Age-Related Perioperative Neurocognitive Disorders: Experimental Models and Druggable Targets.

With the worldwide increase in life span, surgical patients are becoming older and have a greater propensity for postoperative cognitive impairment, either new onset or through deterioration of an existing condition; in both conditions, knowledge of the patient's preoperative cognitive function and postoperative cognitive trajectory is imperative. We describe the clinical utility of a tablet-based technique for rapid assessment of the memory and attentiveness domains required for executive function. The pathogenic mechanisms for perioperative neurocognitive disorders have been investigated in animal models in which excessive and/or prolonged postoperative neuroinflammation has emerged as a likely contender. The cellular and molecular species involved in postoperative neuroinflammation are the putative targets for future therapeutic interventions that are efficacious and do not interfere with the surgical patient's healing process.

CircAKT3 alleviates postoperative cognitive dysfunction by stabilizing the feedback cycle of miR-106a-5p/HDAC4/MEF2C axis in hippocampi of aged mice.

Circular RNAs (circRNAs) have garnered significant attention in the field of neurodegenerative diseases including Alzheimer's diseases due to their covalently closed loop structure. However, the involvement of circRNAs in postoperative cognitive dysfunction (POCD) is still largely unexplored. To identify the genes differentially expressed between non-POCD (NPOCD) and POCD mice, we conducted the whole transcriptome sequencing initially in this study. According to the expression profiles, we observed that circAKT3 was associated with hippocampal neuronal apoptosis in POCD mice. Moreover, we found that circAKT3 overexpression reduced apoptosis of hippocampal neurons and alleviated POCD. Subsequently, through bioinformatics analysis, our data showed that circAKT3 overexpression in vitro and in vivo elevated the abundance of miR-106a-5p significantly, resulting in a decrease of HDAC4 protein and an increase of MEF2C protein. Additionally, this effect of circAKT3 was blocked by miR-106a-5p inhibitor. Interestingly, MEF2C could activate the transcription of miR-106a-5p promoter and form a positive feedback loop. Therefore, our findings revealed more potential modulation ways between circRNA-miRNA and miRNA-mRNA, providing different directions and targets for preclinical studies of POCD.

The P38MAPK/ATF2 signaling pathway is involved in PND in mice.

Accumulating evidence indicates that microglia-mediated neuroinflammation in the hippocampus contributes to the development of perioperative neurocognitive disorder (PND). P38MAPK, a point of convergence for different signaling processes involved in inflammation, can be activated by various stresses. This study aims to investigate the role of the P38MAPK/ATF2 signaling pathway in the development of PND in mice. Aged C57BL/6 mice were subjected to tibial fracture surgery under isoflurane anesthesia to establish a PND animal model. The open field test was used to evaluate the locomotor activity of the mice. Neurocognitive function was assessed with the Morris water maze (MWM) and fear conditioning test (FCT) on postoperative days 1, 3 and 7. The mice exhibited cognitive impairment accompanied by increased expression of proinflammatory factors (IL-1ß, TNF-α), proapoptotic molecules (caspase-3, bax) and microglial activation in the hippocampus 1, 3 and 7 days after surgery. Treatment with SB239063 (a P38MAPK inhibitor) decreased the expression of proinflammatory factors, proapoptotic molecules and Iba-1 in the CA1 region of the hippocampus. The number of surviving neurons was significantly increased. Inhibition of the P38MAPK/ATF2 signaling pathway attenuates hippocampal neuroinflammation and neuronal apoptosis in aged mice with PND, thus improving the perioperative cognitive function of the mice.

The influence of dexmedetomidine added to ropivacaine for transversus abdominis plane block on perioperative neurocognitive disorders after radical colorectal cancer surgery: randomized, double-blind, controlled trial.

OBJECTIVE: Perioperative Neurocognitive Disorders (PND) is a common neurological complication after radical colorectal cancer surgery, which increases adverse outcomes. So, our objective is to explore the influence of dexmedetomidine added to ropivacaine for transversus abdominis plane block (TAPB) on perioperative neurocognitive disorders, and to provide a new way to reduce the incidence of PND. METHODS: One hundred and eighty patients submitted to radical laparoscopic colorectal cancer surgery were randomly divided into Control group and Dex group. Ultrasound guided TAPB was performed after anesthesia induction: 0.5% ropivacaine 20 ml was injected into each transversus abdominis plane in Control group, 0.5% ropivacaine + 1 µg/kg dexmedetomidine (amounting to 20 ml) in Dex group. We observed the incidence of PND within 30 days after surgery. RESULTS: One hundred and sixty-nine cases were finally analyzed, including 84 cases in Control group and 85 cases in Dex group. Compared with Control group, there was no significant difference in terms of the incidence of PND on the 3rd day and the 7th day (P > 0.05), but the incidence significantly decreased at the 6th hour, at the 24th hour and on the 30th day after surgery (P < 0.05) in Dex group. CONCLUSION: Dexmedetomidine added to ropivacaine for TAPB can reduce the incidence of PND in the first 24 h after surgery and on the 30th postoperative day, which may be related to reduce the consumption of general anesthetics and provide satisfactory postoperative analgesia. TRIAL REGISTRATION: 29 /05/ 2021, ChiCTR2100046876.

Association of preoperative frailty with the risk of postoperative delirium in older patients undergoing hip fracture surgery: a prospective cohort study.

OBJECTIVE: This study aimed to explore the correlation between preoperative frailty and the risk of postoperative delirium (POD) in older patients undergoing hip fracture surgery. METHODS: In total, 148 patients with hip fractures who were admitted to Tsinghua Changgung Hospital (Beijing, China) between January 2022 and January 2023 were involved in this study. Preoperative frailty scales were assessed, of which the CAM scale was postoperatively administered every morning and evening on days 1, 2, 3, 5, and 7. Binary logistic regression analysis was conducted to determine the correlation between preoperative frailty and the risk of POD. RESULTS: Among 148 older patients with hip fractures, 71 (48.0%) were identified as preoperative frail and 77 (52.0%) as non-frail. The overall incidence of POD on day 7 was 24.3% (36/148), and preoperative frailty was associated with a significantly higher risk of POD compared with non-frailty (42.3% vs. 7.8%, P < 0.001). The binary logistic regression analysis revealed that preoperative frailty was noted as an independent risk factor for the risk of POD in older patients undergoing hip fracture surgery (P = 0.002). CONCLUSION: Preoperative frailty increased the risk of POD in older patients undergoing hip fracture surgery. DISCUSSION: Preoperative assessment of frailty in geriatric hip surgery can timely identify potential risks and provide interventions targeting frailty factors to reduce the incidence of POD in older patients undergoing hip fracture surgery. The findings suggested that preoperative frailty could increase the risk of POD in older patients undergoing hip fracture surgery. Further research is necessary to determine whether perioperative interventions aimed at enhancing frailty can mitigate the risk of POD and improve prognosis in older patients undergoing hip fracture surgery.

Research Progress of Hippocampal Dopamine System Changes in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorders (PND) are a cognitive impairment that occurs after anesthesia, especially in elderly patients and significantly affects their quality of life. The hippocampus, as a critical region for cognitive function and an important location in PND research, has recently attracted increasing attention. However, in the hippocampus the impact of anesthesia and its underlying mechanisms remain unclear. This review focuses on investigation of the effects of anesthesia on the hippocampal dopamine (DA) system and explores its potential association with PND. Through comprehensive review of existing studies, it was found that anesthesia affects the hippocampus through various pathways involved in metabolism, synaptic plasticity and oxygenation. Anesthesia may also influence the DA neurotransmitter system in the brain which plays a role in emotions, rewards, learning and memory functions. Specifically, anesthesia may participate in the pathogenesis of PND by affecting the DA system within the hippocampus. Future studies should explore the molecular mechanisms of these effects through techniques such as neuroimaging to study real-time effects to improve animal models to better simulate clinical observations. For clinical application, it is recommended that physicians exercise caution when selecting and managing anesthetic drugs by adopting comprehensive cognitive assessment methods to reduce post-anesthesia cognitive risk. Overall, this review provides a better understanding of the relationship between the hippocampal DA system and perioperative neurocognitive function and provides valuable guidance for prevention and treatment strategies for PND.

Depletion of PIEZO1 expression is accompanied by upregulating p53 signaling in mice with perioperative neurocognitive disorder.

As the common complications observed in surgical elder patients, perioperative neurocognitive disorders (PND) cause a series of serious perioperative health problems. However, there are no effective treatments, and the exact mechanisms are still largely unknown. In this study, transcriptome sequencing was performed to investigate the differentially expressed genes (DEGs) in the hippocampus of C57BL/6J aged mice with or without PND. Compared with the Mock group, the expression of 352, 395, and 772 genes changed significantly in the PND group at days 1, 7, and 21 after surgery, respectively. Gene ontology (GO) and gene set enrichment analysis (GSEA) showed that DEGs were mainly associated with p53 signaling. Moreover, GSEA revealed potentially p53-related DEGs such as leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1), monooxygenase DBH-like 1 (MOXD1), and piezo type mechanosensitive ion channel component 1 (PIEZO1). Furthermore, we confirmed the decreased interaction of PIEZO1 with p53 in PND, and upregulation of PIEZO1 resulted in a decrease in p53 protein levels through increased ubiquitination of p53. In conclusion, this study contributes to the knowledge of global changes in gene expression and mechanisms during PND.

Prolonged anesthesia induces neuroinflammation and complement-mediated microglial synaptic elimination involved in neurocognitive dysfunction and anxiety-like behaviors.

BACKGROUND: Perioperative neurocognitive disorders (PND) with a high incidence frequently occur in elderly surgical patients closely associated with prolonged anesthesia-induced neurotoxicity. The neuromorphopathological underpinnings of anesthesia-induced neurotoxicity have remained elusive. METHODS: Prolonged anesthesia with sevoflurane was used to establish the sevoflurane-induced neurotoxicity (SIN) animal model. Morris water maze, elevated plus maze, and open field test were employed to track SIN rats' cognitive behavior and anxiety-like behaviors. We investigated the neuropathological basis of SIN through techniques such as transcriptomic, electrophysiology, molecular biology, scanning electron microscope, Golgi staining, TUNEL assay, and morphological analysis. Our work further clarifies the pathological mechanism of SIN by depleting microglia, inhibiting neuroinflammation, and C1q neutralization. RESULTS: This study shows that prolonged anesthesia triggers activation of the NF-κB inflammatory pathway, neuroinflammation, inhibition of neuronal excitability, cognitive dysfunction, and anxiety-like behaviors. RNA sequencing found that genes of different types of synapses were downregulated after prolonged anesthesia. Microglial migration, activation, and phagocytosis were enhanced. Microglial morphological alterations were also observed. C1qa, the initiator of the complement cascade, and C3 were increased, and C1qa tagging synapses were also elevated. Then, we found that the "Eat Me" complement pathway mediated microglial synaptic engulfment in the hippocampus after prolonged anesthesia. Afterward, synapses were remarkably lost in the hippocampus. Furthermore, dendritic spines were reduced, and their genes were also downregulated. Depleting microglia ameliorated the activation of neuroinflammation and complement and rescued synaptic loss, cognitive dysfunction, and anxiety-like behaviors. When neuroinflammatory inhibition or C1q neutralization occurred, complement was also decreased, and synaptic elimination was interrupted. CONCLUSIONS: These findings illustrated that prolonged anesthesia triggered neuroinflammation and complement-mediated microglial synaptic engulfment that pathologically caused synaptic elimination in SIN. We have demonstrated the neuromorphopathological underpinnings of SIN, which have direct therapeutic relevance for PND patients.

NLRP3-GABA signaling pathway contributes to the pathogenesis of impulsive-like behaviors and cognitive deficits in aged mice.

BACKGROUND: Perioperative neurocognitive disorders (PND), such as delirium and cognitive impairment, are commonly encountered complications in aged patients. The inhibitory neurotransmitter γ-aminobutyric acid (GABA) is aberrantly synthesized from reactive astrocytes following inflammatory stimulation and is implicated in the pathophysiology of neurodegenerative diseases. Additionally, the activation of NOD-like receptor protein 3 (NLRP3) inflammasome is involved in PND. Herein, we aimed to investigate whether the NLRP3-GABA signaling pathway contributes to the pathogenesis of aging mice's PND. METHODS: 24-month-old C57BL/6 and astrocyte-specific NLRP3 knockout male mice were used to establish a PND model via tibial fracture surgery. The monoamine oxidase-B (MAOB) inhibitor selegiline (1 mg/kg) was intraperitoneally administered once a day for 7 days after the surgery. PND, including impulsive-like behaviors and cognitive impairment, was evaluated by open field test, elevated plus maze, and fear conditioning. Thereafter, pathological changes of neurodegeneration were explored by western blot and immunofluorescence assays. RESULTS: Selegiline administration significantly ameliorated TF-induced impulsive-like behaviors and reduced excessive GABA production in reactive hippocampal astrocytes. Moreover, astrocyte-specific NLRP3 knockout mice reversed TF-induced impulsive-like and cognitive impairment behaviors, decreased GABA levels in reactive astrocytes, ameliorated NLRP3-associated inflammatory responses during the early stage, and restored neuronal degeneration in the hippocampus. CONCLUSIONS: Our findings suggest that anesthesia and surgical procedures trigger neuroinflammation and cognitive deficits, which may be due to NLRP3-GABA activation in the hippocampus of aged mice.

The Thalamus in Perioperative Neurocognitive Disorders.

Thalamus function and structure are known predictors of individual differences in the risk of age-related neurocognitive disorders (NCD), such as dementia. However, to date, little is known about their role in the perioperative setting. Here, we provide a narrative review of brain-imaging studies of preoperative and postoperative thalamus scanning parameters associated with risks of developing perioperative NCD, such as postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) during the postoperative phase. These findings are discussed in light of the concept of reserve capacity.

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 homeostasis of 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.

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.

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.

Perioperative changes in neurocognitive and Alzheimer's disease-related cerebrospinal fluid biomarkers in older patients randomised to isoflurane or propofol for anaesthetic maintenance.

BACKGROUND: Animal studies have shown that isoflurane and propofol have differential effects on Alzheimer's disease (AD) pathology and memory, although it is unclear whether this occurs in humans. METHODS: This was a nested randomised controlled trial within a prospective cohort study; patients age ≥60 yr undergoing noncardiac/non-neurological surgery were randomised to isoflurane or propofol for anaesthetic maintenance. Cerebrospinal fluid (CSF) was collected via lumbar puncture before, 24 h, and 6 weeks after surgery. Cognitive testing was performed before and 6 weeks after surgery. Nonparametric methods and linear regression were used to evaluate CSF biomarkers and cognitive function, respectively. RESULTS: There were 107 subjects (54 randomised to isoflurane and 53 to propofol) who completed the 6-week follow-up and were included in the analysis. There was no significant effect of anaesthetic treatment group, time, or group-by-time interaction for CSF amyloid-beta (Aß), tau, or phospho-tau181p levels, or on the tau/Aß or p-tau181p/Aß ratios (all P>0.05 after Bonferroni correction). In multivariable-adjusted intention-to-treat analyses, there were no significant differences between the isoflurane and propofol groups in 6-week postoperative change in overall cognition (mean difference [95% confidence interval]: 0.01 [-0.12 to 0.13]; P=0.89) or individual cognitive domains (P>0.05 for each). Results remained consistent across as-treated and per-protocol analyses. CONCLUSIONS: Intraoperative anaesthetic maintenance with isoflurane vs propofol had no significant effect on postoperative cognition or CSF Alzheimer's disease-related biomarkers within 6 weeks after noncardiac, non-neurological surgery in older adults. CLINICAL TRIAL REGISTRATION: NCT01993836.

Advancing our understanding of postoperative cognitive trajectories in older adults.

The use of large amounts of uniform electronic data over long periods provides a step toward understanding and ultimately shaping the perioperative cognitive trajectory of older patients. With the improvements in the quality, uniformity, and amount of data contained within the electronic health record, along with developments in machine learning and big data analysis, we can look forward to enhanced studies that will help advance clinical practice and scientific understanding of perioperative brain health, including the severe and debilitating risk of dementia.

Cognitive deficits after general anaesthesia in animal models: a scoping review.

BACKGROUND: It remains controversial whether general anaesthetic drugs contribute to perioperative neurocognitive disorders in adult patients. Preclinical studies have generated conflicting results, likely because of differing animal models, study protocols, and measured outcomes. This scoping review of preclinical studies addressed the question: 'Do general anaesthetic drugs cause cognitive deficits in adult animals that persist after the drugs have been eliminated from the brain?' METHODS: Reports of preclinical studies in the MEDLINE database published from 1953 to 2021 were examined. A structured review process was used to assess original studies of cognitive behaviours, which were measured after treatment (≥24 h) with commonly used general anaesthetic drugs in adult animals. RESULTS: The initial search yielded 380 articles, of which 106 were fully analysed. The most frequently studied animal model was male (81%; n=86/106) rodents (n=106/106) between 2-3 months or 18-20 months of age. Volatile anaesthetic drugs were more frequently studied than injected drugs, and common outcomes were memory behaviours assessed using the Morris water maze and fear conditioning assays. Cognitive deficits were detected in 77% of studies (n=82/106) and were more frequent in studies of older animals (89%), after inhaled anaesthetics, and longer drug treatments. Limitations of the studies included a lack of physiological monitoring, mortality data, and risk of bias attributable to the absence of randomisation and blinding. CONCLUSIONS: Most studies reported cognitive deficits after general anaesthesia, with age, use of volatile anaesthetic drugs, and duration of anaesthesia as risk factors. Recommendations to improve study design and guide future research are presented.

Volatile versus intravenous anaesthesia and perioperative neurocognitive disorders: anything to see here?

There is a potential differential effect of sevoflurane compared with propofol on postoperative delirium and other perioperative neurocognitive disorders. More generally, there are perhaps differences between volatile and intravenous anaesthetic agents in their possible impact on perioperative neurocognitive disorders. Strengths and limitations of a recent study in this journal and its contribution to our understanding of the impact of anaesthetic technique on perioperative neurocognitive disorders are discussed.

Postoperative delirium in older patients after undergoing pelvic organ prolapse surgery.

INTRODUCTION AND HYPOTHESIS: To determine the 7-day incidence and risk factors of postoperative delirium (POD) occurring after prolapse surgery in women aged ≥60 years. METHODS: A prospective study of women ≥60 years undergoing prolapse surgery at a large academic center. The primary outcome is positive Confusion Assessment Method delirium screen administered in person or by telephone at the time of hospital discharge and postoperative days 1, 3, 5, and 7. RESULTS: This analysis included 165 patients, mean ± SD age of 72.5 ± 6.1 years, with median (IQR) years of education of 13 (12-16), and baseline Modified Mini-Mental Status (3MS) Exam score of 95 (92-98). Prolapse repair type was vaginal for 70% (n=115) and laparoscopic for 30% (n=50) of patients; most under general anesthesia, 151 (92.1%). The incidence of positive delirium screen during the first week after surgery was 12.1% (n=20). Most of these participants screened positive on postoperative day 0, 8.4% (n=14). In univariate analyses, a positive screen was associated with older age and fewer education years, lower 3MS exam score, greater baseline geriatric depression scale score, and greater frailty score. Lower 3MS score was the only variable that remained significant in the final model (adjusted odds ratio 0.84, 95% CI 0.75-0.95). CONCLUSIONS: One in 12 women ≥60 years deemed eligible for discharge on the day of prolapse surgery screens positive for delirium. The 7-day POD incidence is comparable to other elective non-cardiac surgery cohorts. Given the increasing trend toward same day discharge after major prolapse surgery, more research is needed to determine the impact of universal delirium screening as part of discharge assessments.

Effects of permissive hypercapnia on intraoperative cerebral oxygenation and early postoperative cognitive function in older patients with non-acute fragile brain function undergoing laparoscopic colorectal surgery: protocol study.

BACKGROUND: Perioperative brain protection in older patients has been the focus of research recently; meanwhile, exploring the relationship between regional cerebral oxygen saturation (rSO2) and brain function in the perioperative period has been an emerging and challenging area-the difficulties related to the real-time monitoring of rSO2 and the choice of feasible interventions. As an advanced instrument for intraoperative rSO2 monitoring, the clinical application of near-infrared spectrum (NIRS) cerebral oxygen monitoring has gradually increased in popularity and is being recognized for its beneficial clinical outcomes in patients undergoing cardiac and noncardiac surgery. In addition, although sufficient evidence to support this hypothesis is still lacking, the effect of permissive hypercapnia (PHC) on rSO2 has expanded from basic research to clinical exploration. Therefore, monitoring intraoperative rSO2 in older patients with NIRS technology and exploring possible interventions that may change rSO2 and even improve postoperative cognitive performance is significant and clinically valuable. METHODS: This study is a single-center randomized controlled trial (RCT). 76 older patients are enrolled as subjects. Patients who meet the screening criteria will be randomly assigned 1:1 to the control and intervention groups. PHC-based mechanical ventilation will be regarded as an intervention. The primary outcome is the absolute change in the percent change in rSO2 from baseline to the completion of surgery in the intervention and control groups. Secondary outcomes mainly include observations of intraoperative cerebral oxygenation and metabolism, markers of brain injury, and assessments of patients' cognitive function using scale through postoperative follow-up. DISCUSSION: The findings of this RCT will reveal the effect of PHC on intraoperative rSO2 in older patients with nonacute fragile brain function (NFBF) and the approximate trends over time, and differences in postoperative cognitive function outcomes. We anticipate that the trial results will inform clinical policy decision-makers in clinical practice, enhance the management of intraoperative cerebral oxygen monitoring in older patients with comorbid NFBF, and provide guidance for clinical brain protection and improved postoperative cognitive function outcomes. TRIAL REGISTRATION: ChiCTR, ChiCTR2200062093, Registered 9/15/2022.

Involvement of KCa3.1 channel activity in immediate perioperative cognitive and neuroinflammatory outcomes.

BACKGROUND: Potassium channels (KCa3.1; Kv1.3; Kir2.1) are necessary for microglial activation, a pivotal requirement for the development of Perioperative Neurocognitive Disorders (PNDs). We previously reported on the role of microglial Kv1.3 for PNDs; the present study sought to determine whether inhibiting KCa3.1 channel activity affects neuroinflammation and prevents development of PND. METHODS: Mice (wild-type [WT] and KCa3.1-/-) underwent aseptic tibial fracture trauma under isoflurane anesthesia or received anesthesia alone. WT mice received either TRAM34 (a specific KCa3.1 channel inhibitor) dissolved in its vehicle (miglyol) or miglyol alone. Spatial memory was assessed in the Y-maze paradigm 6 h post-surgery/anesthesia. Circulating interleukin-6 (IL-6) and high mobility group box-1 protein (HMGB1) were assessed by ELISA, and microglial activitation Iba-1 staining. RESULTS: In WT mice surgery induced significant cognitive decline in the Y-maze test, p = 0.019), microgliosis (p = 0.001), and increases in plasma IL-6 (p = 0.002) and HMGB1 (p = 0.001) when compared to anesthesia alone. TRAM34 administration attenuated the surgery-induced changes in cognition, microglial activation, and HMGB1 but not circulating IL-6 levels. In KCa3.1-/- mice surgery neither affected cognition nor microgliosis, although circulating IL-6 levels did increase (p < 0.001). CONCLUSION: Similar to our earlier report with Kv1.3, perioperative microglial KCa3.1 blockade decreases immediate perioperative cognitive changes, microgliosis as well as the peripheral trauma marker HMGB1 although surgery-induced IL-6 elevation was unchanged. Future research should address whether a synergistic interaction exists between blockade of Kv1.3 and KCa3.1 for preventing PNDs.