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Objectives: Adenosine monophosphate-activated kinase (AMPK) is an energy-specific sensor within the central nervous system. In this study, we observed AMPK and its phosphorylated form (pAMPK) in the hippocampal CA1 region after 5 minutes of transient forebrain ischemia. In addition, we also investigated the effects of Compound C, an AMPK inhibitor, against ischemic damage in gerbils. Methods: Adenosine monophosphate-activated kinase and pAMPK immunoreactivity was observed in the hippocampal CA1 region at various time points after ischemia and Compound C was intraperitoneally administered to gerbils immediately after reperfusion and the animals were sacrificed at 5 days after ischemia/reperfusion. Results: Adenosine monophosphate-activated kinase immunoreactivity was transiently increased in the hippocampal CA1 region 1-2 days after ischemia/reperfusion, while AMPK immunoreactivity was almost undetectable in the stratum pyramidale of the CA1 region 4-7 days after ischemia/reperfusion. The administration of Compound C caused a dose-dependent decrease in the ischemia-induced hyperactive behavior, the depletion of ATP, and lactate accumulation in the hippocampal CA1 region within 24 hours after ischemia/reperfusion. In addition, the administration of Compound C decreased reactive gliosis (astrocytes and microglia) and increased the number of cresyl violet-positive neurons when compared to the vehicle-treated group at 5 days post-ischemia/reperfusion. Conclusion: These results suggest that AMPK is transiently phosphorylated following forebrain ischemia in the hippocampal CA1 region and inhibition of AMPK has neuroprotective effects against ischemic damage through the reduction of ATP depletion and lactate accumulation in the hippocampal CA1 region. [ABSTRACT FROM AUTHOR]

The present study explored the effects of endophilin A1 (SH3GL2) against oxidative damage brought about by H2O2 in HT22 cells and ischemic damage induced upon transient forebrain ischemia in gerbils. Tat-SH3GL2 and its control protein (Control-SH3GL2) were synthesized to deliver it to the cells by penetrating the cell membrane and blood–brain barrier. Tat-SH3GL2, but not Control-SH3GL2, could be delivered into HT22 cells in a concentration- and time-dependent manner and the hippocampus 8 h after treatment in gerbils. Tat-SH3GL2 was stably present in HT22 cells and degraded with time, by 36 h post treatment. Pre-incubation with Tat-SH3GL2, but not Control-SH3GL2, significantly ameliorated H2O2-induced cell death, DNA fragmentation, and reactive oxygen species formation. SH3GL2 immunoreactivity was decreased in the gerbil hippocampal CA1 region with time after ischemia, but it was maintained in the other regions after ischemia. Tat-SH3GL2 treatment in gerbils appreciably improved ischemia-induced hyperactivity 1 day after ischemia and the percentage of NeuN-immunoreactive surviving cells increased 4 days after ischemia. In addition, Tat-SH3GL2 treatment in gerbils alleviated the increase in lipid peroxidation as assessed by the levels of malondialdehyde and 8-iso-prostaglandin F2α and in pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6; while the reduction of protein levels in markers for synaptic plasticity, such as postsynaptic density 95, synaptophysin, and synaptosome associated protein 25 after transient forebrain ischemia was also observed. These results suggest that Tat-SH3GL2 protects neurons from oxidative and ischemic damage by reducing lipid peroxidation and inflammation and improving synaptic plasticity after ischemia. [ABSTRACT FROM AUTHOR]

Introduction: We examined the effects of exogenous protein disulfide isomerase A3 (PDIA3) on hippocampal neurogenesis in gerbils under control and ischemic damage. Methods: To facilitate the delivery of PDIA3 to the brain, we constructed Tat‐PDIA3 protein and administered vehicle (10% glycerol) or Tat‐PDIA3 protein once a day for 28 days. On day 24 of vehicle or Tat‐PDIA3 treatment, ischemia was transiently induced by occlusion of both common carotid arteries for 5 min. Results: Administration of Tat‐PDIA3 significantly reduced ischemia‐induced spontaneous motor activity, and the number of NeuN‐positive nuclei in the Tat‐PDIA3‐treated ischemic group was significantly increased in the CA1 region compared to that in the vehicle‐treated ischemic group. Ki67‐ and DCX‐immunoreactive cells were significantly higher in the Tat‐PDIA3‐treated group compared to the vehicle‐treated control group. In vehicle‐ and Tat‐PDIA3‐treated ischemic groups, the number of Ki67‐ and DCX‐immunoreactive cells was significantly higher as compared to those in the vehicle‐ and Tat‐PDIA3‐treated control groups, respectively. In the dentate gyrus, the numbers of Ki67‐immunoreactive cells were comparable between vehicle‐ and Tat‐PDIA3‐treated ischemic groups, while more DCX‐immunoreactive cells were observed in the Tat‐PDIA3‐treated group. Transient forebrain ischemia increased the expression of phosphorylated cAMP‐response element‐binding protein (pCREB) in the dentate gyrus, but the administration of Tat‐PDIA3 robustly increased pCREB‐positive nuclei in the normal gerbils, but not in the ischemic gerbils. Brain‐derived neurotrophic factor (BDNF) mRNA expression was significantly increased in the Tat‐PDIA3‐treated group compared to that in the vehicle‐treated group. Transient forebrain ischemic increased BDNF mRNA levels in both vehicle‐ and Tat‐PDIA3‐treated groups, and there were no significant differences between groups. Conclusions: These results suggest that Tat‐PDIA3 enhances cell proliferation and neuroblast numbers in the dentate gyrus in normal, but not in ischemic gerbils, by increasing BDNF mRNA and phosphorylation of pCREB. [ABSTRACT FROM AUTHOR]

Abstract: Response to cerebral ischemia in young animals was very different from that in the adult. The aim of this study was to investigate differences in neuronal death and gliosis in the hippocampal CA1 region (CA1) between adult and young gerbils following 5 and 15min of transient cerebral ischemia. Delayed neuronal death (DND) of pyramidal cells occurred in the CA1 was similar in all the adult gerbils after 5 and 15min of ischemia: the DND occurred 4days after ischemia. In the young groups, DND of pyramidal cells in the CA1 region occurred 7 and 3days after 5 and 15min of ischemia, respectively. On the other hand, the activation of GFAP-immunoreactive (+) astrocytes and Iba-1+ microglia was different in the young groups from the adult groups after ischemia. The change pattern of GFAP immunoreactivity in the adult groups was similar in both the adult groups after ischemia; in the young groups, the activation of GFAP+ astrocytes after 5min of ischemia was much delayed than that after 15min of ischemia. Activated Iba-1+ microglia were aggregated in the stratum pyramidale 4days after ischemia in all the adult ischemia-operated groups; in the young groups, activated Iba-1+ microglia were aggregated in the stratum pyramidale 7days after 5min of ischemia and 3days after 15min of ischemia. These observations indicate that DND in young animals is very different from the adult according to different duration of transient cerebral ischemia and glial activation is very different in young animals after different duration of transient ischemia. [Copyright &y& Elsevier]