Development Of Postoperative Cognitive Dysfunction Research Articles

SS-31 inhibits mtDNA-cGAS-STING signaling to improve POCD by activating mitophagy in aged mice.

Neuroinflammation is crucial in the development of postoperative cognitive dysfunction (POCD), and microglial activation is an active participant in this process. SS-31, a mitochondrion-targeted antioxidant, is widely regarded as a potential drug for neurodegenerative diseases and inflammatory diseases. In this study, we sought to explore whether SS-31 plays a neuroprotective role and the underlying mechanism. Internal fixation of tibial fracture was performed in 18-month-old mice to induce surgery-associated neurocognitive dysfunction. LPS was administrated to BV2 cells to induce neuroinflammation. Neurobehavioral deficits, hippocampal injury, protein expression, mitophagy level and cell state were evaluated after treatment with SS-31, PHB2 siRNA and an STING agonist. Our study revealed that SS-31 interacted with PHB2 to activate mitophagy and improve neural damage in surgically aged mice, which was attributed to the reduced cGAS-STING pathway and M1 microglial polarization by decreased release of mitochondrial DNA (mtDNA) but not nuclear DNA (nDNA). In vitro, knockdown of PHB2 and an STING agonist abolished the protective effect of SS-31. SS-31 conferred neuroprotection against POCD by promoting PHB2-mediated mitophagy activation to inhibit mtDNA release, which in turn suppressed the cGAS-STING pathway and M1 microglial polarization.

Single-Photon Emission Computed Tomography in the Diagnosis of Early Postoperative Cognitive Dysfunction After Combined Carotid Endarterectomy and Coronary Artery Bypass Grafting

Objective: to study the contribution of regional cerebral blood flow (rCBF) indicators to the diagnosis of early postoperative cognitive dysfunction (POCD) in patients with multifocal atherosclerosis (MFA) with heart and brain revascularization.Material and methods. The study involved 45 patients with MFA of coronary and precerebral arteries. We analyzed patients’ cognitive indicators and conducted brain scintigraphy before and after revascularization. The criteria for inclusion in the study were: scheduled combined revascularization of coronary and precerebral arteries; signed informed consent to participate in the study. Criteria for exclusion were: refusal to participate in the study, diseases that would prevent examination. The study of cognitive functions was performed using flow was assessed by single-photon emission computed tomography using lipophilic radiopharmaceutical 99mTc-HMPAO “Ceretec”.Results. The frequency of early POCD in the isolated coronary artery bypass grafting (CABG) group was 73.3%, in the combined carotid endarterectomy (СEA) and CABG group it was 72.5% (p ˃ 0.05). The rCBF index in the isolated CABG group compared with the combined СEA and CABG group was higher in the right and left temporal lobes (p = 0.01 and p = 0.04), in the right frontal lobe (p = 0.03), right parietal lobe (p = 0.005), and in the right and left occipital lobes (p = 0.03 and p = 0.03). In the postoperative period, in the isolated CABG group, right parietal lobe perfusion (p = 0.01), and right and left occipital lobe perfusion (p = 0.01 and p = 0.01) decreased compared to the baseline values. In the combined СEA and CABG group, in the early postoperative period, cerebral perfusion did not change significantly. Right parietal lobe perfusion was higher in the isolated CABG group compared with the combined CABG and СEA group (p = 0.04). The greatest contribution to the development of early POCD in patients after isolated CABG was made by the left temporal lobe perfusion (p = 0.025), in patients after combined CABG and СEA – by the right parietal lobe perfusion (p = 0.04) in the early postoperative period.Conclusion. Assessment of cerebral perfusion in patients before and after surgery can be used to identify areas affected during surgery, as a method for monitoring the safety of procedure, and as an assessment of the preventive methods against POCD.

Genetic basis of postoperative cognitive dysfunction

This review highlights literature data on potential genetic markers that potentially influence the development of postoperative cognitive dysfunction, such as TOMM40, APOE, TREM2, METTL3, PGC1a, HMGB1 and ERMN. The main pathogenetic mechanisms triggered by these genes and leading to the development of cognitive impairment after anesthesia are described. The paper systematizes previously published works that provide evidence of the impact of specific genetic variants on the development of postoperative cognitive dysfunction.

What Do Cancer Surgery and orthopedic Surgery Elderly Patients Have in Common? A Long-term Postoperative Cognitive Dysfunction in Orthopedic and Cancer Patients Original Research.

Postoperative cognitive dysfunction (POCD) involves decline in several cognitive domains after surgery and is particularly common after cardiac surgery, while also common among other types of surgery. Given the potential effects of such cognitive dysfunction on the quality of life, it is important to study it in multiple populations in order to limit its occurrence. We present the long-term neuropsychological outcome of 200 patients, 100 of whom had orthopedic surgery and 100 oncological surgery. We administered a series of neuropsychological tests assessing attention, complex scanning, verbal working memory, executive functioning, short-term and long-term memory, and visuospatial perception before surgery, prior to discharge, at 3-month follow-up and 6 years after surgery. We compared the performance of these patients to normative datasets. Despite equivalent levels of pre-surgery performance between patients, oncology patients exceeded their preoperative neurocognitive levels, suggesting less postoperative cognitive dysfunction in orthopedic patients overall, in all neuropsychological domains at a 6-year follow-up, except short-term retention. In contrast, orthopedic patients showed no improvement, and, instead, showed some cognitive decline, which remained consistent over time. Our findings highlight the critical role of the type of surgery utilized in the development of POCD and have implications for clinical management and patients' quality of life in the very long term. Health policy professionals should be aware that patients' low POCD may persist in the long term, and this is useful from a clinician's point of view.

Взаимосвязь колебаний уровней окситоцина в крови и слюне с когнитивными нарушениями у пациента с ишемической болезнью сердца до и после аортокоронарного шунтирования

Aim. To assess the dynamics of cognitive status and oxytocin levels in biological fluids (blood and saliva), as well as their relationship before and after coronary artery bypass surgery. Key points. According to the literature, postoperative cognitive dysfunction occurs in patients after coronary artery bypass grafting. The reasons for its development are factors that influence the preoperative, operational and postoperative stages. Timely diagnosis of cognitive deficit is extremely important, since the more pronounced the cognitive impairment, the less opportunities there are to provide assistance to patients. In this clinical observation, special attention is paid to oxytocin as a biomarker of degenerative brain lesions. Conclusion. We identified the development of postoperative cognitive dysfunction in a patient who did not have such disorders before surgery. There is a direct relationship between the state of cognitive functions and the level of oxytocin in the blood and saliva. Taking into account the data obtained, we propose to consider oxytocin as a biomarker of vascular cognitive disorders. Keywords: coronary heart disease, coronary artery bypass grafting, cognitive status, oxytocin, postoperative cognitive dysfunction.

Post-operative cognitive dysfunction is exacerbated by high-fat diet via TLR4 and prevented by dietary DHA supplementation

Post-operative cognitive dysfunction (POCD) is an abrupt decline in neurocognitive function arising shortly after surgery and persisting for weeks to months, increasing the risk of dementia diagnosis. Advanced age, obesity, and comorbidities linked to high-fat diet (HFD) consumption such as diabetes and hypertension have been identified as risk factors for POCD, although underlying mechanisms remain unclear. We have previously shown that surgery alone, or 3-days of HFD can each evoke sufficient neuroinflammation to cause memory deficits in aged, but not young rats. The aim of the present study was to determine if HFD consumption before surgery would potentiate and prolong the subsequent neuroinflammatory response and memory deficits, and if so, to determine the extent to which these effects depend on activation of the innate immune receptor TLR4, which both insults are known to stimulate. Young-adult (3mo) & aged (24mo) male F344xBN F1 rats were fed standard chow or HFD for 3-days immediately before sham surgery or laparotomy. In aged rats, the combination of HFD and surgery caused persistent deficits in contextual memory and cued-fear memory, though it was determined that HFD alone was sufficient to cause the long-lasting cued-fear memory deficits. In young adult rats, HFD + surgery caused only cued-fear memory deficits. Elevated proinflammatory gene expression in the hippocampus of both young and aged rats that received HFD + surgery persisted for at least 3-weeks after surgery. In a separate experiment, rats were administered the TLR4-specific antagonist, LPS-RS, immediately before HFD onset, which ameliorated the HFD + surgery-associated neuroinflammation and memory deficits. Similarly, dietary DHA supplementation for 4 weeks prior to HFD onset blunted the neuroinflammatory response to surgery and prevented development of persistent memory deficits. These results suggest that HFD 1) increases risk of persistent POCD-associated memory impairments following surgery in male rats in 2) a TLR4-dependent manner, which 3) can be targeted by DHA supplementation to mitigate development of persistent POCD.

Overexpression of SESN1 improves mitochondrial damage and mitophagy, a potential therapeutic strategy for cognitive dysfunction after anaesthesia.

Postoperative cognitive dysfunction (POCD) is a prevalent central nervous system complication predominantly observed in elderly patients. Sevoflurane, a general anaesthetic agent, has been implicated in the development of POCD, yet the underlying regulatory mechanisms potentially involving Sestrin1 (SESN1), a stress-responsive protein that plays a critical role in cellular homeostasis and protection against stress-induced damage, including oxidative stress and DNA damage, remain elusive. This study endeavoured to elucidate the impact of SESN1 on sevoflurane-induced cognitive impairment in rats. Employing a model in which SESN1 was transfected into SD male rats and cognitive dysfunction was induced by sevoflurane. The Morris Water Maze test was used for behavioural evaluation, Enzyme-Linked Immunosorbent Assay, Western blotting and immunofluorescence were applied to assess the influence of SESN1 on the inflammatory response and mitophagy in the rat hippocampus. The study further aimed to uncover the putative mechanism by which SESN1, through SIRT1, might modulate cognitive function. Concurrently, levels of malondialdehyde, superoxide dismutase and mitochondrially produced ATP within the rat hippocampus were quantified. Experimental outcomes suggested that SESN1 overexpression significantly mitigated the deleterious effects of sevoflurane anaesthesia, ameliorated neuroinflammation and inflammasome activation, modified mitochondrial function and facilitated mitophagy. Additionally, SESN1, via the activation of SIRT1, may suppress inflammasome activation and mitochondrial dysfunction. Collectively, these findings underscore SESN1's integral role in counteracting sevoflurane-induced cognitive impairment, impeding inflammasome activation, enhancing mitochondrial function and fostering mitophagy, which appear to be intricately linked to SESN1-mediated SIRT1 activation. SESN1 is a novel therapeutic target for POCD, potentially advancing neuroprotective strategies in clinical settings.

THE IMPACT OF TOTAL INTRAVENOUS ANESTHESIA VERSUS INHALATIONAL ANESTHESIA ON POSTOPERATIVE COGNITIVE DYSFUNCTION IN ELDERLY PATIENTS

Postoperative cognitive dysfunction (POCD) is a common complication among elderly patients undergoing surgery. Anesthesia type has been suggested as a potential factor influencing the occurrence of POCD. This study aims to investigate and compare the impact of total intravenous anesthesia (TIVA) and inhalational anesthesia on the development of POCD in elderly patients. The primary aim of this study is to assess and compare the incidence of POCD in elderly patients receiving TIVA or inhalational anesthesia during surgical procedures. The secondary objectives include evaluating the duration of cognitive impairment, perioperative clinical parameters, and potential risk factors contributing to POCD. This prospective cohort study will enroll elderly patients (65 and above) scheduled for elective surgery. Participants will be divided into two groups: one receiving TIVA and the other receiving inhalational anesthesia. Preoperative, intraoperative, and postoperative data will be collected and analyzed. Cognitive function will be assessed using standardized neuropsychological tests before surgery and at specified postoperative intervals. Additionally, perioperative clinical parameters, anesthesia-related data, and potential risk factors for POCD will be recorded and analyzed. The study results will include the incidence of POCD in both groups and the duration and severity of cognitive impairment. Perioperative clinical parameters, such as length of surgery and anesthesia duration, will be compared. Additionally, risk factors for POCD, such as age, comorbidities, and type of surgery, will be evaluated to identify their association with the development of cognitive dysfunction. This study will provide valuable insights into the impact of total intravenous anesthesia versus inhalational anesthesia on postoperative cognitive dysfunction in elderly patients. The findings will help anesthesiologists and surgeons make informed decisions regarding anesthesia for this vulnerable population, ultimately improving patient outcomes and quality of care.

Altered intestinal barrier contributes to cognitive impairment in old mice with constipation after sevoflurane anesthesia.

Elderly patients have a high risk of developing postoperative cognitive dysfunction (POCD). Gastrointestinal disorders, such as constipation, in the elderly population may be involved in the pathogenesis of neurological disorders by promoting inflammatory responses due to a 'leaky gut'. General anesthetic sevoflurane may impair gastrointestinal function in elderly patients to trigger neurological complications following surgery. Therefore, we hypothesized that elderly individuals with gastrointestinal dysfunction may be more vulnerable to sevoflurane and consequently develop POCD. Aged mice were randomly divided into four groups: control (CTRL), CTRL+sevoflurane (Sev), slow transit constipation (STC), and STC + Sev. Mice in the STC and STC + Sev groups were intra-gastrically administrated loperamide (3 mg/kg, twice a day for 7 days) to induce a slow transit constipation (STC) model determined with fecal water content and the time of first white fecal pellet, whereas mice in the other groups received the similar volume of saline. One week later, mice in the CTRL+Sev group and STC + Sev group received 2% sevoflurane for 2 h. The gut permeability evaluated with 4-kDa fluorescein isothiocyanate (FITC)-dextran, serum cytokines, microglia density, TLR4/NF-κB signaling expression, and POCD-like behavioral changes were determined accordingly. The loperamide-induced STC mice had decreased fecal water content and prolonged time of first white fecal pellet. Sevoflurane exposure caused significantly increased gut permeability and serum cytokines, as well as the activation of microglia and the TLR4/NF-κB signaling pathway in the prefrontal cortex of the aged STC mice. Sevoflurane also caused cognitive impairment and emotional phenotype abnormality in aged STC mice. Aged STC mice were more vulnerable to sevoflurane anesthesia and consequently developed POCD-like behavioral changes. Our data suggest that gastrointestinal disorders including constipation may contribute to the development of POCD.

Evaluation of the brain cellular damage during liver transplantations.

Neuroinflammation in patients undergoing major surgery can lead to neuronal damage, and neuronal damage can be detected through the measurement of biochemical markers of brain damage. S100 beta (S100 β), neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP) levels are considered good biomarkers to detect brain damage that emerged with neurotoxicity. To evaluate neuronal damage during liver transplantations. After approval of the ethics committee and patient consents, preoperative and postoperative cognitive functions of 33 patients undergoing liver transplantation were measured using the Mini Mental State Examination (MMSE), whereas simultaneous neuronal damage was evaluated through the measurement of S100β, NSE, and GFAP levels. There was no statistically significant difference between preoperative and postoperative MMSE. There was a statistically significant decrease in postoperative GFAP (P < 0.05) and a statistically significant increase in NSE (P < 0.05) compared to preoperative values. The decrease in S100β (P > 0.05) level was statistically insignificant. Neuroprotective approaches in anesthesia protocol protect patients from brain damage during liver transplantation and prevent the development of postoperative cognitive dysfunction. Since the significant increase in NSE levels during liver transplantations was deemed to have been associated with causes other than neuronal damage, NSE should not be evaluated as a marker of brain damage in these operations.

M1-Type Microglia-Derived Extracellular Vesicles Overexpressing IL-1R1 Promote Postoperative Cognitive Dysfunction by Regulating Neuronal Inflammation.

Postoperative cognitive dysfunction (POCD) is a common complication after surgical anesthesia, mainly manifested as memory impairment, decreased attention, and cognitive function with mood and personality changes. Activated microglia (M1-type microglia) have been demonstrated to release inflammatory substances (IL-1β, TNF-α, etc.) that cause neuronal degeneration and death by activating the NF-κB signaling pathway and upregulating Caspase-3 and Bax. However, the pathogenesis of POCD is still not fully understood and needs further research. In the present study, we investigated the effect of M1-type microglia-derived extracellular vesicles (EVsM1-Microglia) in the pathological process of POCD. The levels of NF-κB phosphorylation and IL-1β protein expression in hippocampal neurons were significantly increased in the Surgery group, while PSD95 and MAP2 were significantly decreased. Surgery induced microglia activation, synapse-associated protein decrease, and neuronal degeneration in hippocampus. And the amount of spine and mushroom spine significantly decreased in surgical mice, which was reverted in the presence of IL-1R1 siRNA. In addition, EVsM1-Microglia promoted synaptic loss and neuron degeneration independent of surgery and microglia activation. Furthermore, EVsM1-Microglia promoted memory defects in surgical mice. We demonstrated that EVsM1-Microglia with high expression of IL-1R1 promote POCD development by regulating neuronal inflammation.

Formyl peptide receptor 1 is involved in surgery-induced neuroinflammation and dysfunction of learning and memory in mice

Postoperative cognitive dysfunction (POCD) is a common complication after surgery. Peripheral immune cells may contribute to the development of POCD. However, molecules that are important for this contribution are not known. We hypothesize that formyl peptide receptor 1 (FPR1), a molecule critical for the migration of the monocytes and neutrophils into the brain after brain ischemia, is central to the development of postoperative neuroinflammation and dysfunction of learning and memory. Male C57BL/6 (wild-type) mice and FPR1-/- mice received right carotid artery exposure surgery. Some wild-type mice received cFLFLF, an FPR1 antagonist. Mouse brains were harvested 24 h after the surgery for biochemical analysis. Mice were subjected to the Barnes maze and fear conditioning tests to determine their learning and memory from 2 weeks after the surgery. We found that surgery increased FPR1 in the brain and proinflammatory cytokines in the blood and brain of wild-type mice. Surgery also impaired their learning and memory. cFLFLF attenuated these effects. Surgery did not induce an increase in the proinflammatory cytokines and impairment of learning and memory in FPR1-/- mice. These results suggest that FPR1 is important for the development of neuroinflammation and dysfunction of learning and memory after surgery. Specific interventions that inhibit FPR1 may be developed to reduce POCD.

TAK1 Reduces Surgery-induced Overactivation of RIPK1 to Relieve Neuroinflammation and Cognitive Dysfunction in Aged Rats.

Postoperative cognitive dysfunction (POCD) is a common clinical complication in elderly patients, but its underlying mechanism remains unclear. Receptor-interacting protein kinase 1 (RIPK1), a key molecule mediating necroptosis and regulated by transforming growth factor β-activated kinase 1 (TAK1), was reported to be associated with cognitive impairment in several neurodegenerative diseases. This study was conducted to investigate the possible role of TAK1/RIPK1 signalling in POCD development following surgery in rats. Young (2-month-old) and old (24-month-old) Sprague-Dawley rats were subjected to splenectomy under isoflurane anaesthesia. The young rats were treated with the TAK1 inhibitor takinib or the RIPK1 inhibitor necrostatin-1 (Nec-1) before surgery, and old rats received adeno-associated virus (AAV)-TAK1 before surgery. The open field test and contextual fear conditioning test were conducted on postoperative day 3. The changes in TNF-α, pro-IL-1β, AP-1, NF-κB p65, pRIPK1, pTAK1 and TAK1 expression and astrocyte and microglia activation in the hippocampus were assessed. Old rats had low TAK1 expression and were more susceptible to surgery-induced POCD and neuroinflammation than young rats. TAK1 inhibition exacerbated surgery-induced pRIPK1 expression, neuroinflammation and cognitive dysfunction in young rats, and this effect was reversed by a RIPK1 inhibitor. Conversely, genetic TAK1 overexpression attenuated surgery-induced pRIPK1 expression, neuroinflammation and cognitive dysfunction in old rats. Ageing-related decreases in TAK1 expression may contribute to surgery-induced RIPK1 overactivation, resulting in neuroinflammation and cognitive impairment in old rats.

The Effects of Anesthesia on Post-Operative Cognitive Dysfunction: A Systematic Review (P5-12.008)

<h3>Objective:</h3> This review aims to highlight the impacts of anesthesia in developing POCD <h3>Background:</h3> Postoperative cognitive dysfunction (POCD) is one of the most common postoperative complications, with a higher occurrence among the elderly. POCD is characterized by impaired memory, reduced attention deficit, and alteration in mood and personality changes. Its diagnosis is validated by conducting a baseline cognitive performance test preoperatively and compared with the mental status postoperatively. <h3>Design/Methods:</h3> Using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines a systematic review was conducted on the anesthesiological effects of POCD in the elderly. A PubMed search was performed with the keywords “Elderly”, “anesthesia”, and “postoperative cognitive dysfunction”. Four reviewers extracted the data independently and the risk of bias assessment was completed. <h3>Results:</h3> Of the 32 studies that were qualified, nineteen of them met the inclusion criteria and were finalized for review. The finalized studies concluded a 94% positive correlation between anesthesia and POCD and reported a wide range of cognitive function as early as six hours, seven days, and up to a year post-anesthesia. Some studies suggested the presence of other etiologies of POCD that were unmasked by anesthesia. These studies were well sampled from a similar demographic population regarding age, sex, cognitive function, and comorbidities. <h3>Conclusions:</h3> Despite the variation of type and route of administration of anesthetic, evidence from the analyzed studies highlights the increase in the incidence of POCD in the elderly who underwent anesthesia. Some factors contributing to the rise in the development of POCD include older age, pre-existing conditions, substance use, low literacy status, and coexistence of intra- and postoperative complications. Furthermore, the geriatric population has a higher probability of requiring surgical treatment and developing cognitive dysfunction, hence the need for more studies on this topic to better understand, prevent and manage these effects. <b>Disclosure:</b> Dr. Hassan has nothing to disclose. Dr. Dai has nothing to disclose. Dr. Mustafa has nothing to disclose. Dr. Nasereldin has nothing to disclose. Mrs. Advani has nothing to disclose. Dr. Alamin has nothing to disclose. Dr. Mezzoni has nothing to disclose. Dr. Elsheikh has nothing to disclose. Dr. Abdelrahman has nothing to disclose.

Stellate ganglion block alleviates postoperative cognitive dysfunction via inhibiting TLR4/NF-κB signaling pathway

Postoperative cognitive dysfunction (POCD) is common in aged patients after major surgery and is associated with increased risk of long-term morbidity and mortality. However, the underlying mechanism remains largely unknown and the clinical management of POCD is still controversial. Stellate ganglion block (SGB) is a clinical treatment for nerve injuries and circulatory issues. Recent evidence has identified the benefits of SGB in promoting learning and memory. We thus hypothesize that SGB could be effective in improving cognitive function after surgery. In present study, we established POCD model in aged rats via partial liver resection surgery. We found that the development of POCD was associated with the activation of toll-like receptor 4/nuclear factor kapa-B (TLR4/NF-κB) signaling pathway in the microglia in dorsal hippocampus, which induced the production of pro-inflammatory mediators (TNF-α, IL-1β, IL-6) and promoted neuroinflammation. More importantly, we showed evidence that preoperative treatment with SGB could inhibit microglial activation, suppress TLR4/NF-κB-mediated neuroinflammation and effectively attenuate cognitive decline after the surgery. Our study suggested that SGB may serve as a novel treatment to prevent POCD in elderly patients. As SGB is safe procedure widely used in clinic, our findings can be easily translated into clinical practice and benefit more patients.

Mannose-coated superparamagnetic iron oxide nanozyme for preventing postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is associated with increased postoperative morbidity and mortality in patients. Excessive production of reactive oxygen species (ROS) and the consequent inflammatory response in the postoperative brain play crucial roles in the development of POCD. However, effective ways to prevent POCD have yet to be developed. Moreover, effective penetration of the blood-brain barrier (BBB) and maintaining viability in vivo are major challenges for preventing POCD using traditional ROS scavengers. Herein, mannose-coated superparamagnetic iron oxide nanoparticles (mSPIONs) were synthesized by co-precipitation method. The BBB penetration of mSPIONs was verified through fluorescent imaging and ICP-MS quantification. The ROS scavenging and anti-inflammatory of mSPIONs were evaluated in H2O2-treated J774A.1​cells and in tibial fracture mice model. The novel object recognition (NOR) and trace-fear conditioning (TFC) were used to test the cognitive function of postoperative mice. The average diameter of mSPIONs was approximately 11​nm. mSPIONs significantly reduced ROS levels in H2O2-treated cells and in hippocampus of surgical mice. mSPIONs administration reduced the levels of IL-1β and TNF-α in the hippocampus and inhibited surgery-upregulated HIF1-α/NF-κB signaling pathway. Moreover, mSPIONs significantly improved the cognitive function of postoperative mice. This study provides a new approach for preventing POCD using a nanozyme.

Tregs dysfunction aggravates postoperative cognitive impairment in aged mice

ObjectivesEnhanced neuroinflammation is an important mechanism underlying perioperative neurocognitive disorders. Regulatory T cells (Tregs) play a crucial role in regulating systemic immune responses. The present study was aimed to investigate the participation of Tregs in the development of postoperative cognitive dysfunction (POCD).MethodsSurgery-associated neurocognitive disorder was induced in 18-month-old mice subjected to internal fixation of tibial fracture. Morris water maze was used to examine mice cognitive function. Splenic Tregs were collected for RNA sequencing and flow cytometry. Levels of inflammatory factors in the circulation and hippocampus were measured by enzyme-linked immunosorbent assay. Protein presences of tight junction proteins were detected by immunofluorescence.ResultsSurgery of internal fixation of tibial fracture induced cognitive impairment in aged mice, accompanied by elevated plasma levels of inflammatory factors and increased circulating Tregs. Transfusion of Tregs from young mice partially restored the structure of the blood–brain barrier and alleviated POCD in aged mice. Compared with young Tregs, differentially expressed genes in aged Tregs were enriched in tumor necrosis factor (TNF) signaling pathway and cytokine–cytokine receptor interaction. Flow cytometry revealed that aged Tregs had blunted functions under basal and stimulated conditions. Blockade of the CD25 epitope protected the blood–brain barrier structure, reduced TNF-α levels in the hippocampus, and improved surgery-associated cognition in aged mice.ConclusionsBlocking peripheral regulatory T cells improves surgery-induced cognitive function in aged mice. Therefore, aged Tregs play an essential role in the occurrence of POCD.

Downregulation of Nrf2 in the Hippocampus Contributes to Postoperative Cognitive Dysfunction in Aged Rats by Sensitizing Oxidative Stress and Neuroinflammation.

Postoperative cognitive dysfunction (POCD) is a recognized clinical complication defined by a new cognitive impairment arising after a surgical procedure. Elderly patients are especially vulnerable to cognitive impairment after surgical operations, but the underlying mechanisms remain elusive. Oxidative stress and neuroinflammation in the hippocampus, a brain region involved in memory formation, are considered as major contributors to the development of POCD. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of endogenous inducible defense system, plays a crucial role in protecting cells against oxidative stress and inflammation by enhancing transcription of antioxidant and anti-inflammatory target genes. Here, we examined whether aging downregulates Nrf2 in the hippocampus and, if so, whether downregulation of hippocampal Nrf2 contributes to POCD in aging. Young and aged rats underwent abdominal surgery or sham operation. One week later, cognitive function was assessed, and brains were collected for molecular studies. Compared with young sham rats, aged sham rats exhibited a significant reduction in expression of Nrf2 in the hippocampus. Interestingly, the expression of Nrf2 downstream target genes and levels of reactive oxygen species (ROS) and proinflammatory cytokines in the hippocampus as well as cognitive function were comparable between aged sham and young sham rats. After abdominal surgery, young rats showed significant upregulation of Nrf2 and its target genes in the hippocampus. However, aged rats did not show changes in expression of Nrf2 and its target genes but had increased levels of ROS and proinflammatory cytokines in the hippocampus, along with cognitive impairment as indicated by reduced contextual freezing time. Moreover, upregulation of hippocampal Nrf2 in aged rats with intracerebroventricular infusion of a Nrf2 activator reduced levels of ROS and proinflammatory cytokines in the hippocampus, ameliorating cognitive dysfunction after surgery. The results suggest that aging-induced downregulation of Nrf2 in the hippocampus causes the failure to activate Nrf2-regulated antioxidant defense system in response to surgical insult, which contributes to POCD by sensitizing oxidative stress and neuroinflammation. Nrf2 activation in the brain may be a novel strategy to prevent the cognitive decline in elderly patients after surgery.

Etiology and Pathogenesis of Postoperative Cognitive Dysfunction (Review)

Impairment of higher mental functions can complicate the course of the postoperative period even after short and minimally invasive, including laparoscopic, surgical procedures. Postoperative cognitive dysfunction significantly challenges patients’ quality of life, negating real success of surgical intervention and anesthetic support. In some cases, early postoperative cognitive dysfunction may be one of the main predictors of persistent cognitive impairment.The purpose of the review. To contemplate etiology, pathogenesis and the current perspective of postoperative cognitive dysfunction.We analyzed 96 publications in various databases (PubMed, Medline, RSCI and others), including 67 papers published over the past 5 years.The review provides an overview of current definitions and classification of postoperative cognitive dysfunction, data on the prevalence, polyethyology and risk factors, potential impact of the type of anesthesia and surgical intervention on the development of postoperative cognitive dysfunction. Various pathogenetic mechanisms of higher mental functions impairment alongside with available effective pharmacotherapies to correct them were considered.Conclusion. Numerous adverse factors of the perioperative period, such as neurotoxic effects of general anesthetics, neuroinflammation in response to operational stress and surgical trauma, impaired autoregulation of the cerebral blood flow, imperfect oxygen homeostasis, interactions of neurotransmitter, etc., can potentially cause postoperative cognitive dysfunction. Further deeper insights into etiology and pathogenesis of early postoperative cognitive dysfunction are relevant and necessary to improve prevention strategies and identify most effective pharmacotherapies to correct such disorders.

Dual roles of anesthetics in postoperative cognitive dysfunction: Regulation of microglial activation through inflammatory signaling pathways.

Postoperative cognitive dysfunction (POCD) is a prevalent clinical entity following surgery and is characterized by declined neurocognitive function. Neuroinflammation mediated by microglia is the essential mechanism of POCD. Anesthetics are thought to be a major contributor to the development of POCD, as they promote microglial activation and induce neuroinflammation. However, this claim remains controversial. Anesthetics can exert both anti- and pro-inflammatory effects by modulating microglial activation, suggesting that anesthetics may play dual roles in the pathogenesis of POCD. Here, we review the mechanisms by which the commonly used anesthetics regulate microglial activation via inflammatory signaling pathways, showing both anti- and pro-inflammatory properties of anesthetics, and indicating how perioperative administration of anesthetics might either relieve or worsen POCD development. The potential for anesthetics to enhance cognitive performance based on their anti-inflammatory properties is further discussed, emphasizing that the beneficial effects of anesthetics vary depending on dose, exposure time, and patients' characteristics. To minimize the incidence of POCD, we recommend considering these factors to select appropriate anesthetics.