Mechanism Of Postoperative Cognitive Dysfunction Research Articles

An Amino Acids and Dipeptide Injection Inhibits the TNF-α/HMGB1 Inflammatory Signaling Pathway to Reduce Pyroptosis and M1 Microglial Polarization in POCD Mice: the Gut to the Brain.

Peripheral surgery-induced neural inflammation is a key pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the mechanism underlying neuroinflammation and associated neural injury remains elusive. Surgery itself can lead to gut damage, and the occurrence of POCD is accompanied by high levels of TNF-α in the serum and blood‒brain barrier (BBB) damage. Reductions in stress, inflammation and protein loss have been emphasized as strategies for enhanced recovery after surgery (ERAS). We designed an amino acids and dipeptide (AAD) formula for injection that could provide intestinal protection during surgery. Through the intraoperative infusion of AAD based on the ERAS concept, we aimed to explore the effect of AAD injection on POCD and its underlying mechanism from the gut to the brain. Here, we observed that AAD injection ameliorated neural injury in POCD, in addition to restoring the function of the intestinal barrier and BBB. We also found that TNF-α levels decreased in the ileum, blood and hippocampus. Intestinal barrier protectors and TNF-α inhibitors also alleviated neural damage. AAD injection treatment decreased HMGB1 production, pyroptosis, and M1 microglial polarization and increased M2 polarization. In vitro, AAD injection protected the impaired gut barrier and decreased TNF-α production, alleviating damage to the BBB by stimulating cytokine transport in the body. HMGB1 and Caspase-1 inhibitors decreased pyroptosis and M1 microglial polarization and increased M2 polarization to protect TNF-α-stimulated microglia in vitro. Collectively, these findings suggest that the gut barrier-TNF-α-BBB-HMGB1-Caspase-1 inflammasome-pyroptosis-M1 microglia pathway is a novel mechanism of POCD related to the gut-brain axis and that intraoperative AAD infusion is a potential treatment for POCD.

Serum metabolomics analysis combined with network pharmacology reveals possible mechanisms of postoperative cognitive dysfunction in the treatment of Mongolian medicine Eerdun Wurile basic formula.

This study analyzed the endogenous metabolites and metabolic pathways in the serum of Sprague-Dawley (SD) rats gavaged with the Eerdun Wurile basic formula (EWB) using metabolomics methods and network pharmacology to explore the possible mechanism of action of the EWB in improving postoperative cognitive dysfunction (POCD). SD rats were divided into the basic formula group, which received the EWB, and the control group, which received equal amounts of distilled water. The blood was collected from the abdominal aorta and analyzed for metabolite profiles using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). Network pharmacology predicts the targets of the differential metabolites and disease targets; takes the intersection and constructs a "metabolite-disease-target" network; and performs protein-protein interaction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses. A total of 56 metabolites were selected for significant differences between the groups, mainly affecting amphetamine addiction, alcoholism, and regulation of lipolysis in adipocytes. A total of 177 potential targets for differential metabolite action in POCD were selected. The PI3K-Akt pathway, the HIF-1 pathway, and the FoxO pathway were in key positions. The studies have shown that EWB could improve POCD through multicomponents, multitargets, and multipathways, providing new possibilities and reference values for the treatment of POCD.

Research progress of postoperative cognitive dysfunction in cardiac surgery under cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) is often used in cardiothoracic surgery because its nonphysiological state causes pathophysiological changes in the body, causing multiorgan and multitissue damage to varying degrees. Postoperative cognitive dysfunction (POCD) is a common central nervous system complication after cardiac surgery. The etiology and mechanism of POCD are not clear. Neuroinflammation, brain mitochondrial dysfunction, cerebral embolism, ischemia, hypoxia, and other factors are related to the pathogenesis of POCD. There is a close relationship between CPB and POCD, as CPB can cause inflammation, hypoxia and reperfusion injury, and microemboli formation, all of which can trigger POCD. POCD increases medical costs, seriously affects patients' quality of life, and increases mortality. Currently, there is a lack of effective treatment methods for POCD. Commonly used methods include preoperative health management, reducing inflammation response during surgery, preventing microemboli formation, and implementing individualized rehabilitation programs after surgery. Strengthening preventive measures can minimize the occurrence of POCD and its adverse effects.

The role of epigenetic modification in postoperative cognitive dysfunction.

With the ageing of the population, the health problems of elderly individuals have become particularly important. Through a large number of clinical studies and trials, it has been confirmed that elderly patients can experience postoperative cognitive dysfunction after general anesthesia/surgery. However, the mechanism of postoperative cognitive dysfunction is still unknown. In recent years, the role of epigenetics in postoperative cognitive dysfunction has been widely studied and reported. Epigenetics includes the genetic structure and biochemical changes of chromatin not involving changes in the DNA sequence. This article summarizes the epigenetic mechanism of cognitive impairment after general anesthesia/surgery and analyses the broad prospects of epigenetics as a therapeutic target for postoperative cognitive dysfunction.

Involvement of microRNA-138-5p in cardiac surgery-induced postoperative cognitive dysfunction

Background: Despite being one of the main concerns in cardiac surgery, the molecular basis and regulatory mechanisms of postoperative cognitive dysfunction (POCD) are still unclear. In this study, we demonstrate the critical role of miR-138-5p in POCD in mice.
 Methods: We first established an animal model for POCD caused by cardiac surgery. We then used quantitative reverse transcription polymerase chain reaction to examine the expression levels of miR-138-5p and its target mRNAs. The protein level of sirtuin 1 (SIRT1) was determined using Western blot assays. To assess the mice’s recognition abilities, we performed the Morris water maze (MWM) test. Enzyme-linked immunosorbent assays were used to evaluate the expression levels of hippocampal inflammatory cytokines. Finally, we used a luciferase assay to confirm that miR-138-5p directly targeted the mRNA of SIRT1.
 Results: MiR-138-5p was upregulated in the hippocampus of mice following cardiac surgery. Inhibiting miR-138-5p reduced the occurrence of POCD and the hippocampus inflammation in the mice. MiR-138-5p targeted the mRNA of SIRT1, thereby suppressing its expression in the hippocampus of mice following cardiac surgery.
 Conclusion: Our findings suggest that miR-138-5p contributes to cardiac surgery-induced POCD by directly targeting and suppressing the expression of SIRT1 in the hippocampus.

HDAC6 Inhibition Alleviates Anesthesia and Surgery-Induced Less Medial Prefrontal-Dorsal Hippocampus Connectivity and Cognitive Impairment in Aged Rats.

To investigate the underlying mechanisms of postoperative cognitive dysfunction and the impairment of medial prefrontal cortex-hippocampus connectivity. Postoperative cognitive dysfunction frequently affects elderly following surgery. The role of inter-brain-region connectivity abnormality after anesthesia and surgery on postoperative cognitive dysfunction development remains unclear. Medial prefrontal cortex-hippocampus connectivity of aged and adult rats was evaluated by injecting neurotracer biotinylated dextranamine (BDA) into bilateral hippocampus 3days before partial hepatectomy, and biotinylated dextranamine positive cells of medial prefrontal cortex 2days after hepatectomy were counted. HDAC6 shRNA was injected into medial prefrontal cortex and hippocampus bilaterally before hepatectomy or an HDAC6 activity inhibitor Tubastatin A was administered systemically after hepatectomy. Neuroinflammation and HDAC6 down-target ac-tubulin in medial prefrontal cortex and hippocampus were detected. Learning and memory of rats were evaluated by Barnes Maze task during 2-5days after surgery and delayed matching-to-place water maze task during 10-23days after surgery. Compared to the age-matched normal controls, anesthesia and surgery significantly decreased BDA-positive neurons in medial prefrontal cortex of aged rats, but not young adult rats. Local HDAC6 knockdown and systemic HDAC6 inhibition both increased BDA-positive neurons number of medial prefrontal cortex, alleviated learning and memory impairment in the Barnes Maze task and water maze task, decreased HDAC6 expression, inflammatory cytokines, astrocyte and microglial activation, and increased ac-tubulin expression in aged rats which received surgery. Our data indicated that anesthesia and surgery impaired medial prefrontal cortex-hippocampus connectivity and cognition which was associated with HDAC6 overexpression.

Mechanisms of hypoxia in the hippocampal CA3 region in postoperative cognitive dysfunction after cardiopulmonary bypass

BackgroundPostoperative cognitive dysfunction (POCD) is a complication with high morbidity and mortality, commonly observed in the elderly who underwent anesthesia and surgery. The incidence is much higher in cardiac surgery. However, the reason and the mechanism of POCD remains unclear, but cerebral hypoxia is a common neurological complication after cardiac surgery. This study aims to investigate what role cerebral hypoxia plays in the pathogenesis of POCD.MethodsThe POCD model was established using cardiopulmonary bypass (CPB) surgery. Cognitive function was detected using Y maze and Morris water maze. The hypoxia in central nervous system was assessed using HE staining, western blot, and immunofluorescence. Inflammatory factors in hippocampus and plasma were detected by enzyme-linked immunosorbent assay. Evans blue was used to detect destruction of the blood brain barrier (BBB).ResultsCognitive impairment markedly occurred to rats underwent 2-h CPB operation. Cerebral thrombosis and hypoxia occurred in the hippocampal CA3 region of rats after surgery. In addition, microglia in hippocampal was activated and the expression of inflammatory factors such as IL-1β, IL-6 and TNF-α was upregulated. Moreover, the permeability of BBB increased in rats after CPB.ConclusionHypoxia in hippocampal CA3 region was involved in the occurrence and the mechanism may be associated with neuroinflammation and the damage of BBB.

Neuroinflammation as the Underlying Mechanism of Postoperative Cognitive Dysfunction and Therapeutic Strategies.

Postoperative cognitive dysfunction (POCD) is a common neurological complication following surgery and general anesthesia, especially in elderly patients. Severe cases delay patient discharge, affect the patient’s quality of life after surgery, and are heavy burdens to society. In addition, as the population ages, surgery is increasingly used for older patients and those with higher prevalences of complications. This trend presents a huge challenge to the current healthcare system. Although studies on POCD are ongoing, the underlying pathogenesis is still unclear due to conflicting results and lack of evidence. According to existing studies, the occurrence and development of POCD are related to multiple factors. Among them, the pathogenesis of neuroinflammation in POCD has become a focus of research in recent years, and many clinical and preclinical studies have confirmed the correlation between neuroinflammation and POCD. In this article, we reviewed how central nervous system inflammation occurred, and how it could lead to POCD with changes in peripheral circulation and the pathological pathways between peripheral circulation and the central nervous system (CNS). Furthermore, we proposed some potential therapeutic targets, diagnosis and treatment strategies at the cellular and molecular levels, and clinical applications. The goal of this article was to provide a better perspective for understanding the occurrence of POCD, its development, and preventive strategies to help manage these vulnerable geriatric patients.

Sevoflurane induces inflammation in primary hippocampal neurons by regulating Hoxa5/Gm5106/miR-27b-3p positive feedback loop

ABSTRACT Postoperative cognitive dysfunction (POCD) is a normal condition that develops after surgery with anesthesia, leading to deterioration of cognitive functions. However, the mechanism of POCD still remains unknown. To elucidate the POCD molecular mechanism, sevoflurane was employed in the present study to generate neuroinflammation mice model. Sevoflurane treatment caused inflammatory markers IL6, IL-10 and TNF-α high expression in primary hippocampal neurons and blood samples. Long non-coding RNA Gm5106 was found to be increased after being stimulated with sevoflurane. Silencing Gm5106 inhibited neuron inflammation. In the meanwhile, Gm5106 was identified as a direct target of miR-27b-3p that was inhibited by sevoflurane and related to inflammation suppression. In addition, transcription factor (TF) Hoxa5 was validated to activate Gm5106 through two binding motifs in the promoter region after sevoflurane exposure. Furthermore, miR-27b-3p also directly targeted Hoxa5 3ʹUTR, which affected nuclear Hoxa5 protein served as TF. Hoxa5 protein instead of 3ʹUTR reduced miR-27b-3p, in which Gm5106 knocking down abrogated this effect. In conclusion, sevoflurane induces neuroinflammation through increasing long non-coding RNA Gm5106, which is transcriptionally activated by Hoxa5 and directly targeted by miR-27-3p. Apart from that, Hoxa5, Gm5106, and miR-27b-3p form a positive feedback loop in sevoflurane stimulation.

Neuroinflammation-mediated mitochondrial dysregulation involved in postoperative cognitive dysfunction

Neuroinflammation following peripheral surgery is a pivotal pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the key site of inflammation-mediated neural damage remains unclear. Impaired mitochondrial function is a vital feature of degenerated neurons. Dynamin-related protein 1 (DRP1), a crucial regulator of mitochondrial dynamics, has been shown to play an essential role in synapse formation. Here, we designed experiments to assess whether Drp1-regulated mitochondrial dynamics and function are involved in the pathological processes of POCD and elucidate its relationship with neuroinflammation. Aged mice were subjected to experimental laparotomy under isoflurane anesthesia. Primary neurons and SH-SY5Y cells were exposed to tumor necrosis factor (TNF). We found an increase in Drp1 activation as well as mitochondrial fragmentation both in the hippocampus of mice after surgery and primary neurons after TNF exposure. Pretreatment with Mdivi-1, a Drp1 specific inhibitor, reduced this mitochondrial fragmentation. Drp1 knockdown with small interfering RNA blocked TNF-induced mitochondrial fragmentation in SH-SY5Y cells. However, the application of Mdivi-1 exhibited a negative impact on mitochondrial function and neurite growth in primary neurons. Calcineurin activity was increased in primary neurons after TNF exposure and contributed to the Drp1 activation. The calcineurin inhibitor FK506 exhibited a Drp1-independent function that mitigated mitochondrial dysfunction. Finally, we found that FK506 pretreatment ameliorated the neurite growth in neurons treated with TNF and the learning ability of mice after surgery. Overall, our research indicated a crucial role of mitochondrial function in the pathological processes of POCD, and neuronal metabolic modulation may represent a novel and important target for POCD.

Pay attention to the reversible changes of anesthetics and postoperative cognitive dysfunction.

The progress of human civilization and the development in the new era have put forward higher-level demands for medical industry. The enhancement of health awareness and the improvement of diagnosis and treatment methods have promoted the development of comfortable medicine. Anesthesiologists play such an important role in perioperative period and the comfortable medicine. Evidences show that the diagnosis and treatment of anesthesiologists enable patients to recover quickly, improve treatments, save money, reduce family and social burdens. Postoperative cognitive dysfunction is one of the most common problems faced in perioperative medicine. Although postoperative cognitive dysfunction isn’t a direct threat for life, it may reduce the degree of medical cooperation, occur adverse events unnecessarily, prolong hospital stay, increase expenses and the anxiety of patients and other negative effects. Therefore, clarifying the risk factors of postoperative cognitive dysfunction and exploring effective medical methods are necessary to solve the above problems. The Anesthesiology Branch of the Chinese Medical Association has established a special group for the research of postoperative cognitive dysfunction. At present, research teams in China have been committed to related research on postoperative cognitive dysfunction for a long time. Many results provided valuable suggestions for the prevention and treatment of cognitive dysfunction. Studies showed that age and coronary artery bypass grafting and other major operations are important risk factors for postoperative cognitive dysfunction. This provides warnings for the prevention of postoperative cognitive function in clinical diagnosis and treatment. The management of specific populations and types of surgery are necessary for anesthesiologists to carry out early psychological construction, humanistic care and even medical intervention for patients in particular. Another important finding in these studies is that the occurrence of postoperative cognitive dysfunction is reversible, and the risk period is mainly the early postoperative period and barely has a serious impact on the long-term cognition. These results point out the direction for further improvement of perioperative medicine. With the development of the western region of China, the team of Professor Zhao-Qiong Zhu from the Affiliated Hospital of Zunyi Medical University committed a lot for years in the field of postoperative cognitive dysfunction. The research team found that patients with postoperative cognitive dysfunction are mainly elderly people in clinical studies, and this phenomenon is reversible, and mainly happened in 1 week after surgery. It rarely lasts for months or years. This provides an important theoretical basis to explain the occurrence of this phenomenon and diagnosis as same as provide treatment timely in clinic. On this basis, the team of Professor Zhao-Qiong Zhu carried out further research from the perspectives of behavior, molecular biology, cell biology, morphology, imaging, etc. in order to ascertain the relevant mechanism of postoperative cognitive dysfunction. The results also revealed that the behavioral effects of inhalation anesthetics on experimental animals at clinical and subclinical concentrations are only limited to the early stage after drug application, and the related mechanism may be related to the activation of inflammasomes and central cholinergic receptors. The series of researches provide valuable suggestions for rationally explaining the occurrence of postoperative cognitive dysfunction in clinical diagnosis as well as treatment and further research for postoperative cognitive dysfunction in the future. With the improvement of living standards, the demand for health increases for people. The reversible changes of postoperative cognitive dysfunction as one of the key medical problems in the world will cause concerns for scholars committed to solving. With the efforts of diligent researchers, it is bound to promote the development of medicine.

Gut microbiome improves postoperative cognitive function by decreasing permeability of the blood-brain barrier in aged mice

BackgroundIncreased permeability of blood-brain barrier (BBB) is a major pathophysiological mechanism of postoperative cognitive dysfunction (POCD) in the elderly. The reduced beneficial gut microbiome due to aging results in a decline in the production of sodium butyrate (NaB), which might enhance the BBB permeability. The present study investigated whether gut microbiome or NaB could improve the postoperative cognitive function in aged and gut dysbiosis mouse model. MethodsA total of 210 male C57BL/6 J mice were randomly and equally divided into 7 groups (young control, young anesthesia/surgery, young anesthesia/surgery + antibiotic, aged control, aged anesthesia/surgery, aged anesthesia/surgery + Lactobacillus, aged anesthesia/surgery + NaB). Lactobacillus mix and antibiotic mix were administered by oral gavage to establish the gut dysbiosis and microbiome restoration model. Splenectomy was performed under sevoflurane anesthesia. Spatial memory learning ability was measured by Y maze. BBB permeability was detected by FITC-dextran imaging and brain tissue dextran spectrum. Tight junction (TJ) protein of hippocampus brain tissue was quantitated by Western blot. ResultAging and antibiotic mix decreased the expression of the TJ, increased the BBB permeability and induced POCD, which could be reversed by the application of Lactobacillus and NaB. ConclusionLactobacillus and NaB increased the expression of TJ protein between endothelial cells (ECs), reduced the BBB permeability, and consequently protected the postoperative cognitive functions of the aged and gut dysbiosis mice.

Progress on the roles of glia in postoperative cognitive dysfunction

Postoperative cognitive dysfunction (POCD) is one of the most common complications after surgery under general anesthesia and usually manifests as newly presented cognitive impairment. However, the mechanism of POCD is still unclear. In addition to neurons, glial cells including microglia, astrocytes and oligodendrocytes, represent a large cell population in the nervous system. The bi-directional communication between neurons and glia provides basis for neural circuit function. Recent studies suggest that glial dysfunctions may contribute to the occurrence and progress of POCD. In this paper, we review the relevant work on POCD, which may provide new insights into the mechanism and therapeutic strategy for POCD.

Perioperative neurocognitive dysfunction: thinking from the gut?

With the aging of the world population, and improvements in medical and health technologies, there are increasing numbers of elderly patients undergoing anaesthesia and surgery. Perioperative neurocognitive dysfunction has gradually attracted increasing attention from academics. Very recently, 6 well-known journals jointly recommended that the term perioperative neurocognitive dysfunction (defined according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition) should be adopted to improve the quality and consistency of academic communications. Perioperative neurocognitive dysfunction currently includes preoperatively diagnosed cognitive decline, postoperative delirium, delayed neurocognitive recovery, and postoperative cognitive dysfunction. Increasing evidence shows that the gut microbiota plays a pivotal role in neuropsychiatric diseases, and in central nervous system functions via the microbiota-gut-brain axis. We recently reported that abnormalities in the composition of the gut microbiota might underlie the mechanisms of postoperative cognitive dysfunction and postoperative delirium, suggesting a critical role for the gut microbiota in perioperative neurocognitive dysfunction. This article therefore reviewed recent findings on the linkage between the gut microbiota and the underlying mechanisms of perioperative neurocognitive dysfunction.

The potential mechanism of postoperative cognitive dysfunction in older people.

Postoperative cognitive dysfunction (POCD) is a common disorder following surgery, which seriously threatens the quality of patients' life, especially the older people. Accumulating attention has been paid to POCD worldwide in pace with the popularization of anesthesia/surgery. The development of medical humanities and rehabilitation medicine sets higher demands on accurate diagnosis and safe treatment system of POCD. Although the research on POCD is in full swing, underlying pathogenesis is still inconclusive due to these conflicting results and controversial evidence. Generally, POCD is closely related to neuropsychiatric diseases such as dementia, depression and Alzheimer's disease in molecular pathways. Researchers have come up with various hypotheses to reveal the mechanisms of POCD, including neuroinflammation, oxidative stress, autophagy disorder, impaired synaptic function, lacking neurotrophic support, etc. Recent work focused on molecular mechanism of POCD in older people has been thoroughly reviewed and summed up here, concerning the changes of peripheral circulation, pathological pathways of central nervous system (CNS), the microbiota-gut-brain axis and the related brain regions. Accordingly, this article provides a better perspective to understand the development situation of POCD in older people, which is conductive to uncover the pathological mechanism and exploit reasonable treatment strategy of POCD.

Methane ameliorates post-operative cognitive dysfunction by inhibiting microglia NF-κB/MAPKs pathway and promoting IL-10 expression in aged mice

Postoperative cognitive dysfunction (POCD) is one of the most common complications after surgery. Accumulating evidence suggests that postoperative neuro-inflammation plays a critical role in the mechanism of POCD. Recently, exogenous methane is reported to have anti-inflammatory properties and play a neuro-protective role in acute carbon monoxide poisoning injury. Therefore, we investigated the protective effect of methane on a POCD model induced by abdominal surgery and its underlying mechanism in aged mice. Methane-rich saline (MS) or normal saline (NS) (16 ml/kg) was injected intraperitoneally 30 min after the abdominal surgery. The result showed that methane attenuated spatial memory loss in Morris water maze (MWM) with decreasing pro-inflammatory cytokines production and activation of microglia in hippocampus after surgery. Meanwhile, methane treatment suppressed lipopolysaccharide (LPS)-stimulated phosphorylation of MAPKs pathways and its downstream target TNF-α and IL-6 in BV2 cells. Moreover, methane increased expression of IL-10 in the hippocampus 24 h after surgery, and blockade of IL-10 repressed the protective effect of methane on the cognitive impairments observed in MWM test, decreased microglial activation and the pro-inflammatory cytokine in plasma and hippocampal. Blockade of IL-10 abrogated the suppression effect of methane on the pro-inflammatory cytokine production and phosphorylation of NF-κB and p38MAPK both in hippocampus and in BV2 cells. In conclusion, our study suggests exogenous methane could be a novel agent for the therapy of POCD through its anti-inflammation properties.

Postoperative Cognitive Dysfunction after Coronary Artery Bypass Grafting.

Postoperative cognitive dysfunction is a common complication following cardiac surgery. The incidence of cognitive dysfunction is more pronounced in patients receiving a cardiac operation than in those undergoing a non-cardiac operation. Clinical observations demonstrated that pulsatile flow was superior to nonpulsatile flow, and membrane oxygenator was superior to bubble oxygenator in terms of postoperative cognitive status. Nevertheless, cognitive assessments in patients receiving an on-pump and off-pump coronary artery bypass surgery have yielded inconsistent results. The exact mechanisms of postoperative cognitive dysfunction following coronary artery bypass grafting remain uncertain. The dual effects, neuroprotective and neurotoxic, of anesthetics should be thoroughly investigated. The diagnosis should be based on a comprehensive cognitive evaluation with neuropsychiatric tests, cerebral biomarker inspections, and electroencephalographic examination. The management strategies for cognitive dysfunction can be preventive or therapeutic. The preventive strategies of modifying surgical facilities and techniques can be effective for preventing the development of postoperative cognitive dysfunction. Investigational therapies may offer novel strategies of treatments. Anesthetic preconditioning might be helpful for the improvement of this dysfunction.

Role of hippocampal cannabinoid receptor 2 in postoperative cognitive dysfunction in mice

Objective To investigate the role of hippocampal cannabinoid receptor 2 (CB2R) in postoperative cognitive dysfunction (POCD) in mice. Methods Fifty-four healthy male C57BL/6 mice, aged 12-16 weeks, weighing 20-30 g, were divided into 3 groups (n=18 each) using a random number table: control group (group C), group POCD and POCD plus CB2R agonist JWH133 group (group POCD+ J). The mice were subjected to an intramedullary fixation for tibial fracture under 1.5% isoflurane anesthesia to establish POCD model.In group POCD+ J, 2 mg/kg JWH133 was injected intraperitoneally at a total volume of 10 ml/kg after emergence from anesthesia and then the injection was repeated once a day until the 7th day after surgery.Open field test was carried out on 1 day before surgery and 1, 3 and 7 days after surgery to evaluate the locomotor activity.Fear conditioning test was carried out at 15 min after completion of open field test.Mice were sacrificed at 2 h after the end of behavioral test, and the hippocampus was harvested for determination of the expression of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), monocyte chemotactic protein-1 (MCP-1) and CB2R (by Western blot) and expression of CD11b in hippocampal tissues (by immunofluorescence). Results There was no significant difference in the total exploring distance in open field test, percentage of freezing time in contextual fear conditioning test or percentage of freezing time in tone-fear conditioning text at each time point among the three groups (P>0.05). Compared with group C, the percentage of freezing time in contextual fear conditioning test was significantly decreased, and the expression of TNF-α, IL-1β, MCP-1, CD11b and CB2R was up-regulated after surgery in group S (P<0.05). Compared with group S, the percentage of freezing time in contextual fear conditioning test was significantly increased, and the expression of TNF-α, IL-1β, MCP-1, CD11b and CB2R was down-regulated after surgery in group S+ J (P<0.05). Conclusion Activation of hippocampal CB2R may be involved in the endogenous protective mechanism of POCD in mice, and the mechanism is related to inhibiting activation of hippocampal microglia and attenuating central inflammatory responses. Key words: Receptor, cannabinoid, CB2; Cognition disorders; Postoperative complications; Hippocampus

Determination of the Effects of Sevoflurane Anesthesia in Different Maturing Stages of the Mouse Hippocampus by Transcriptome Analysis

Purpose: Postoperative cognitive dysfunction (POCD) is a serious complication after general anesthesia. POCD is more likely to occur in elderly patients, but the mechanism of POCD has not been fully elucidated. We hypothesized that the difference of mRNA expression profile in the brain depending on the maturing stage causes the difference in the effect of sevoflurane anesthesia. We investigated the mRNA expression profile of hippocampal cells in young mice and in aged mice under sevoflurane anesthesia using transcriptome analysis. Methods: This study was conducted after approval from our institutional animal ethics committee, the Animal Research Center of Sapporo Medical University School of Medicine (project number: 12-033). Eight mice were assigned to two groups: a young group and an aged group. Each of the 4 mice in the two groups was anesthetized with 3.5% sevoflurane for 1 hour. Subsequently, mRNA was isolated from hippocampal cells and RNA sequencing was performed on an Illumina HiSeq 2500 platform. Mapping of the quality-controlled, filter paired-end reads to mouse genomes and quantification of the expression level of each gene were performed using R software. Results: The Lhx9 gene, which is thought to be associated with neuronal inflammation, was the most highly upregulated gene in aged mice. The Epyc gene, which encodes a protein related to the phospholipase-C pathway and ERK signaling, was the most down-regulated gene in aged mice. Conclusions: The findings suggest that sevoflurane anesthesia induces neuronal inflammation via a LIMhomeodomain family related gene in aged mice and causes POCD.

Deferoxamine pre-treatment protects against postoperative cognitive dysfunction of aged rats by depressing microglial activation via ameliorating iron accumulation in hippocampus

Postoperative cognitive dysfunction (POCD) is a common complication of elderly patients after surgery. The mechanisms of POCD have not been clarified. Iron accumulation is a feature of neurodegeneration. Recent reports showed that iron content was increased with impaired cognition induced by surgery. We sought to investigate whether iron chelation would attenuate POCD. In this study, male aged (18 months) Sprague-Dawley rats received 100 mg/kg deferoxamine or saline solution (0.9%) for 6 days before exploratory laparotomy. Cognition was evaluated by Morris water maze before and after surgery. Additional rats received deferoxamine or saline were used to determine hippocampal iron content, iron transport-related proteins (transferrin receptor, divalent metal transporter 1, ferroportin 1 and hepcidin), oxidative stress, microglial activation and brain cell apoptosis. It was found that deferoxamine improved postoperative spatial memory in aged rats. Deferoxamine significantly reduced hippocampal iron concentration and ferritin. Surgery increased divalent metal transporter 1 and hepcidin, decreased transferrin receptor and ferroportin 1, and enhanced ferroportin 1 mRNA. However, deferoxamine reversed the changes of these proteins. Furthermore, deferoxamine sharply reduced the hippocampal reactive oxygen species, malondialdehyde concentration and OX-42 that is a marker of microglia, which might reduce postoperative brain cell apoptosis. This study showed that deferoxamine may improve postoperative cognition of aged rats by ameliorating oxidative stress induced by hippocampal iron accumulation, microglial activation and brain cell apoptosis. This study suggests a potential therapeutic method for reducing POCD.