The complement system plays an important role in many neurological disorders. Complement modulation, including C3/C3a receptor signaling, shows promising therapeutic effects on cognition and neurodegeneration. Yet, the implications for this pathway in perioperative neurocognitive disorders (PND) are not well established. Here, we evaluated the possible role for C3/C3a receptor signaling after orthopedic surgery using an established mouse model of PND. A stabilized tibial fracture surgery was performed in adult male C57BL/6 mice under general anesthesia and analgesia to induce PND-like behavior. Complement activation was assessed in the hippocampus and choroid plexus. Changes in hippocampal neuroinflammation, synapse numbers, choroidal blood-cerebrospinal fluid barrier (BCSFB) integrity, and hippocampal-dependent memory function were evaluated after surgery and treatment with a C3a receptor blocker. C3 levels and C3a receptor expression were specifically increased in hippocampal astrocytes and microglia after surgery. Surgery-induced neuroinflammation and synapse loss in the hippocampus were attenuated by C3a receptor blockade. Choroidal BCSFB dysfunction occurred 1 day after surgery and was attenuated by C3a receptor blockade. Administration of exogenous C3a exacerbated cognitive decline after surgery, whereas C3a receptor blockade improved hippocampal-dependent memory function. Orthopedic surgery activates complement signaling. C3a receptor blockade may be therapeutically beneficial to attenuate neuroinflammation and PND.

Postoperative cognitive dysfunction (POCD) is a disturbing neurological complication in patients undergoing anesthesia and surgical procedures. Brain-derived neurotrophic factor (BDNF) and its precursor proBDNF binding to their corresponding receptors tyrosine kinase (TrkB) and p75 neurotrophin receptor (p75NTR) exert quite an opposite biological function in neuron survival and synaptic function. This study aimed to demonstrate the critical role of the BDNF/proBDNF ratio in modulating synaptic plasticity, which further leads to anesthesia-/surgery-induced POCD. It also showed that the exogenous BDNF or p75NTR inhibitor could ameliorate cognitive dysfunction. In detail, 16-month-old C57BL/6 mice were subjected to a stabilized tibial fracture surgery with isoflurane anesthesia to establish the POCD animal model. The mice were then microinjected with either p75NTR inhibitor or exogenous BDNF into the dorsal hippocampus. Behavioral experiments were performed by open field and fear conditioning tests (FCTs). Western blotting was also used to measure the expression levels of BDNF, proBDNF, TrkB, p-TrkB, p75NTR, and synapse proteins. Golgi staining and electrophysiology were applied to evaluate the neuronal synaptic plasticity. Here, we demonstrated that anesthesia/surgery induced a reduction of BDNF/proBDNF, which negatively regulates the synaptic function in hippocampus, subsequently leading to cognitive impairment in aged mice. P75NTR inhibitor and exogenous BDNF could attenuate cognitive deficits by rescuing the dendritic spine loss and long-term potentiation (LTP) via altering the BDNF/proBDNF ratio. This study unveiled that the BDNF/proBDNF ratio in the hippocampus played a key role in anesthesia-/surgery-induced POCD. Thereby, tuning the ratio of BDNF/proBDNF is supposed to be a promising therapeutic target for POCD.

Postoperative cognitive dysfunction (POCD) is a common postoperative complication observed in elderly patients. Using microarray analyses, we comprehensively compared long non-coding RNA (lncRNA), messenger RNA (mRNA), and microRNA (miRNA) expression profiles in hippocampal tissues from a mouse model of POCD and control mice. A total of 175 lncRNAs, 117 mRNAs, and 26 miRNAs were differentially expressed between POCD and control mice. Gene ontology (GO) and KEGG pathway enrichment analyses were performed to explore the principal functions of dysregulated genes. Correlated coding-noncoding co-expression (CNC) and competing endogenous RNA (ceRNA) expression networks were constructed using bioinformatics methods. lncRNA NONMMUT000708 correlated positively with expression of the inflammation-related gene Hif3a. lncRNAs NONMMUT043249 and NONMMUT028705 mediated gene expression by binding the transcription factor cAMP response element-binding protein (CREB). The constructed ceRNA network suggested lncRNA NONMMUT055714 binds competitively with miR-7684-5p, increasing expression of its target gene, Sorl1. Finally, eight dysregulated lncRNAs, four miRNAs, and ten mRNAs were confirmed via quantitative real-time polymerase chain reaction (PCR) in 10 POCD-healthy mouse paired samples. These results suggest that lncRNAs and miRNAs are involved in POCD pathogenesis and progression. Our ceRNA network will improve understanding of lncRNA-mediated ceRNA regulatory mechanisms operating during the pathogenesis of POCD.

BACKGROUND: Postoperative delirium is a major debilitating complication for patients and is associated with poor outcomes. Previous studies have suggested that excessive general anesthesia may lead to postoperative delirium. Electroencephalography (EEG)-based monitors have been administered in clinical practice in an attempt to deliver appropriate anesthesia. The aim of this updated meta-analysis was to evaluate the current body of research concerning the effects of EEG-based monitor on postoperative delirium. METHODS: We conducted a meta-analysis of randomized controlled trials of the effect of processed EEG monitor on postoperative delirium as the primary outcome. The search was performed in CENTRAL, MEDLINE, and EMBASE, with no language restrictions from inception until June 23, 2019. Two independent reviewers screened records and full-text articles for inclusion. Data extraction and risk-of-bias assessment were conducted by 3 independent reviewers. Random-effects models were used to calculate combined-effect estimates. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of evidence. RESULTS: Of 5904 records screened, 5 studies met our inclusion criteria, including 3612 patients. Meta-analysis revealed no significant effect of EEG-based monitors on postoperative delirium (risk ratio [RR], 0.79; 95% confidence interval [CI], 0.60–1.05; I ² = 73%). The results showed a statistically significant reduction in intensive care unit (ICU) length of stay (3 studies, weight mean difference [WMD] −0.29 days; 95% CI, −0.53 to −0.05) in patients with EEG monitored. EEG-guided anesthesia did not have a statistically significant difference in all-cause mortality (3 studies, RR, 0.63; 95% CI, 0.31–1.29) and hospital length of stay (4 studies, WMD −0.61 days; 95% CI, −1.34 to 0.11). Few studies investigated the effects of EEG-guided anesthesia on perioperative major nonneurological complications and did not come up with promising results. CONCLUSIONS: The current evidence is not sufficient to support the prevention effects of EEG monitor on postoperative delirium. More robustly designed and well-conducted studies with emphasis on this matter are warranted.