ABSTRACT
It has been reported that the gut microbiome modulates postoperative cognitive dysfunction (POCD), and that administration of probiotics (VSL#3) may effectively relieve POCD. In this study, we aimed to identify the underlying mechanism of VSL#3 in POCD. A mouse model of POCD was constructed in adult male C57BL/6 mice, which were then treated with VSL#3. VSL#3 exerted a protective role against POCD and resultant neuronal apoptosis. The expression of miR-146a was found to be downregulated in hippocampal tissues of POCD mice, while VSL#3 could restore its expression. Loss- and gain-function approaches were conducted to determine the roles of microRNA (miR)-146a, B-cell translocation gene 2 (BTG2), and Bcl-2-associated X protein (Bax) in post-operative effects on cognitive function and neuronal apoptosis. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured to determine oxidative stress in brain tissue. The dual-luciferase reporter gene assay identified that miR-146a could target BTG2 and negatively regulate its expression. BTG2 knockdown suppressed neuronal apoptosis and contributed to shortened time of latency, prolonged time of mice spent in the target quadrant, and reduced oxidative stress through downregulating Bax expression. Finally, VSL#3 treatment upregulated the expression of miR-146a to block BTG2/Bax axis and consequently inhibited neuronal apoptosis and reduced oxidative stress in POCD mice. Taken together, the study suggested that miR-146a-mediated suppression of BTG2/Bax contributed to the protective role of probiotics treatment against POCD.
Subject(s)
Immediate-Early Proteins/biosynthesis , MicroRNAs/biosynthesis , Postoperative Cognitive Complications/diet therapy , Postoperative Cognitive Complications/metabolism , Probiotics/administration & dosage , Tumor Suppressor Proteins/biosynthesis , bcl-2-Associated X Protein/biosynthesis , Animals , Cell Line , Gene Expression , Immediate-Early Proteins/antagonists & inhibitors , Male , Mice , Mice, Inbred C57BL , Postoperative Cognitive Complications/prevention & control , Tumor Suppressor Proteins/antagonists & inhibitors , bcl-2-Associated X Protein/antagonists & inhibitorsABSTRACT
With the acceleration of an aging population, postoperative cognitive dysfunction (POCD) has become a large problem. Preoperative carbohydrate (CHO) loading has been reported to attenuate surgery stress response and insulin resistance. The present study aimed to investigate whether preoperative vitamin-rich CHO loading has an effect on POCD, endoplasmic reticulum (ER) stress, and apoptosis. Eighty male Sprague-Dawley rats (20-month old) were randomly assigned to four groups (20 per group): control group (no anesthesia and surgery), fasting group (fasting 14â¯h before surgery), water group (oral water 3â¯h before surgery), and CHO group (oral vitamin-rich CHO 3â¯h before surgery). The POCD rat model was established by splenectomy under intraperitoneal injection of pentobarbital sodium. Cognitive function was assessed using the Morris water maze (MWM) after surgery. The levels of endoplasmic reticulum (ER) stress markers and apoptosis related proteins in the hippocampus were examined by western blot analysis. The vitamin-rich CHO treated animals performed better in the MWM tests than the animals in the fasting and water groups. Furthermore, preoperative CHO loading reduced ER stress and neuronal apoptosis in the hippocampus of aged rats, as indicated by the protein biomarkers of GRP78, eIF2a, Beclin1, Bax, and Bcl-2. In conclusion, preoperative vitamin-rich CHO loading could improve POCD by attenuating ER stress and neural apoptosis, providing a basis as a potential treatment against POCD.
