Perioperative Neurocognitive Disorders Research Articles

60 Surgical inpatient delirium: a re-audit of the documentation of the 4AT score

Abstract Background Postoperative delirium and perioperative neurocognitive disorder are the commonest postoperative complications in patients over 65. This has implications for brain health, hospital length of stay and incidences of morbidity and mortality. Our aim was to perform a re-audit of the documentation of 4AT scores for surgical inpatients >65 following educational sessions across key ward-based staff (medical, nursing, and allied-health). Methods Using the guidelines for Perioperative Care for People Living with Frailty undergoing Elective and Emergency Surgery from the Centre of Perioperative Care (CPOC) and the British-Geriatric-Society (BGS) as a standard, a re-audit of surgical inpatients >65 was performed on four surgical wards over two weeks. Data was collected on 4AT documentation on admission, day one and day three post-operatively, type-of-surgery, anaesthesia and risk factors for delirium (dementia, polypharmacy, opioid & benzodiazepine use, alcohol excess, ≥2 medical co-morbidities, number of ward moves and surgery >2 hours). Results Of the 55 surgical patients, the average age was 76 (65–93). 32.7% of patients presented for hip fracture surgery (n = 18), 40% abdominal/pelvic surgery (n = 22), 15% other surgeries (n = 15). 35% of patients (n = 19) had baseline 4AT documented preoperatively compared to 25%(n = 9) in the initial audit. 4AT score documentation during admission was 47.3%(n = 26) compared to 33%(n = 11). ≥2 surgical risk factors for delirium were found in all patients. The incidence of delirium was 14.5% with eight patients having a 4AT score > 4. Patients who developed delirium had 3–8 risk factors. Four of eight patients with delirium had pre-existing cognitive impairment and/or dementia. Conclusion There was an increase in frequency of 4AT assessments as a delirium screening tool in our cohort following successful collaboration between medical, surgical, anaesthesia, nursing and allied-health staff. Regular educational sessions to maintain awareness and screening of delirium peri-operatively in surgical patients >65 will be a focus for continued quality improvement.

Perspectives on Ethnic and Language Diversity in Perioperative Neurocognitive Disorders.

Perspectives on Ethnic and Language Diversity in Perioperative Neurocognitive Disorders.

Systemic inflammation, neuroinflammation and perioperative neurocognitive disorders.

Perioperative neurocognitive disorder (PND) is a common disorder following anesthesia and surgery, especially in the elderly. The complex cellular and molecular processes are involved in PND, but the underlying pathogenesis of which remains inconclusive due to conflicting data. A growing body of evidence has been shown that perioperative systemic inflammation plays important roles in the development of PND. We reviewed the relevant literature retrieved by a search in the PubMed database (on July 20, 2023). The search terms used were "delirium", "post operative cognitive dysfunction", "perioperative neurocognitive disorder", "inflammation" and "systemic", alone and in combination. All articles identified were English-language, full-text papers. The ones cited in the review are those that make a substantial contribution to the knowledge about systemic inflammation and PNDs. The aim of this review is to bring together the latest evidence for the understanding of how perioperative systemic inflammation mediates neuroinflammation and brain injury, how the inflammation is regulated and how we can translate these findings into prevention and/or treatment for PND.

Effects of perioperative intravenous glucocorticoids on perioperative neurocognitive disorders in adults after surgery: A PRISMA-compliant meta-analysis of randomized controlled trials.

Randomized controlled trials (RCTs) have shown uncertain clinical benefits from perioperative intravenous glucocorticoids for perioperative neurocognitive disorders (PND). Thus, this meta-analysis was performed to evaluate whether perioperative intravenous glucocorticoids can decrease the occurrence of PND among adults undergoing surgery. We searched 4 databases (MEDLINE, Embase, CENTRAL and Web of Science) for RCTs that assessed the incidence of PND in adults (aged ≥ 18 years old) after surgery. Two reviewers independently assessed the studies for eligibility, extracted data, and assessed the risk of bias in each study. We assessed the certainty of evidence using GRADEpro software. A total of 10 studies (N = 14,967) were eligible. Compared with controls, glucocorticoids were not associated with reducing the risk of postoperative cognitive dysfunction (POCD) (risk ratio [RR]: 0.79 95% confidence interval [CI]: 0.41-1.55, P = .50, I2 = 85%), risk of postoperative delirium (POD) (RR: 0.87 95% CI: 0.74-1.03, P = .10, I2 = 36%), the length of stay in intensive care unit (ICU) (mean difference [MD] -0.21 95% CI: -1.20 to 0.79, P = .68, I2 = 84%), 30-day mortality (RR: 0.92 95% CI: 0.59-1.46, P = .73, I2 = 0%), or postoperative atrial fibrillation (RR: 0.94 95% CI: 0.86-1.01, P = .11, I2 = 25%). However, there was significant difference between glucocorticoids and control group in the length of hospital stay (LOS) (MD: -0.39 95% CI: -0.62 to -0.16, P = .001, I2 = 0%), and postoperative infections (RR: 0.65 95% CI: 0.56-0.76, P < .00001, I2 = 0%). Perioperative intravenous glucocorticoids did not reduce the risk of PND in adults after surgery but might be associated with shorter the LOS and lower the incidence of postoperative infections. More, larger, higher-quality RCTs including neurological surgery or hip fracture surgery and different doses of glucocorticoids compared with placebos are needed to explore the intervention effects.

Siglec-E Ligand Downregulation on Hippocampus Neurons Induced Inflammation in Sevoflurane-Associated Perioperative Neurocognitive Disorders in Aged Mice.

Activated microglia-induced inflammation in the hippocampus plays an important role in perioperative neurocognitive disorders. Previous studies have shown that sialic acid-binding immunoglobulin-like lectin 3 (hSiglec-3, ortholog of mouse Siglec-E) engagement in microglia and its glycan ligands on neurons contributes to inflammatory homeostasis through an endogenous negative regulation pathway. This study aimed to explore whether the glycan ligand alteration on neurons plays a role in sevoflurane-induced perioperative neurocognitive disorders. This study's data has shown that a slight Siglec-E ligands' expression decrease does not induce inflammation homeostasis disruption. We also demonstrated that the ligand level on neurons was decreased with age, and the reduced Siglec-E ligand expression on neurons caused via sevoflurane was induced by neuraminidase 1. Furthermore, this study has shown that the Siglec-E ligand expression decline caused by age and sevoflurane treatment could decrease the ligands' level, thus leading to inflammatory homeostasis disruption. This research provided a novel mechanism for perioperative neurocognitive disorder susceptibility in the elderly.

LXA4 attenuates perioperative neurocognitive disorders by suppressing neuroinflammation and oxidative stress

Perioperative neurocognitive disorder (PND) is a common complication that increases morbidity and mortality in elderly patients undergoing surgery. Abnormal microglia activation causes neuroinflammation and contributes to the development of PND. Growing evidence shows that lipoxin A4 (LXA4), a lipid mediator, possesses potent anti-inflammatory activities. In this study, we investigated whether LXA4 exerted a protective effect against surgery-induced neurocognitive deficits and explored the underlying mechanisms. Mice were subjected to laparotomy under sevoflurane anesthesia to establish an animal model of PND. LXA4 (15 μg/kg/d, ip) was administered three days prior surgery. We showed that LXA4 significantly alleviated surgery-induced cognitive impairments, attenuated neuroinflammation and microglial activation in hippocampus. In BV2 microglial cells treated with LPS (100 ng/mL), pre-application of LXA4 (100 nΜ) significantly inhibited M1 polarization and promoted M2 polarization, and decreased the levels of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and increased the levels of anti-inflammatory cytokine (IL-10). LXA4 also mitigated LPS-regulated expression of HO-1, NOX2, and SOD1, elevated SOD activity, and attenuated ROS production. Furthermore, we revealed that LXA4 increased the expression of SIRT1 and decreased the protein level of acetylated NF-κB p65. SIRT1 inhibitor EX-527 abolished the anti-inflammatory and antioxidant response effects of LXA4 in BV2 microglial cells. Hence, LXA4 is a potential therapeutic agent for surgery-induced neuroinflammation, oxidative stress, and cognitive deficit, and the effect of LXA4 is probably mediated by the activation of the SIRT1/NF-κB signaling pathway in microglia.

The locus coeruleus-dorsal hippocampal CA1 pathway is involved in depression-induced perioperative neurocognitive disorders in adult mice.

Patients undergoing surgical anesthesia increasingly suffer from preoperative depression. Clinical studies have shown that depression is a risk factor for perioperative neurocognitive disorders (PNDs) in elder patients. However, the underlying mechanism, especially at the neural circuit level, remains poorly understood. Right carotid artery separation under sevoflurane and chronic social defeat stress (CSDS) in adult mice were used to establish surgical anesthesia and chronic depression models. Cognitive function was assessed by the Y maze and novel object recognition tests. A chemogenetic approach was used to modulate the locus coeruleus-dorsal hippocampal CA1 (LC-dCA1) circuit. Hippocampal synaptic alterations were evaluated by Golgi staining and whole-cell patch clamp recording. We found that CSDS induced synaptic impairments in dorsal hippocampal CA1 pyramidal neurons and cognitive deficits in adult mice after surgery under sevoflurane. Chemogenetic activation of the LC-dCA1 pathway significantly alleviated the CSDS-induced synaptic impairments and cognitive dysfunction. On the contrary, inhibition of this pathway could mimic CSDS-induced deficits. Furthermore, we showed that dopamine played an important role in CSDS-induced PNDs in adult mice after surgery/sevoflurane. Overall, our results have demonstrated a vital role for the LC-dCA1 pathway in CSDS-induced PNDs in adult mice undergoing surgery with sevoflurane anesthesia.

DHT inhibits REDOX damage and neuroinflammation to reduce PND occurrence in aged mice via mmu_circ_0001442/miR-125a-3p/NUFIP2 axis.

Perioperative neurocognitive disorder (PND) is the main cause of poor postoperative recovery in elderly patients with age-related reductions in androgen levels. However, the underlying mechanisms have not been completely elucidated. A mouse model of PND was constructed using abdominal surgery. Dihydrotestosterone (DHT), as the primary androgen, can improve the cognitive function of mice with PNDs by reducing REDOX damage. To clarify the role of circular RNA (circRNA) in DHT in improving cognitive function in mice with PND, circRNA sequencing was performed to analyze the expression of circRNA in the hippocampus of mice. We confirmed that mmu_circ_0001442 is the primary circRNA responsive to DHT stimulation in mice with PND. The mmu_circ_0001442/miR-125a-3p/NUFIP2 axis was predicted and constructed according to the analysis of databases, including pita, miRanda, TargetScan, miRDB, micro-CDS, PolymiRTS, and TarBase v.8. Subsequently, the axis was verified by qPCR and double-luciferase reporter gene assays. In vitro, we found that DHT rarely had an effect on the growth of BV2 cells using the CCK-8 assay, but it attenuated the cytotoxic effect of lipopolysaccharide (LPS) on BV2 cells. In addition, we found that LPS stimulation promoted the release of proinflammatory cytokines, including IL-6 and TNF-α, in BV2 cells, whereas mmu_circ_0001442 knockdown and NUFIP2 knockdown partially abrogated this effect. Taken together, DHT inhibited REDOX damage and neuroinflammation in the hippocampus to alleviate cognitive disorders in mice with PNDs via activation of the mmu_circ_0001442/miR-125a-3p/NUFIP2 axis. This study provides a novel rationale for developing DHT as a potential therapeutic agent for PND prevention.

Perioperative neurocognitive disorders.

Perioperative neurocognitive disorders are a group of conditions characterised by changes in cognitive function, which affect older people after surgery and anaesthesia. Multicomponent interventions may reduce the impact of perioperative neurocognitive disorders on patients and healthcare systems.

Effect of Electroacupuncture Prestimulation with Mental Tri-Needles on the Inflammatory Response of Hippocampus in Aged Rats with Perioperative Neurocognitive Disorders

Effect of Electroacupuncture Prestimulation with Mental Tri-Needles on the Inflammatory Response of Hippocampus in Aged Rats with Perioperative Neurocognitive Disorders

Tbx2 knockdown alleviated sevoflurane-induced cognitive disorder and neuron damages in aged rats via suppressing oxidative stress and ferroptosis.

Anesthesia with sevoflurane contributes to perioperative neurocognitive disorder (PND), which is characterized by the deficiency in study and memory. T-Box transcription factor 2 (Tbx2), which is involved in the development of hippocampus neurons, was upregulated in the hippocampus of rats exposed to sevoflurane. Our study aimed to explore the role of Tbx2 in sevoflurane-induced cognitive disorder and hippocampus neuron damages. The expression of Tbx2 in hippocampus was upregulated after sevoflurane exposure, which was accompanied by the accumulation of reactive oxygen species and lipid peroxidation, as well as the loss of neurons in hippocampus. In vitro, silencing Tbx2 suppressed oxidative stress and ferroptosis induced by sevoflurane, whereas exogenous overexpression of Tbx2 exacerbated these processes. Importantly, Tbx2 knockdown improved sevoflurane-induced cognitive disorder in aged rats, as evidenced by the increases in behavioral indexes. Mechanistically, the expression of brain-derived neurotrophic factor (BDNF), as well as the downstream nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling, was repressed by Tbx2. Mimicking the activation of BDNF with 7,8-dihydroxyflavone rescued the effects of Tbx2 overexpression on oxidative stress and ferroptosis in vitro, indicating that the BDNF/Nrf2/HO-1 signaling may mediate the role of Tbx2 in sevoflurane-induced cognitive disorder and neuron damages. In summary, Tbx2 may contribute to neuronal damages via enhancing the oxidative stress and ferroptosis caused by sevoflurane. BDNF/Nrf2/HO-1 signaling mediates the role of Tbx2 in sevoflurane-induced cognitive disorder. Knockdown of Tbx2 improves sevoflurane-induced cognitive impairment. Our finding provides a novel insight for PND treatment.

Transforming Growth Factor β1 Ameliorates Microglial Activation in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorder (PND) is a common complication of surgery and anesthesia, especially among older patients. Microglial activation plays a crucial role in the occurrence and development of PND and transforming growth factor beta 1 (TGF-β1) can regulate microglial homeostasis. In the present study, abdominal surgery was performed on 12-14 months-old C57BL/6 mice to establish a PND model. The expression of TGF-β1, TGF-β receptor 1, TGF-β receptor 2, and phosphor-smad2/smad3 (psmad2/smad3) was assessed after anesthesia and surgery. Additionally, we examined changes in microglial activation, morphology, and polarization, as well as neuroinflammation and dendritic spine density in the hippocampus. Behavioral tests, including the Morris water maze and open field tests, were used to examine cognitive function, exploratory locomotion, and emotions. We observed decreased TGF-β1 expression after surgery and anesthesia. Intranasally administered exogenous TGF-β1 increased psmad2/smad3 colocalization with microglia positive for ionized calcium-binding adaptor molecule 1. TGF-β1 treatment attenuated microglial activation, reduced microglial phagocytosis, and reduced surgery- and anesthesia-induced changes in microglial morphology. Compared with the surgery group, TGF-β1 treatment decreased M1 microglial polarization and increased M2 microglial polarization. Additionally, surgery- and anesthesia-induced increase in interleukin 1 beta and tumor necrosis factor-alpha levels was ameliorated by TGF-β1 treatment at postoperative day 3. TGF-β1 also ameliorated cognitive function after surgery and anesthesia as well as rescue dendritic spine loss. In conclusion, surgery and anesthesia induced decrease in TGF-β1 levels in older mice, which may contribute to PND development; however, TGF-β1 ameliorated microglial activation and cognitive dysfunction in PND mice.

Role of non-invasive imaging in perioperative neurocognitive disorders

Perioperative Neurocognitive disorders, including delirium and long-term cognitive dysfunction following surgery, are an ever-increasing focus of investigation for anesthesiologists and researchers. The desire to bring patients safely through the perioperative period with an absolute minimum impact of the anesthetic, surgery, and post-operative period on the patient's functional status has brought a high level of scrutiny to entities that most impact patients. Perioperative neurocognitive disorders (PND) have the potential to vastly alter patient functional status after surgery and anesthesiologists are often the first physician asked about the effects this may have on the patient during the informed consent process. While the underlying mechanisms of PND are not well understood, more tools are being brought to bear with non-invasive imaging shedding light on the pathophysiology of PND. In this narrative mini-review, we discuss the current investigation into PND with a focus on non-invasive imaging and preventative strategies that are being employed to better protect patients.

Peripheral Nerve Block and Peri-operative Neurocognitive Disorders in Older Patients With Hip Fractures: A Systematic Review With Meta-analysis.

Poor pain control and opioid use are risk factors for perioperative neurocognitive disorders (PND). The peripheral nerve block (PNB) can reduce pain and opioid consumption. This systematic review aimed to investigate the effects of PNB on PND in older patients with hip fractures. The PubMed, Cochrane Central Registers of Controlled Trial, Embase and ClinicalTrials.gov databases were searched from inception until November 19, 2021 for all randomized controlled trials (RCTs) comparing PNB with analgesics. The quality of the selected studies was assessed according to Version 2 of the Cochrane tool for assessing the risk of bias in RCTs. The primary outcome was the incidence of PND. Secondary outcomes included pain intensity and the incidence of postoperative nausea and vomiting. Subgroup analyses were based on population characteristics, type and infusion method of local anesthetics, and type of PNB. Eight RCTs comprising 1015 older patients with hip fractures were included. Compared with analgesics, PNB did not reduce the incidence of PND in the elderly hip fracture population comprising patients with intact cognition and those with pre-existing dementia or cognitive impairment (risk ratio [RR] = .67; 95% confidence interval [CI] = .42 to 1.08; P = .10; I2 = 64%). However, PNB reduced the incidence of PND in older patients with intact cognition (RR = .61; 95% CI = .41 to .91; P = .02; I2 = 0%). Fascia iliaca compartment block, bupivacaine, and continuous infusion of local anesthetics were found to reduce the incidence of PND. PNB effectively reduced PND in older patients with hip fractures and intact cognition. When the study population included patients with intact cognition and those with pre-existing dementia or cognitive impairment, PNB showed no reduction in the incidence of PND. These conclusions should be confirmed with larger, higher-quality RCTs.

Alcohol consumption may be associated with postoperative delirium in the elderly: the PNDABLE study

ObjectivesThis study aimed to reveal the relationship between alcohol consumption and Postoperative delirium (POD) in the elderly.MethodsWe selected 252 patients from the Perioperative Neurocognitive Disorder And Biomarker Lifestyle (PNDABLE ) study. Patients in the PNDABLE database have been measured for Alzheimer-related biomarkers in CSF (Aβ40, Aβ42, P-tau, and tau protein). Mini-Mental State Examination (MMSE) was used to assess the preoperative mental status of patients. POD was diagnosed using the Confusion Assessment Method (CAM) and assessed for severity using the Memorial Delirium Assessment Scale (MDAS). Logistic regression analysis was utilized to explore the association of alcohol consumption with POD. Linear regression analysis was used to study the relationship between alcohol consumption and CSF biomarkers. Mediation analyses with 10,000 bootstrapped iterations were used to explore the mediation effects. Finally, we constructed the receiver operating characteristic (ROC) curve and the nomogram model to evaluate the efficacy of alcohol consumption and CSF biomarkers in predicting POD. ResultThe incidence of POD was 17.5%. Logistic regression showed that alcohol consumption (OR = 1.016, 95%CI 1.009–1.024, P < 0.001) is a risk factor for POD. What’s more, Aβ42 is a protective factor for POD (OR = 0.993, 95%CI 0.989–0.997, P < 0.05), and P-Tau was a risk factor for POD (OR = 1.093, 95%CI 1.022–1.168, P < 0.05). Linear regression analysis revealed that alcohol consumption was negatively associated with CSF Aβ42 (β = -0.638, P < 0.001) in POD patients. Mediation analyses showed that alcohol consumption is likely to partially mediate POD through Aβ42 (proportion:14.21%). ROC curve showed that alcohol consumption (AUC = 0.904; P < 0.001) exhibited a relatively better discriminatory ability in POD prediction compared to Aβ42 (AUC = 0.798; P < 0.001). The calibration curve indicated a good nomogram prediction (P = 0.797).ConclusionAlcohol consumption is a risk factor for POD (particularly for those with > 24 g a day on average) in the elderly, and contributes to POD through the mediation of Aβ42.

Role of gut microbiota in perioperative neurocognitive disorders after cardiopulmonary bypass surgery in rats with humanized gut flora

To investigate whether gut microbiota disturbance after cardiopulmonary bypass (CPB) contributes to the development of perioperative neurocognitive disorders (PND). Fecal samples were collected from healthy individuals and patients with PND after CPB to prepare suspensions of fecal bacteria, which were transplanted into the colorectum of two groups of pseudo-germ-free adult male SD rats (group NP and group P, respectively), with the rats without transplantation as the control group (n=10). The feces of the rats were collected for macrogenomic sequencing analysis, and serum levels of IL-1β, IL-6 and TNF-α were measured with ELISA. The expression levels of GFAP and p-Tau protein in the hippocampus of the rats were detected using Western blotting, and the cognitive function changes of the rats were assessed with Morris water maze test. In all the 3 groups, macrogenomic sequencing analysis showed clustering and clear partitions of the gut microbiota after the transplantation. The relative abundances of Klebsiella in the control group (P < 0.005), Akkermansia in group P (P < 0.005) and Bacteroides in group NP (P < 0.005) were significantly increased after the transplantation. Compared with those in the control group, the rats in group NP and group P showed significantly decreased serum levels of IL-1β, IL-6 and TNF-α and lowered expression levels of GFAP and p-Tau proteins (all P < 0.05). Escape platform crossings and swimming duration in the interest quadrant increased significantly in group NP (P < 0.05), but the increase was not statistically significant in group N. Compared with those in group P, the rats in group NP had significantly lower serum levels of IL-1β, IL-6 and TNF-α and protein expressions of GFAP and p-Tau (all P < 0.05) with better performance in water maze test (P < 0.05). In patients receiving CPB, disturbances in gut mirobiota contributes to the development of PND possibly in relation with inflammatory response.

Metabolic syndrome and the risk of postoperative delirium and postoperative cognitive dysfunction: a multi-centre cohort study

BackgroundMetabolic syndrome and its components are risk factors for cognitive impairment, but their contribution to perioperative neurocognitive disorders is unknown. We examined their associations with the risk of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) in older patients. MethodsIn 765 male and female participants aged ≥65 years, we measured preoperative metabolic parameters and screened for POD for 7 days or until discharge. POCD was defined through comparison of cognitive change on six neuropsychological tests with non-surgical controls. Multiple logistic regression analyses examined the association of metabolic parameters with risk of POD and POCD with adjustment for age, sex, and surgery type. ResultsA total of 149 patients (19.5% of 765) developed POD and 53 (10.1% of 520 attendees) had POCD at 3 months. Patients with metabolic syndrome were at 1.85-fold higher risk of POD (95% confidence interval [CI] 1.26–2.70). Each 1 mM higher high-density lipoprotein cholesterol (HDL-C) was associated with a 0.47-fold lower POD risk (95% CI 0.30–0.74). Each 1 kg m−2 higher body mass index (BMI) was associated with a 1.09-fold higher POCD risk (95% CI 1.02– 1.16). ConclusionsOlder surgical patients with metabolic syndrome were at increased risk of POD. Only reduced HDL-C was significantly associated with POD. For POCD, a higher preoperative BMI was identified as a risk factor. These findings add to mounting evidence of a distinct epidemiology of POD and POCD. Screening programmes taking advantage of HDL-C and BMI measurements and of metabolic interventions in reducing perioperative neurocognitive disorders should be evaluated. Clinical trial registrationNCT02265263.

Research Advances of Mitochondrial Dysfunction in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorders (PND) increases postoperative dementia and mortality in patients and has no effective treatment. Although the detailed pathogenesis of PND is still elusive, a large amount of evidence suggests that damaged mitochondria may play an important role in the pathogenesis of PND. A healthy mitochondrial pool not only provides energy for neuronal metabolism but also maintains neuronal activity through other mitochondrial functions. Therefore, exploring the abnormal mitochondrial function in PND is beneficial for finding promising therapeutic targets for this disease. This article summarizes the research advances of mitochondrial energy metabolism disorder, inflammatory response and oxidative stress, mitochondrial quality control, mitochondria-associated endoplasmic reticulum membranes, and cell death in the pathogenesis of PND, and briefly describes the application of mitochondria-targeted therapies in PND.

Novel Mechanisms of Perioperative Neurocognitive Disorders: Ferroptosis and Pyroptosis.

Perioperative neurocognitive disorders (PNDs) are some of the most common postoperative complications among the elderly and susceptible individuals, which significantly worsens the clinical outcome of patients. However, the prevention and treatment strategies of PNDs are difficult to determine and implement since the pathogenesis of PNDs is not well understood. The development of living organisms is associated with active and organized cell death, which is essential for maintaining the homeostasisof life. Ferroptosis is a programmed cell death (different from apoptosis and necrosis) mainly caused by an imbalance in the generation and degradation of intracellular lipid peroxides due to iron overload. Pyroptosis is an inflammatory cell death characterized by the creation of membrane holes mediated by the gasdermin (GSDM) family, followed by cell lysis and the release of pro-inflammatory cytokines. Ferroptosis and pyroptosis are involved in the pathogenesis of various central nervous system (CNS) diseases. Furthermore, ferroptosis and pyroptosis are closely associated with the occurrence and development of PNDs. This review summarizes the main regulatory mechanisms of ferroptosis and pyroptosis and the latest related to PNDs. Based on the available evidence, potential intervention strategies that can alleviate PNDs by inhibiting ferroptosis and pyroptosis have also been provided.

Reduced excitatory neurotransmission in the hippocampus after inflammation and sevoflurane anaesthesia

BackgroundInflammation and general anaesthesia likely contribute to perioperative neurocognitive disorders, possibly by causing a neuronal imbalance of excitation and inhibition. We showed previously that treatment with lipopolysaccharide (LPS) and sevoflurane causes a sustained increase in a tonic inhibitory conductance in the hippocampus; however, whether excitatory neurotransmission is also altered remains unknown. The goal of this study was to examine excitatory synaptic currents in the hippocampus after treatment with LPS and sevoflurane. Synaptic plasticity in the hippocampus, a cellular correlate of learning and memory, was also studied. MethodsMice were injected with vehicle or LPS (1 mg kg−1 i.p.), and after 24 h they were then exposed to vehicle or sevoflurane (2.3%; 2 h). Hippocampal slices were prepared 48 h later. Excitatory synaptic currents were recorded from pyramidal neurones. Long-term potentiation (LTP) and long-term depression (LTD) were studied in the Schaffer collateral–cornu ammonis 1 pathway. ResultsThe amplitude of miniature excitatory postsynaptic currents (EPSCs) was reduced after LPS+sevoflurane (P<0.001), whereas that of spontaneous EPSCs was unaltered, as evidenced by cumulative distribution plots. The frequency, area, and kinetics of both miniature and spontaneous EPSCs were unchanged, as were LTP and LTD. ConclusionsThe reduced amplitude of miniature EPSCs, coupled with the previously reported increase in tonic inhibition, indicates that the combination of LPS and sevoflurane markedly disrupts the balance of excitation and inhibition. Restoring this balance by pharmacologically enhancing excitatory neurotransmission and inhibiting the tonic current may represent an effective therapeutic option for perioperative neurocognitive disorders.