Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication that can impair learning and memory for days, months, or even years after anesthesia/surgery. POCD is strongly associated with an altered composition of the gut microbiota (dysbiosis), but the accompanying metabolic changes and their role in gut-brain communication and POCD pathogenesis remain unclear. Here, the present study reports that anesthesia/surgery in aged mice induces elevated intestinal indoleamine 2,3-dioxygenase (IDO) activity, which shiftes intestinal tryptophan (TRP) metabolism toward more IDO-catalyzed kynurenine (KYN) and less gut bacteria-catabolized indoleacetic acid (IAA). Both anesthesia/surgery and intraperitoneal KYN administration induce increased KYN levels that correlate with impaired spatial learning and memory, whereas dietary IAA supplementation attenuates the anesthesia/surgery-induced cognitive impairment. Mechanistically, anesthesia/surgery increases the proportion of interferon-γ (IFN-γ)-producing group 1 innate lymphoid cells (ILC1) in the small intestine lamina propria and elevates intestinal IDO expression and activity, as indicated by the higher ratio of KYN to TRP. The IDO inhibitor 1-MT and antibodies targeting IFN-γ or ILCs mitigate anesthesia/surgery-induced cognitive dysfunction, suggesting that intestinal ILC1 expansion and the ensuing IFN-γ-induced IDO upregulation may be the primary pathway mediating the shift to the KYN pathway in POCD. The ILC1-KYN pathway in the intestine could be a promising therapeutic target for POCD.

BACKGROUND: The molecular biology mechanisms underlying postoperative cognitive dysfunction (POCD) remain unclear, resulting in a lack of specific therapeutic targets and limited clinical treatment options. The NLRP3 pyroptotic pathway, induced by neuroinflammation, is known to promote the development of POCD. Research has shown that lncRNA MEG3 exacerbates cell pyroptosis in various neurological injuries, though the precise mechanism remains to be investigated.
METHODS: In vitro and in vivo models of POCD were established through treatment with sevoflurane. Gene and protein expression were investigated using qRT-PCR, Western blot analysis, ELISA, and histological staining. Additionally, cell viability and injury were assessed through CCK-8 and LDH assays. Hippocampal-dependent memory and cognitive abilities were evaluated using the Morris Water Maze (MWM) test. Furthermore, the interactions between MEG3 and EZH2/YTHDC1 were validated through RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP).
RESULTS: Our findings reveal that sevoflurane significantly reduced MEG3 and pyroptosis-related proteins in mice. The overexpression of MEG3 protected mice against sevoflurane-induced cognitive dysfunction and reversed sevoflurane-induced pyroptosis in hippocampal neurons. MEG3 induced the downregulation of NLRP3 expression and reduced mRNA stability through its interaction with EZH2/YTHDC1.
CONCLUSIONS: In conclusion, our study elucidates that MEG3 inhibits the NLRP3 inflammasome and hippocampal neuron pyroptosis through the recruitment of EZH2/YTHDC1. These findings shed light on the underlying mechanism of MEG3 in the regulation of POCD and suggest that MEG3 could serve as a potential therapeutic target for the treatment of POCD.

UNASSIGNED: Mini-mental State Examination (MMSE) is widely accepted clinically for postoperative cognitive dysfunction (POCD) assessment. This study aims to investigate the post-operative cognitive changes among high-risk cardiothoracic patients and establish a standardised approach to post-surgery cognitive assessment.
UNASSIGNED: This is a prospective cohort study, where cognitive assessments were done 1-day before surgery, at discharge, and during 6 weeks of follow-up. Sample size calculation, accounting for an estimated 20% dropout rate, determined a minimum of 170 subjects were required for the study. Reduction of MMSE score of more than 2.5 was considered as having POCD. Score differences between groups were analysed using T-test and analysis of variance (ANOVA), while consistency between tools was analysed using correlation and regression.
UNASSIGNED: A total of 188 patients completed the study, with a POCD prevalence of 20.2% and 6.9% at discharge and at the 6 week follow up, respectively. All cognitive tools show a significant difference between preoperative and postoperative scores. All tests show a significant moderate correlation with MMSE.
UNASSIGNED: In conclusion, it is imperative to employ a battery of cognitive assessments to evaluate cognitive changes comprehensively.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is related to an increased risk of postoperative cognitive dysfunction (POCD), which may be caused by neuronal hyperexcitability. Astrocyte glutamate transporter 1 (GLT-1) plays a crucial role in regulating neuron excitability. We investigated if T2DM would magnify the increased neuronal excitability induced by anesthesia/surgery (A/S) and lead to POCD in young adult mice, and if so, determined whether these effects were associated with GLT-1 expression.
METHODS: T2DM model was induced by high fat diet (HFD) and injecting STZ. Then, we evaluated the spatial learning and memory of T2DM mice after A/S with the novel object recognition test (NORT) and object location test (OLT). Western blotting and immunofluorescence were used to analyze the expression levels of GLT-1 and neuronal excitability. Oxidative stress reaction and neuronal apoptosis were detected with SOD2 expression, MMP level, and Tunel staining. Hippocampal functional synaptic plasticity was assessed with long-term potentiation (LTP). In the intervention study, we overexpressed hippocampal astrocyte GLT-1 in GFAP-Cre mice. Besides, AAV-Camkllα-hM4Di-mCherry was injected to inhibit neuronal hyperexcitability in CA1 region.
RESULTS: Our study found T2DM but not A/S reduced GLT-1 expression in hippocampal astrocytes. Interestingly, GLT-1 deficiency alone couldn\'t lead to cognitive decline, but the downregulation of GLT-1 in T2DM mice obviously enhanced increased hippocampal glutamatergic neuron excitability induced by A/S. The hyperexcitability caused neuronal apoptosis and cognitive impairment. Overexpression of GLT-1 rescued postoperative cognitive dysfunction, glutamatergic neuron hyperexcitability, oxidative stress reaction, and apoptosis in hippocampus. Moreover, chemogenetic inhibition of hippocampal glutamatergic neurons reduced oxidative stress and apoptosis and alleviated postoperative cognitive dysfunction.
CONCLUSIONS: These findings suggest that the adult mice with type 2 diabetes are at an increased risk of developing POCD, perhaps due to the downregulation of GLT-1 in hippocampal astrocytes, which enhances increased glutamatergic neuron excitability induced by A/S and leads to oxidative stress reaction, and neuronal apoptosis.

BACKGROUND: Perioperative neurocognitive disorders are often neglected and undiagnosed. There are known risk factors for these disorders (e.g., higher levels of frailty, cognitive decline before surgery). However, these factors are usually not assessed in the daily clinical setting. One of the main reasons for this lack of examination is the absence of a suitable cognitive function test that can be used in acute clinical settings. The primary aim of this study was to determine correlations between preoperative and postoperative scores on three cognitive tests (the Mini Mental State Exam (MMSE), the Clock Drawing Test (CDT) and the Test of Gestures (TEGEST).
METHODS: This was a prospective, monocentric, observational study that included one cohort of patients aged 65 years and older. Patients underwent acute or elective surgical operations. Preanaesthesia tests were administered. After the operation, the patients completed the same tests between the 2nd postoperative day and discharge. Preoperative and postoperative cognitive test scores were assessed.
RESULTS: This study included 164 patients. The arithmetic mean age was 74.5 years. The strongest correlations were observed between MMSE scores and TEGEST scores (r = 0.830 before and 0.786 after surgery, P < 0.001). To compare the MMSE and the TEGEST, the MMSE was divided into 2 categories-normal and impaired-and good agreement was found among 76.2% of the participants (ϰ = 0.515). If the TEGEST scoring system was changed so that scores of 4-6 indicated normal cognition and scores of 0-3 indicated cognitive impairment, the level of agreement would be 90.8%, ϰ = 0.817. Only 5.5% of the patients had impaired MMSE scores and normal TEGEST scores, whereas 3.7% of the respondents normal MMSE scores and impaired TEGEST scores.
CONCLUSIONS: According to our results, the TEGEST is a suitable option for assessing cognitive functioning before surgery among patients who are at risk of developing perioperative neurocognitive disorders. This study revealed that it is necessary to change the rating scale for the TEGEST so that scores of 4-6 indicate normal cognition and scores of 0-3 indicate cognitive impairment. In clinical practice, the use of the TEGEST may help to identify patients at risk of perioperative neurocognitive disorders.

Peri-operative neurocognitive disorders (PNDs) include postoperative delirium (POD) and postoperative cognitive dysfunction (POCD). Children and the elderly are the two populations most vulnerable to the development of POD and POCD, which results in both high morbidity and mortality. There are many factors, including neuroinflammation and oxidative stress, that are associated with POD and POCD. General anesthesia is a major risk factor of PNDs. However, the molecular mechanisms of PNDs are poorly understood. Dexmedetomidine (DEX) is a useful sedative agent with analgesic properties, which significantly improves POCD in elderly patients. In this review, the current understanding of anesthesia in PNDs and the protective effects of DEX are summarized, and the underlying mechanisms are further discussed.

Volatile anesthetics are currently believed to cause unconsciousness by acting on one or more molecular targets including neural ion channels, receptors, mitochondria, synaptic proteins, and cytoskeletal proteins. Anesthetic gases including isoflurane bind to cytoskeletal microtubules (MTs) and dampen their quantum optical effects, potentially contributing to causing unconsciousness. This possibility is supported by the finding that taxane chemotherapy consisting of MT-stabilizing drugs reduces the effectiveness of anesthesia during surgery in human cancer patients. In order to experimentally assess the contribution of MTs as functionally relevant targets of volatile anesthetics, we measured latencies to loss of righting reflex (LORR) under 4% isoflurane in male rats injected subcutaneously with vehicle or 0.75 mg/kg of the brain-penetrant MT-stabilizing drug epothilone B (epoB). EpoB-treated rats took an average of 69 s longer to become unconscious as measured by latency to LORR. This was a statistically significant difference corresponding to a standardized mean difference (Cohen\'s d) of 1.9, indicating a \"large\" normalized effect size. The effect could not be accounted for by tolerance from repeated exposure to isoflurane. Our results suggest that binding of the anesthetic gas isoflurane to MTs causes unconsciousness and loss of purposeful behavior in rats (and presumably humans and other animals). This finding is predicted by models that posit consciousness as a property of a quantum physical state of neural MTs.

OBJECTIVE: Postoperative cognitive dysfunction (POCD) is prevalent among the elderly, characterized primarily by cognitive decline after surgery. This study aims to explore how extracellular vesicles (EVs) derived from BV2 microglial cells, with and without the C-C chemokine receptor type 5 (CCR5), affect neuroinflammation, neuronal integrity, and cognitive function in a POCD mouse model.
METHODS: We collected EVs from LPS-stimulated BV2 cells expressing CCR5 (EVsM1) and from BV2 cells with CCR5 knockdown (EVsM1-CCR5). These were administered to POCD-induced mice. Protein interactions between CCR5, G-protein-coupled receptors (GPCRs), and Ras were analyzed using structure-based docking and co-immunoprecipitation (Co-IP). We assessed the phosphorylation of p38 and Erk, the expression of synaptic proteins PSD95 and MAP2, and conducted Morris Water Maze tests to evaluate cognitive function.
RESULTS: Structure-based docking and Co-IP confirmed interactions between CCR5, GPR, and Ras, suggesting a CCR5-GPCRs-Ras-MAPK pathway involvement in neuroinflammation. EVsM1 heightened neuroinflammation, reduced synaptic integrity, and impaired cognitive function in POCD mice. In contrast, EVsM1-CCR5 reduced neuroinflammatory markers, preserved synaptic proteins, enhanced dendritic spine structure, and improved cognitive outcomes.
CONCLUSIONS: EVsM1 induced neuroinflammation via the CCR5-GPCRs-Ras-MAPK pathway, with EVsM1-CCR5 showing protective effects on POCD progression, suggesting a new therapeutic strategy for POCD management via targeted modification of microglial EVs.

BACKGROUND: Myocardial ischemia-reperfusion (MI/R) can lead to structural and functional abnormalities in the hippocampal neurons of the brain. High-mobility group box-l (HMGB1) is implicated in the activation of immune cells and the stimulation of inflammatory responses. However, the specific role of HMGB1 in cognitive impairment induced by MI/R in elderly rats has yet to be elucidated.
METHODS: Elderly rats underwent surgical procedures to induce MI/R. To evaluate the learning and memory abilities of these rats, a water maze test and a new-object recognition test were administered. Nissl staining was utilised to examine hippocampal neuron damage. Enzyme-linked immunosorbent assay, western blotting, and real-time quantitative polymerase chain reaction (RT-qPCR) analyses were conducted to measure the expression levels of HMGB1, inflammatory cytokines, and molecular pathways.
RESULTS: The study found that MI/R induced cognitive impairment in elderly rats. There was an observed increase in serum HMGB1 levels, along with elevated concentrations of pro-inflammatory cytokines in the plasma and hippocampus, accompanied by a decrease in anti-inflammatory cytokines. Moreover, substantial damage was evident in the hippocampal neurons of rats exposed to MI/R. In the brains of these rats, there was an increased expression of HMGB1, the receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), phosphorylated p65, interleukin-1β (IL-1β), IL-6, IL-23, tumour necrosis factor-α (TNF-α), caspase-3, and Bax. In contrast, the expression of B-cell lymphoma 2 was decreased. The RT-qPCR analyses indicated elevated levels of HMGB1, RAGE, TLR4, IL-1β, IL-6, IL-23, TNF-α, caspase-3, and Bax mRNA.
CONCLUSIONS: The increased concentration of serum and hippocampal inflammatory factors in the brains of elderly rats subjected to MI/R suggests that cognitive impairment may be induced through the activation of the HMGB1/TLR4/NF-κB signalling pathway.

OBJECTIVE: To investigate the effects of dexmedetomidine on the cognitive dysfunction of aged rats after open tibia fracture surgery and the expression of inflammatory cytokines in the hippocampus.
METHODS: A total of 45 aged healthy male Sprague Dawley rats were divided into control group, sham group, and dexmedetomidine group. The open tibia fracture surgery rat model was established, and dexmedetomidine was intraperitoneally injected before operation. The cognitive function of aged rats was examined by Morris Water-Maze Test, open field experiment, and passive avoidance memory test. The expression levels of IL-6, IL-1β, and TNF-α in the hippocampus were examined by enzyme-linked immunosorbent assay (ELISA).
RESULTS: The escape latency over 5 continuous days in the dexmedetomidine group was significantly shorter than that in the control group (all P<0.05). The number of swimming times and the percentage of swimming time in the dexmedetomidine group were significantly higher and longer than those in the control group (all P<0.05). Moreover, rats in the dexmedetomidine group exhibited shorter time of stay at the central square and higher number of standing times in comparison with the control group (all P<0.05). Compared with the control group, dexmedetomidine intraperitoneally injected before surgery significantly inhibited the expression levels of IL-6, IL-1β, and TNF-α in the hippocampus (all P<0.05).
CONCLUSIONS: Dexmedetomidine could significantly relieve the postoperative cognitive dysfunction in aged rats. The mechanism may be associated with the decreased inflammatory cytokines in the hippocampus.