Differential roles of exogenous protein disulfide isomerase A3 on proliferating cell and neuroblast numbers in the normal and ischemic gerbils

Abstract

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.