE1 and ATF6 and inhibits their activation in non-stressed cells [33]. When unfolded proteins in the ER lumen reach a critical level, GRP78 disassociates from PERK, IRE1aand ATF6 to bind the unfolded protein to prevent its aggregation [34], [35]. In this study, we showed that the mRNA and protein expression level of GRP78 increased at 1 day, peaked at 4 days, and decreased atdays after SPS. The increase in GRP78 expression at the early time points after SPS indicates GRP78 accumulation in the ER, which is the initial event to protect against SPS-induced apoptosis. The increase in GRP78 expression is beneficial because GRP78 binds unfolded proteins in order to eliminate denatured proteins and to re-establish cellular homeostasis. At 7 days after SPS, we observed a decrease in GRP78 expression and an increase in the number of TUNEL-positive cells, suggesting that SPS compromised ER function in the hippocampus and that ER-stress cannot be resolved through increased GRP78 expression, consequently leading to cell death. These data also confirm that an increase in GRP78 expression protects against ER stress-induced apoptosis. Recently, GRP78 has been intensively studied as the master regulator of ER stress. Prolonged ER stress leads to cell death and is linked to the pathogenesis of some neurodegenerative disorders including ischemia, Alzheimer’s and Parkinson’s diseases [36]. For example, following ischemic injury, the mRNA and protein expression of GRP78 in the hippocampus increased immediatelyER- Pathway is Involved in PTSD-Induced Apoptosisafter the injury, but then decreased at a later time [37]. However, it remains to be determined what the exact role of GRP78 in ameliorating PTSD. Our results suggest that understanding GRP78 function in the context of PTSD may reveal the mechanisms underlying PTSD pathogenesis. Caspase-12 is localized to the ER and activated by ER stress, which includes disruption of calcium homeostasis and accumulation of unfolded proteins in the ER. It is not activated, however, by membrane- or mitochondrial-targeted apoptotic signals [17]. This suggests that caspase-12 is specific to ER-related pathways. Shibata and colleagues have found that concomitant to the temporal increase in GRP78 expression is the increase in the level of activated caspase-12 when the ER is stressed [38]. Interestingly, mice deficient in caspase-12 are resistant to ER stress-induced apoptosis [17]. In our study, caspase-12 mRNA expression level was unchanged in the control group. However, it increased in rats examined 1 day after SPS, remained at a high level at 4 days, but then disappeared at 7 days. It has been suggested that ER stressdependent apoptotic cell death is caused through the activation of ER-specific caspase-12. The stimuli that induce ER stress also induce the recruitment of IRE1, which results in the disassociation of IRE1 from procaspase-12 and consequently, the oligomerization and activation of caspase-12. Thus the signaling pathway that initiates ER stress-induced apoptosis appears to depend on the ER-associated caspase-12 [17]. 23977191 Several lines of evidence support the view that alterations in intracellular Ca2+ homeostasis are important in the apoptotic process [18], [39]. Some stress stimuli damage Ca2+ homeostasis. This can lead to either Ca2+ overload or deprivation, which can compromise ER function and protein synthesis, translation, and folding. The.