Ning Yang

Postoperative delirium (POD), which occurs in hospital up to 1‑week post‑procedure or until discharge, is a common complication, especially in older adult patients. However, the pathogenesis of POD remains unclear. Although damage to blood‑brain barrier (BBB) integrity is involved in the neuropathogenesis of POD, the specific role of the BBB in POD requires further elucidation. Anaesthesia using 2% isoflurane for 4 h results in the upregulation of hippocampal receptor for advanced glycation end‑products (RAGE) expression and β‑amyloid accumulation in aged rats. The present study investigated the role of RAGE in BBB integrity and its mechanisms in POD‑like behaviours. The buried food, open field and Y maze tests were used to evaluate neurobehavioural changes in aged mice following 2.5% sevoflurane anaesthesia administration with exploratory laparotomy. Levels of tight junction proteins were assessed by western blotting. Multiphoton in vivo microscopy was used to observe the ultrastructural changes in the BBB in the hippocampal CA1 region. Anaesthesia with surgery decreased the levels of tight junction proteins occludin and claudin 5, increased matrix metalloproteinases (MMPs) 2 and 9, damaged the ultrastructure of the BBB and induced POD‑like behaviour. FPS‑ZM1, a specific RAGE antagonist, ameliorated POD‑like behaviour induced by anaesthesia and surgery in aged mice. Furthermore, FPS‑ZM1 also restored decreased levels of occludin and claudin 5 as well as increased levels of MMP2 and MMP9. The present findings suggested that RAGE signalling was involved in BBB damage following anaesthesia with surgery. Thus, RAGE has potential as a novel therapeutic intervention for the prevention of POD.

Postoperative neurocognitive impairment is an urgent problem with global aging accelerating. The prevention and treatment of postoperative neurocognitive impairment have been widely investigated but lack effective strategies. Low-intensity pulsed ultrasound (LIPUS), a non-invasive tool, has shown an effect on neuroprotection, but whether it could attenuate the postoperative neurocognitive impairment and the underlying mechanisms remains unknown. An experimental setup for LIPUS stimulation of the hippocampus was well established. A laparotomy model in aged mice was applied, and a Morris water maze was used to assess cognitive function. RT-qPCR and western blotting were used to detect levels of Piezo1, synapse-associated proteins in the hippocampus, respectively. Immunofluorescent staining was also used to determine the neural activation and Piezo1 expression. The results showed that LIPUS increased synapse-related proteins of the hippocampus and attenuated cognitive impairment in aged mice. Meanwhile, LIPUS suppressed the overexpression of Piezo1 in the hippocampus. We further found that LIPUS promoted Calpain1 activity and increased extracellular regulated protein kinases (Erk) phosphorylation. Our results suggested that LIPUS could improve cognitive impairment and increase hippocampal synaptogenesis through the Piezo1-mediated Calpain1/ Erk pathway. LIPUS could be used as an effective physical intervention to alleviate postoperative cognitive dysfunction in the aged population.

Postoperative neurocognitive disorders (po-NCD), including postoperative delirium (POD) and delayed neurocognitive recovery (dNCR), are common in geriatric surgical patients. However, the ideal diagnostic biomarkers to predict individual risks of po-NCDs have not been identified. In this study, proteomic analysis was used to detect dysregulated proteins in three cognitive-related brain regions, the hippocampus, prefrontal cortex, and temporal lobe, of aged dNCR rats. The common affected proteins in these three brain regions were further verified by real-time polymerase chain reaction and western blotting. Furthermore, serum samples from aged rats with dNCR and elderly hip fracture patients with POD were also assessed with enzyme linked immunosorbent assays to investigate the biomarker potential of these dysregulated proteins. The increased expression levels of haptoglobin, caseinolytic protease (ClpP), and alpha-2 macroglobulin (A2M) as well as decreased expression levels of 14-3-3β/α and biliverdin reductase-A (BVR-A) were validated by proteomic analysis in the hippocampus, prefrontal cortex, and temporal lobe of aged dNCR rats. The increased expression of haptoglobin and decreased expression of 14-3-3β/α were further demonstrated in the three brain regions by western blotting. Moreover, increased levels of S100A6 and BVR-A in the hippocampus, S100A6 in the prefrontal cortex, and A2M in the temporal lobe were also observed. More intriguingly, both decreased serum 14-3-3β/α and increased A2M in geriatric POD patients as well as decreased serum ClpP in aged dNCR rats were verified. These results not only indicate potential diagnostic biomarkers for po-NCD but also provide directions for further pathological investigations.Clinical Trial Registration:www.ClinicalTrials.gov, identifier [ChiCTR1900027393].

Delayed neurocognitive recovery (dNCR) is a major complication after anesthesia and surgery in older adults. Alpha‐synuclein (α‐syn; encoded by the gene, SNCA) has recently been shown to play an important role in hippocampus‐dependent working memory. Aggregated forms of α‐syn are associated with multiple neurotoxic mechanisms, such as mitochondrial dysfunction and cell death. In this study, we found that blocking α‐syn improved both mitochondrial function and mitochondria‐dependent neuronal apoptosis in a mouse model of dNCR. Various forms of α‐syn (including total α‐syn, phosphorylated‐Ser129‐α‐syn, and oligomers) were upregulated in hippocampal tissue and extracted mitochondria after surgical challenge. Clenbuterol is a novel transcription modulator of Scna. Clenbuterol significantly attenuated surgery‐induced progressive accumulation of various toxic α‐syn forms in the hippocampus, as well as mitochondrial damage and memory deficits in aged mice following surgery. We also observed excessive mitochondrial α‐syn accumulation and increased mitochondria‐mediated apoptosis in vitro using nerve growth factor‐differentiated PC12 cells and primary hippocampal neurons exposed to lipopolysaccharide. To further validate the neuroprotective effect of α‐syn inhibition, we used a lentiviral Snca‐shRNA (Lv‐shSnca) to knockdown Snca. Of note, Lv‐shSnca transfection significantly inhibited neuronal apoptosis mediated by the mitochondrial apoptosis pathway in neurons exposed to lipopolysaccharide. This α‐syn inhibition improved the disruption to mitochondrial morphology and function, as well as decreased levels of apoptosis. Our results suggest that targeting pathological α‐syn may achieve neuroprotection through regulation of mitochondrial homeostasis and suppression of apoptosis in the aged hippocampus, further strengthening the therapeutic potential of targeting α‐syn for dNCR.

Long noncoding RNAs (lncRNAs) play important roles in brain function modulation and neurodegenerative diseases. However, whether lncRNA regulations are involved in the mechanisms of perioperative neurocognitive disorders, especially in anesthesia‐related brain dysfunction, remain unknown. Therefore, we explored the expression and regulation pattern profiles of lncRNAs in the hippocampus of aged rats after sevoflurane anesthesia. Three lncRNAs and 772 protein‐coding genes were identified by microarray analysis and evidenced by in vitro and in vivo experiments as differentially expressed. Functional annotation and differentially expressed‐ (DE‐) lncRNA‐mRNA coexpression networks reveal that DE‐lncRNAs are associated with mitochondrial dysfunction and oxidative stress, aging‐related metabolism alterations, DNA damage, and apoptosis, as well as neurodegenerative features during sevoflurane anesthesia. These results suggest that lncRNAs play roles in general anesthesia‐related brain function modulation during the perioperative context and provide insights into the lncRNA‐related modulation mechanisms and targets.

The effects of the intravenous anesthetics propofol and etomidate on circulation are significantly different; however, their differing effects on miRNA expression in the cardiovascular system are not clearly understood. The purpose of this study is to investigate the effects of these two anesthetics on miRNA expression profiles in the heart and blood vessels. Rats were randomly divided into a propofol group and an etomidate group. Spontaneous breathing was maintained throughout the anesthesia process and the rats’ oxygen supply was ensured. Heart and thoracic aorta tissue was harvested 3 h after induction. The expression profiles of cardiovascular miRNAs were detected by microarray 4.0 analysis. Twelve representative miRNAs were selected for qRT-PCR validation, and their target genes were predicted using bioinformatics methods. Microarray analysis showed 16 differentially expressed miRNAs in heart tissue from the propofol group compared with the etomidate group (10 up-regulated and 6 down-regulated), while in the blood vessels there were 25 altered miRNAs (10 up-regulated, 15 down-regulated). After verifying 12 representative miRNAs via qRT-PCR, the results showed no significant difference in the expression of miRNAs in the heart tissue, but a significant difference in the expression of 5 miRNAs in vessel tissue between the two groups. Bioinformatics analysis predicts that the target genes of the 5 differentially expressed miRNAs are associated with chemical synapse signaling pathways. Propofol and etomidate have different effects on the expression of cardiovascular miRNAs, and further research is needed to elucidate the functional consequences of these differentially expressed miRNAs.