Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea.
Department of Anatomy, College of Medicine, Soonchunhyang University, Cheonan, South Korea.
Brain Behav. 2020 Mar;10(3):e01534. doi: 10.1002/brb3.1534. Epub 2020 Jan 20.
We examined the effects of exogenous protein disulfide isomerase A3 (PDIA3) on hippocampal neurogenesis in gerbils under control and ischemic damage.
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.
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.
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.
我们研究了外源性蛋白二硫键异构酶 A3（PDIA3）对控制和缺血性损伤下沙鼠海马神经发生的影响。
为了促进 PDIA3 递送到大脑，我们构建了 Tat-PDIA3 蛋白，并每天给予载体（10%甘油）或 Tat-PDIA3 蛋白一次，共 28 天。在载体或 Tat-PDIA3 处理的第 24 天，通过夹闭双侧颈总动脉 5 分钟来短暂诱导缺血。
Tat-PDIA3 的给药显著降低了缺血诱导的自发性运动活动，并且与载体处理的缺血组相比，Tat-PDIA3 处理的缺血组 CA1 区的 NeuN 阳性核数量显著增加。与载体处理的对照组相比，Tat-PDIA3 处理组的 Ki67 和 DCX 免疫反应性细胞显著增加。在载体和 Tat-PDIA3 处理的缺血组中，Ki67 和 DCX 免疫反应性细胞的数量均显著高于相应的载体和 Tat-PDIA3 处理的对照组。在齿状回中，载体和 Tat-PDIA3 处理的缺血组之间 Ki67 免疫反应性细胞的数量相当，而 Tat-PDIA3 处理组观察到更多的 DCX 免疫反应性细胞。短暂性前脑缺血增加了齿状回中磷酸化 cAMP 反应元件结合蛋白（pCREB）的表达，但 Tat-PDIA3 的给药在正常沙鼠中强烈增加了 pCREB 阳性核，而在缺血沙鼠中则没有。脑源性神经营养因子（BDNF）mRNA 的表达在 Tat-PDIA3 处理组中显著高于载体处理组。与载体处理组相比，短暂性前脑缺血增加了 Tat-PDIA3 处理组的 BDNF mRNA 水平，各组之间无显著差异。
这些结果表明，Tat-PDIA3 通过增加 BDNF mRNA 和 pCREB 的磷酸化，增强了正常而非缺血沙鼠齿状回中的细胞增殖和神经母细胞数量。
