BackgroundMounting evidence indicates that children who experience abuse and neglect are prone to chronic diseases and premature mortality later in life. One mechanistic hypothesis for this phenomenon is that early life adversity alters the expression or functioning of the glucocorticoid receptor (GR) throughout the course of life and thereby increases sensitivity to inflammatory stimulation. An exaggerated pro-inflammatory response is generally considered to be a key cause of postoperative cognitive dysfunction (POCD). The aim of this study was to examine the effects of early life adversity on cognitive function and neuroinflammation after sevoflurane anesthesia in adult rats and to determine whether such effects are associated with the epigenetic regulation of GR.MethodsWistar rat pups were repeatedly subjected to infant maternal separation (early life stress) from postnatal days 2–21. In adulthood, their behavior and the signaling of hippocampal pro-inflammatory factors and nuclear factor-kappa B (NF-κB) after sevoflurane anesthesia were evaluated. We also examined the effects of maternal separation (MS) on the expression of GR and the DNA methylation status of the promoter region of exon 17 of GR and whether behavioral changes and neuroinflammation after anesthesia were reversible when the expression of GR was increased by altering DNA methylation.ResultsMS induced cognitive decline after sevoflurane inhalation in the Morris water maze and context fear conditioning tests and enhanced the release of cytokines and the activation of astrocyte intracellular NF-κB signaling induced by sevoflurane in the hippocampus of adult rats. Blocking NF-κB signaling by pyrrolidine dithiocarbamate (PDTC) inhibited the release of cytokines. MS also reduced the expression of GR and upregulated the methylation levels of the promoter region of GR exon 17, and such effects were reversed by treatment with the histone deacetylase inhibitor trichostatin A (TSA) in adult rats. Moreover, TSA treatment in adult MS rats inhibited the overactivation of astrocyte intracellular NF-κB signaling and the release of cytokines and alleviated cognitive dysfunction after sevoflurane anesthesia.ConclusionsEarly life stress induces cognitive dysfunction after sevoflurane anesthesia, perhaps due to the aberrant methylation of the GR gene promoter, which reduces the expression of the GR gene and facilitates exaggerated inflammatory responses.

Background:Trial design neuroinflammation and postoperative pain after surgery are increasingly reported in association with postoperative cognitive dysfunction (POCD). Parecoxib, a selective cyclooxygenase (COX)-2 inhibitor, is used for postoperative analgesia for its potent anti-inflammatory and analgesic effects. This study aimed to evaluate parecoxib's effects on POCD in elderly patients undergoing total knee arthroplasty.Methods:Around 134 elderly patients undergoing total knee arthroplasty were randomly divided into parecoxib (group P) and control (group C) groups, and treated with parecoxib sodium and saline, respectively, shortly after induction of general anesthesia and 12-h postsurgery, respectively. Perioperative plasma IL-1β, IL-6, TNF-α, and C-reactive protein (CRP) 1evels were measured. Postoperative pain was assessed following surgery. Neuropsychological tests were performed before surgery, and 1 week and 3 months postoperation.Results:POCD incidence in group P was significantly lower compared with that of group C at 1 week after surgery (16.7% vs 33.9%; P < 0.05); no significant difference was found between groups C and P at 3-month follow-up (9.7% vs 6.7%). Compared with group C values, visual analog pain scale (VAS) scores at 3, 6, and 12 hours after surgery were significantly lower in group P(P < 0.05). Plasma IL-1β, IL-6, and TNF-α levels were lower in group P than in group C after the operation (P < 0.05). No significant difference in the plasma CRP level was found between groups P and C.Conclusions:Parecoxib sodium decreases POCD incidence after total knee arthroplasty in elderly patients and may explain how this drug suppresses inflammation and acute postoperative pain caused by surgical trauma.

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Objective: Inflammation plays a key role in the etiology and pathology of postoperative cognitive dysfunction (POCD). Cyclooxygenase (COX)-2 inhibitor celecoxib is used for the treatment of acute pain due to its potent anti-inflammatory and analgesic effects. Herein, we evaluated the effects of celecoxib on POCD in geriatric patients.Methods: A total of 178 geriatric patients undergoing total knee arthroplasty were randomly divided into two groups and treated with celecoxib (group C) or placebo (group P). The levels of perioperative plasma COX-2, IL-1β, IL-6, TNF-α, neuron-specific enolase, and S100β were detected in all patients. The pain intensity was measured by numerical rating scale (NRS). A battery of 9 neuropsychological tests was performed pre-operatively and 1 week, and 3 months postoperatively. Patients, whose postoperative performance declined by ≧1 standard deviation as compared to each preoperative test score on ≧2 tests, were classified as POCD.Results: A significant decrease in POCD incidence was found in group C as compared to group P on postoperative day 7 (12.3% vs. 34.1%; p < 0.05). POCD incidence did not differ between the two groups at the 3-month follow-up (8.8 vs. 9.7%). NRS scores at days 3 and 4 post-surgery were significantly lower in group C (p < 0.05). Patients in group C showed lower level of plasma COX-2, IL-1β, IL-6, TNF-α, and S100β as compared to group P postoperatively (p < 0.05).Conclusion: These results demonstrated that celecoxib can decrease early POCD incidence after total knee arthroplasty in geriatric patients, which might be mediated by suppressing inflammation and acute postoperative pain caused by surgical trauma.Registration: Chinese Clinical Trial Register, ChiCTR-IOR-16008168.

Background Childhood trauma (CT) is considered as a highly risk factor for depression. Although the pathway of CT to depression, especially the mediating or moderating effects of cognitive emotion regulation strategies (CERS) or neuroticism, have investigated by several studies, the results were inconsistent and there is a paucity of full models among these interactive factors. This study aims to examine the relationships among CT, adaptive / maladaptive CERS, neuroticism, and current depression symptoms in university students. Methods We recruited 3009 freshman of 2019, aged averagely 18.00 (SD = 0.772) years, from universities in Hunan province in 2019. A moderated mediation model was built to examine the relationships among CT, CERS, neuroticism, and current depression using the SPSS PROCESS 3.5 macro. We conducted bootstrapping of regression estimates with 5000 samples and 95% confidence interval. Results Results revealed that the significant mediating effects of adaptive CERS (β = 0.012; 95% CI: 0.006 to 0.018) and maladaptive CERS (β = 0.028; 95% CI: 0.016 to 0.040) between CT and depression were observed, accounting for 5.69% and 13.52% of the total effect respectively. Then, moderated mediation analyses results showed that neuroticism simultaneously moderated the direct effect of CT on current depression (β = 0.035; 95% CI: 0.001 to 0.009), and the indirect effects of CT on current depression through adaptive CERS (adaptive CERS – current depression: β = − 0.034; 95% CI: − 0.007 to − 0.001) and maladaptive CERS (maladaptive CERS – current depression: β = 0.157; 95% CI: 0.017 to 0.025). However, the moderating effects of neuroticism in the indirect paths from CT to adaptive CERS (β = 0.037; 95% CI: 0.000 to 0.014) and maladaptive CERS (β = − 0.001; 95% CI: − 0.006 to 0.005) were not significant. Conclusions This study provides powerful evidences through a large university students sample for the mediating role of adaptive / maladaptive CERS and the moderating role of neuroticism between CT and current depression. This manifests that cognitive emotion regulation may be a vital factor for people who suffered from CT and current depression. Furthermore, the influence of neuroticism in this process cannot be ignored.