Elderly individuals undergoing surgical procedures are often confronted with the peril of experiencing postoperative cognitive dysfunction (POCD). Prior research has demonstrated the exacerbating effect of sevoflurane anesthesia on neuroinflammation, which can further deteriorate the condition of POCD in elderly patients. Intermittent fasting (IF) restricts food consumption to a specific time window and has been demonstrated to ameliorate cognitive dysfunction induced by neuropathic inflammation. We subjected 18-month-old male mice to 16hours of fasting and 8hours of unrestricted eating over a 24-hour period for 0, 1, 2, and 4 weeks, followed by abdominal exploration under sevoflurane anesthesia. In this study, we aim to explore the potential impact of IF on postoperative cognitive function in aged mice undergoing sevoflurane surgery through the preoperative implementation of IF measures. The findings indicate two weeks of IF leads to a significant enhancement of learning and memory capabilities in mice following surgery. The cognitive performance, as determined by the novel object recognition and Morris water maze tests, as well as the synaptic plasticity, as measured by in vivo electrophysiological recordings, has demonstrated marked improvements. Furthermore, the administration of IF markedly enhances the expression of synaptic-associated proteins in hippocampal neurons, concomitant with a decreasing expression of pro-inflammatory factors and a reduced density of microglial cells within the hippocampal brain region. To summarize, the results of this study indicate that IF may mitigate inflammation in the hippocampal area of the brain. Furthermore, IF appears to provide a safeguard against cognitive impairment and synaptic plasticity impairment brought on by sevoflurane anesthesia.

BACKGROUND:Sleep deprivation (SD) is a growing global health problem with many deleterious effects, such as cognitive impairment. Microglia activation-induced neuroinflammation may be an essential factor in this. Propofol has been shown to clear sleep debt after SD in rats. This study aims to evaluate the effects of propofol-induced sleep on ameliorating sleep quality impairment and cognitive decline after 48 h SD. METHODS:Almost 8-12-week-old rats were placed in the SD system for 48 h of natural sleep or continuous SD. Afterwards, rats received propofol (20 mg·kg-1·h-1, 6 h) via the tail or slept naturally. The Morris water maze (MWM) and Y-maze test assessed spatial learning and memory abilities. Rat EEG/EMG monitored sleep. The expression of brain and muscle Arnt-like protein 1 (BMAL1), brain-derived neurotrophic factor (BDNF) in the hippocampus and BMAL1 in the hypothalamus were assessed by western blot. Enzyme-linked immunosorbent assay detected IL-6, IL-1β, arginase 1 (Arg1), and IL-10 levels in the hippocampus. Immunofluorescence was used to determine microglia expression as well as morphological changes. RESULTS:Compared to the control group, the sleep-deprived rats showed poor cognitive performance on both the MWM test and the Y-maze test, accompanied by disturbances in sleep structure, including increased total sleep time, and increased time spent and delta power in non-rapid eye movement sleep. In addition, SD induces abnormal expression of the circadian rhythm protein BMAL1, activates microglia, and causes neuroinflammation and nerve damage. Propofol reversed these changes and saved sleep and cognitive impairment. Furthermore, propofol treatment significantly reduced hippocampal IL-1β and IL-6 levels, increased BDNF, Arg1, and IL-10 levels, and switched microglia surface markers from the inflammatory M1 type to the anti-inflammatory M2 type. CONCLUSION:Propofol reduces SD-induced cognitive impairment and circadian rhythm disruption, possibly by lowering neuronal inflammation and switching the microglia phenotype from an M1 to an M2 activated state, thus exerting neuroprotective effects.

Background Mild cognitive impairment (MCI), a syndrome defined as decline of cognitive function greater than expected for an individual’s age and education level, occurs in up to 22.7% of elderly patients in United States, causing the heavy psychological and economic burdens to families and society. Cellular senescence (CS) is a stress response that accompanies permanent cell-cycle arrest, which has been reported to be a fundamental pathological mechanism of many age-related diseases. This study aims to explore biomarkers and potential therapeutic targets in MCI based on CS. Methods The mRNA expression profiles of peripheral blood samples from patients in MCI and non-MCI group were download from gene expression omnibus (GEO) database (GSE63060 for training and GSE18309 for external validation), CS-related genes were obtained from CellAge database. Weighted gene co-expression network analysis (WGCNA) was conducted to discover the key relationships behind the co-expression modules. The differentially expressed CS-related genes would be obtained through overlapping among the above datasets. Then, pathway and GO enrichment analyses were performed to further elucidate the mechanism of MCI. The protein–protein interaction network was used to extract hub genes and the logistic regression was performed to distinguish the MCI patients from controls. The hub gene-drug network, hub gene-miRNA network as well as transcription factor-gene regulatory network were used to analyze potential therapeutic targets for MCI. Results Eight CS-related genes were identified as key gene signatures in MCI group, which were mainly enriched in the regulation of response to DNA damage stimulus, Sin3 complex and transcription corepressor activity. The receiver operating characteristic curves of logistic regression diagnostic model were constructed and presented great diagnostic value in both training and validation set. Conclusion Eight CS-related hub genes – SMARCA4, GAPDH, SMARCB1, RUNX1, SRC, TRIM28, TXN, and PRPF19 – serve as candidate biomarkers for MCI and display the excellent diagnostic value. Furthermore, we also provide a theoretical basis for targeted therapy against MCI through the above hub genes.

Background Homer1, an immediate early gene, is related to sleep deprivation (SD), and its protein products are involved in synaptic plasticity affecting the cognitive process. This study aimed to identify the SD-associated key Homer1 gene in the brain and explore the value of Homer1 proteins acting on synaptic plasticity in SD. Methods GSE9441 was extracted from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between SD and Control samples were achieved by R software and were analyzed by the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and gene set enrichment analysis (GSEA). Protein–protein interactions (PPI) network was built by the GeneMANIA databases. In animal experiments, male C57BL/6 J mice (aged 12–13 weeks) were sleep deprived for 6 h, followed by independent behavioral tests and in vitro assays. Morris water maze (MWM) was used to evaluate learning and memory function. The expression of hippocampal Homer1 proteins was detected by Western blot analysis and its distribution in CA1 by immunohistochemistry and immunofluorescence staining. Synaptic plasticity was assessed by Golgi staining and long-term potentiation (LTP) testing in the hippocampal CA1 region. Results Homer1 was the hub gene most associated with SD, and its protein products specifically acted on the regulation of synaptic plasticity in bioinformatics. SD mice exhibited spatial memory impairment accompanied by increased Homer1a expression in hippocampal tissue and CA1 region. SD did not induce Homer1b/c overexpression of mice in the hippocampus. SD impaired the hippocampal synaptic plasticity of mice by reducing the density of dendritic spines and inhibiting LTP in the hippocampal CA1 region, which may involve the overexpression of Homer1a in the hippocampus. Conclusion Homer1 gene is a core brain molecule associated with acute SD, and its protein product Homer1a is involved in the changes in cognitive brain function following short-term SD, especially the impact on hippocampal synaptic plasticity.

Harmful stimuli trigger mutations lead to uncontrolled accumulation of hnRNPA2/B1 in the cytoplasm, exacerbating neuronal damage. Kapβ2 mediates the bidirectional transport of most substances between the cytoplasm and the nucleus. Kapβ2 guides hnRNPA2/B1 back into the nucleus and restores its function, alleviating related protein toxicity. Here, we aim to explore the involvement of Kapβ2 in neurodegeneration in rats with MCI following sevoflurane anesthesia and surgery. Firstly, novel object recognition test and Barnes maze were conducted to assess behavioral performances, and we found Kapβ2 positively regulated the recovery of memory and cognitive function. In vivo electrophysiological experiments revealed that the hippocampal theta rhythm energy distribution was disrupted, coherence was reduced, and long-term potentiation was attenuated in MCI rats. LTP was greatly improved with positive modulation of Kapβ2. Next, functional MRI and BOLD imaging will be employed to examine the AFLL and FC values of dynamic connectivity between the cortex and hippocampus of the brain. The findings show that regulating Kapβ2 in the hippocampus region enhances functional activity and connections between brain regions in MCI rats. WB results showed that increasing Kapβ2 expression improved the expression and recovery of cognitive-related proteins in the hippocampus of MCI rats. Finally, WB and immunofluorescence were used to examine the changes in hnRNPA2/B1 expression in the nucleus and cytoplasm after overexpression of Kapβ2, and it was found that nucleocytoplasmic mis location was alleviated. Overall, these data show that Kapβ2 reverses the nucleoplasmic misalignment of hnRNPA2/B1, which slows neurodegeneration towards dementia in MCI after sevoflurane anesthesia and surgery. Our findings may lead to new approaches for perioperative neuroprotection of MCI patients.

Background and objective:Postoperative neurocognitive dysfunction (PND) occurs in up to 54% of older patients, giving rise to the heavy psychological and economic burdens to patients and society. To date, the development of PND biomarkers remains a challenge. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) is an RNA-binding protein whose prion-like structure is prone to mutation and hence leads to neurodegenerative diseases, but its expression changes in PND remains unclear. Here, we detect the preoperative hnRNPA2/B1 level in patients with PND, and to explore its value in the prediction and diagnosis of PND.Methods:The study included 161 elderly patients undergoing lumbar decompression and fusion in Nankai University Affinity the Third Central Hospital from September 2021 to July 2022. Neuropsychological and psychometric evaluations were performed before surgery, 1 week and 3 months after surgery to diagnose the occurrence of PND, then the peripheral blood was collected from patients before induction of anesthesia. The concentration in plasma of hnRNPA2/B1 and amyloid-β 42 were determined by enzyme-linked immunosorbent assay. The median fluorescence intensity and mRNA levels of hnRNPA2/B1 in peripheral blood mononuclear cells was detected by indirect intracellular staining flow cytometry and quantitative real-time PCR, respectively.Results:The preoperative hnRNPA2/B1 level in patients with PND was higher both in short-time and long-time follow-up. We found significantly higher concentrations of hnRNPA2/B1 in PND at 7 days after surgery (median, 72.26 pg/mL vs. 54.95 pg/mL, p = 0.022) compared with patients without PND, and so as 3 months after surgery (median, 102.93 pg/mL vs. 56.38 pg/mL, p = 0.012). The area under the curve (AUC) was predicted to be 0.686 at 7 days after surgery and 0.735 at 3 months. In addition, when combining several clinical information, the diagnostic efficiency of hnRNPA2/B1 for PND could further increase (AUC, 0.707 at 7 days, 0.808 at 3 months).Conclusion:Based on the findings reported here, hnRNPA2/B1 may serve as a new and powerful predictive biomarker to identify elderly patients with PND.

Objective: Preoperative levels of cognition-related biomarkers and intraoperative cerebral ischemia and hypoxia might cause postoperative neurocognitive dysfunction (PND). The aim of this study was to evaluate the predictive ability of preoperative plasma biomarkers along with cerebral oxygen saturation (SctO2) for the incidence of PND in elderly patients with mild cognitive impairment (MCI). Methods: A total of 210 patients aged 65–80 years undergoing spinal surgery were randomly assigned to three groups (n = 70 each): propofol, sevoflurane, and propofol/sevoflurane as anesthesia maintenance protocols. Propofol was administrated target-controlled infusion of 4 μg/ml (group P), the minimum alveolar concentration (MAC) of inhalation anesthetic sevoflurane was 1.3 (group S), and propofol was injected with a target-controlled plasma concentration of 1.2 μg/ml, accompanied by sevoflurane inhalation 0.7 MAC (group PS). Cognitive function was evaluated 1 day preoperatively and on the 7th day postoperatively. Preoperative levels of amyloidβ-40 (Aβ-40), Aβ-42, total tau protein (T-tau), phosphorylated tau protein (P-tau), and triggering receptors on myeloid cells-2 (TREM2) were investigated. SctO2 was monitored intraoperatively. Results: Aβ-42 had the strongest significant correlation with preoperative MoCA score. The value of Aβ-42 associated with a high risk of PND was 28.34 pg/ml, and the area under the curve (AUC) was predicted to be 0.711. When the preoperative level of Aβ-42 was 28.34 pg/ml, SctO2max% was 9.92%. The AUC was predicted to be 0.872, and the sensitivity and specificity were 0.833 and 0.841, respectively. Conclusion: Under the conditions of preoperative Aβ-42 less than 28.34 pg/ml, the intraoperative fluctuation range of cerebral oxygen saturation should be maintained within 9.92% to reduce the occurrence of PND in geriatric patients with MCI.

Backgrounds: Aging-related impairment of cerebral blood flow regulation leads to the disruption of neuronal micro-environmental homeostasis. Anesthetics should be carefully selected for aging patients since they have less cognition capacity. Effects and mechanisms of propofol or isoflurane have been widely investigated. However, how different combinations of propofol and isoflurane affect neurons and the mechanism still needs to be demonstrated. Methods: We cultured rat hippocampal neurons and established a hypoxic injury model to imitate the micro-environment of aging brains. Three different combinations of propofol and isoflurane were applied to find out an optimum group via Cell Counting Kit-8 (CCK8) assay, lactic acid dehydrogenase (LDH) assay, real-time qPCR, and immunofluorescence of key proteins. Then BiP was silenced by small interfering RNA (siRNA) to explore the mechanism of how isoflurane and propofol affect neurons. Endoplasmic reticulum (ER) stress was measured by Western blot and immunofluorescence. To detect GABAAR α1 subunit proteostasis and its function, real-time qPCR, immunoprecipitation, and Western blot were carried out. Results: Hypoxic neurons showed no different changes on cell viability, LDH leakage, and ER stress after treatment with 1% isoflurane and 1.2 μg/ml of propofol. Hypoxic neurons showed a sharp increase of LDH leakage and ER stress and a decrease of cell viability after treatment with 1.4% isoflurane and 0.6 μg/ml of propofol or 0.5% isoflurane and 1.8 μg/ml of propofol. After knockdown of BiP, the application of 1% isoflurane and 1.2 μg/ml of propofol led to the decrease of GABAAR α1 subunit protein content and viability of cell, as well as aggravation of ER stress. Conclusion: A combination of 1% isoflurane and 1.2 μg/ml of propofol causes the least damage than do other dosages of both two drugs, and endogenous BiP plays an important role in this process.