Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.To evaluate and, as needed, update definitions for sepsis and septic shock.A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment).Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant.Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less.These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.

Prediction modelling can greatly assist the health-care professionals in the management of diseases, thus sparking interest in neonatal sepsis diagnosis. The main objective of the study was to provide a complete picture of performance of prediction models for early detection of neonatal sepsis.PubMed, Scopus, CINAHL databases were searched and articles which used various prediction modelling measures for the early detection of neonatal sepsis were comprehended. Data extraction was carried out based on Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies checklist. Extricate data consisted of objective, study design, patient characteristics, type of statistical model, predictors, outcome, sample size and location. Prediction model Risk of Bias Assessment Tool was applied to gauge the risk of bias of the articles.An aggregate of ten studies were included in the review among which eight studies had applied logistic regression to build a prediction model, while the remaining two had applied artificial intelligence. Potential predictors like neonatal fever, birth weight, foetal morbidity and gender, cervicovaginitis and maternal age were identified for the early detection of neonatal sepsis. Moreover, birth weight, endotracheal intubation, thyroid hypofunction and umbilical venous catheter were promising factors for predicting late-onset sepsis; while gestational age, intrapartum temperature and antibiotics treatment were utilised as budding prognosticators for early-onset sepsis detection.Prediction modelling approaches were able to recognise promising maternal, neonatal and laboratory predictors in the rapid detection of early and late neonatal sepsis and thus, can be considered as a novel way for clinician decision-making towards the disease diagnosis if not used alone, in the years to come.© 2022. The Author(s).

Sepsis is a major cause of death in intensive care units worldwide. The acute phase of sepsis is often accompanied by sepsis-associated encephalopathy, which is highly associated with increased mortality. Moreover, in the chronic phase, more than 50% of surviving patients suffer from severe and long-term cognitive deficits compromising their daily quality of life and placing an immense burden on primary caregivers. Due to a growing number of sepsis survivors, these long-lasting deficits are increasingly relevant. Despite the high incidence and clinical relevance, the pathomechanisms of acute and chronic stages in sepsis-associated encephalopathy are only incompletely understood, and no specific therapeutic options are yet available. Here, we review the emergence of sepsis-associated encephalopathy from initial clinical presentation to long-term cognitive impairment in sepsis survivors and summarize pathomechanisms potentially contributing to the development of sepsis-associated encephalopathy.

To estimate the economic impact of delirium in the Australian population in 2016–2017, including financial costs, and its burden on health.

Sepsis is a serious medical condition characterized by dysregulated systemic inflammatory responses followed by immunosuppression. To study the pathophysiology of sepsis, diverse animal models have been developed. Polymicrobial sepsis induced by cecal ligation and puncture (CLP) is the most frequently used model because it closely resembles the progression and characteristics of human sepsis. Here we summarize the role of several immune components in the pathogenesis of sepsis induced by CLP. However, several therapies proposed on the basis of promising results obtained by CLP could not be translated to the clinic. This demonstrates that experimental sepsis models do not completely mimic human sepsis. We propose several strategies to narrow the gap between experimental sepsis models and clinical sepsis, including targeting factors that contribute to the immunosuppressive phase of sepsis, and reproducing the heterogeneity of human patients.Copyright © 2011 Elsevier Ltd. All rights reserved.

Sepsis remains a prevalent clinical challenge and the underlying pathophysiology is still poorly understood. To investigate the complex molecular mechanisms of sepsis, various animal models have been developed, the most frequently used being the cecal ligation and puncture (CLP) model in rodents. In this model, sepsis originates from a polymicrobial infectious focus within the abdominal cavity, followed by bacterial translocation into the blood compartment, which then triggers a systemic inflammatory response. A requirement of this model is that it is performed with high consistency to obtain reproducible results. Evidence is now emerging that the accompanying inflammatory response varies with the severity grade of sepsis, which is highly dependent on the extent of cecal ligation. In this protocol, we define standardized procedures for inducing sepsis in mice and rats by applying defined severity grades of sepsis through modulation of the position of cecal ligation. The CLP procedure can be performed in as little as 10 min for each animal by an experienced user, with additional time required for subsequent postoperative care and data collection.

Cognitive dysfunction caused by sepsis-associated encephalopathy (SAE) is still poorly understood. It is reported that vasoactive intestinal peptide (VIP) exerts its anti-inflammatory effects in multiple diseases, while its biological function in SAE remains unclear. We aimed to figure out whether VIP has influence on sepsis-induced neuroinflammation and cognitive dysfunction. To induce sepsis, rats were subjected to cecal ligation and puncture (CLP) operation. Morris water maze test and fear conditioning test were conducted to reveal cognitive dysfunctions. TUNEL assay was performed to evaluate apoptosis. We found out that the expression of VIP was downregulated in the hippocampus of septic rats. VIP was verified to attenuate sepsis-induced memory impairment following CLP. Additionally, we examined apoptosis and inflammation in rats' hippocampus. It is worth noting that VIP inhibited the apoptosis in the hippocampus and reduced the productions of proinflammatory cytokines TNF-α, IL-6 and IL-1β. Furthermore, our data confirmed that VIP was involved in regulating the TLR-4/NF-κB signaling. In conclusion, VIP inhibited neuroinflammation and cognitive impairment in hippocampus of septic rats through the TLR-4/NF-κB signaling pathway.© 2022. The Author(s), under exclusive licence to Springer Nature B.V.

Pre-clinical animal studies precede the majority of clinical trials. While the clinical sepsis definitions and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking. To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling was held in Vienna in May, 2017. The conference goal was to identify limitations of pre-clinical sepsis models and to propose a set of guidelines, defined as the "Minimum Quality Threshold in Pre-Clinical Sepsis Studies" (MQTiPSS), to enhance translational value of these models.31 experts from 13 countries participated and were divided into 6 thematic Working Groups (WG): (1) Study Design, (2) Humane modeling, (3) Infection types, (4) Organ failure/dysfunction, (5) Fluid resuscitation and (6) Antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002-2013).Overall, the participants reached consensus on 29 points; 20 at "recommendation" (R) and 9 at "consideration" (C) strength. This Executive Summary provides a synopsis of the MQTiPSS consensus (Tables 1, 2 and 3).We believe that these recommendations and considerations will serve to bring a level of standardization to pre-clinical models of sepsis and ultimately improve translation of pre-clinical findings. These guideline points are proposed as "best practices" that should be implemented for animal sepsis models. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection and Intensive Care Medicine Experimental.

With animal models, death as an intentional end point is ethically unacceptable. However, in the study of septic shock, death is still considered the only relevant end point. We defined eight humane end points into four stages of severity (from healthy to moribund) and used to design a clinically relevant scoring tool, termed "the mouse clinical assessment score for sepsis" (M-CASS). The M-CASS was used to enable a consistent approach to the assessment of disease severity. This allowed an ethical and objective assessment of disease after which euthanasia was performed, instead of worsening suffering. The M-CASS displayed a high internal consistency (Cronbach α = 0.97) with a high level of agreement and an intraclass correlation coefficient equal to 0.91. The plasma levels of cytokines and markers of oxidative stress were all associated with the M-CASS score (Kruskal-Wallis test, P < 0.05). The M-CASS allows tracking of disease progression and animal welfare requirements.

The lack of a reliable scoring system that predicts the development of septic shock and death precludes comparison of disease and/or treatment outcomes in animal models of sepsis. We developed a murine sepsis score (MSS) that evaluates seven clinical variables, and sought to assess its validity and reliability in an experimental mouse model of polymicrobial sepsis.Stool collected from the cecum of C57BL/6 (B6) mice was dissolved in 0.9% normal saline (NS) and filtered, resulting in a fecal solution (FS) which was injected intraperitoneally into B6 mice. Disease severity was monitored by MSS during the experimental timeline. Blood and tissue samples were harvested for the evaluation of inflammatory changes after sepsis induction. The correlation between pro-inflammatory markers and MSS was assessed by the Spearman rank correlation coefficient.Mice injected with FS at a concentration of 90 mg/mL developed polymicrobial sepsis with a 75% mortality rate at 24 hours. The MSS was highly predictive of sepsis progression and mortality, with excellent discriminatory power, high internal consistency (Cronbach alpha coefficient = 0.92), and excellent inter-rater reliability (intra-class coefficient = 0.96). An MSS of 3 had a specificity of 100% for predicting onset of septic shock and death within 24 hours. Hepatic dysfunction and systemic pro-inflammatory responses were confirmed by biochemical and cytokine analyses where the latter correlated well with the MSS. Significant bacterial dissemination was noted in multiple organs. Furthermore, the liver, spleen, and intestine demonstrated histopathological evidence of injury.The MSS reliably predicts disease progression and mortality in an animal model of polymicrobial sepsis. More importantly, it may be used to assess and compare outcomes among various experimental models of sepsis, and serve as an ethically acceptable alternative to death as an endpoint.

This protocol details a method for using a T-maze to assess the cognitive ability of rodents. The T-maze is an elevated or enclosed apparatus in the form of a T placed horizontally. Animals are started from the base of the T and allowed to choose one of the goal arms abutting the other end of the stem. If two trials are given in quick succession, on the second trial the rodent tends to choose the arm not visited before, reflecting memory of the first choice. This is called 'spontaneous alternation'. This tendency can be reinforced by making the animal hungry and rewarding it with a preferred food if it alternates. Both spontaneous and rewarded alternation are very sensitive to dysfunction of the hippocampus, but other brain structures are also involved. Each trial should be completed in under 2 min, but the total number of trials required will vary according to statistical and scientific requirements.

Collective behaviors are observed throughout nature, from bacterial colonies to human societies. Important theoretical breakthroughs have recently been made in understanding why animals produce group behaviors and how they coordinate their activities, build collective structures, and make decisions. However, standardized experimental methods to test these findings have been lacking. Notably, easily and unambiguously determining the membership of a group and the responses of an individual within that group is still a challenge. The radial arm maze is presented here as a new standardized method to investigate collective exploration and decision-making in animal groups. This paradigm gives individuals within animal groups the opportunity to make choices among a set of discrete alternatives, and these choices can easily be tracked over long periods of time. We demonstrate the usefulness of this paradigm by performing a set of refuge-site selection experiments with groups of fish. Using an open-source, robust custom image-processing algorithm, we automatically counted the number of animals in each arm of the maze to identify the majority choice. We also propose a new index to quantify the degree of group cohesion in this context. The radial arm maze paradigm provides an easy way to categorize and quantify the choices made by animals. It makes it possible to readily apply the traditional uses of the radial arm maze with single animals to the study of animal groups. Moreover, it opens up the possibility of studying questions specifically related to collective behaviors.

Fear memory is the best-studied form of memory. It was thoroughly investigated in the past 60 years mostly using two classical conditioning procedures (contextual fear conditioning and fear conditioning to a tone) and one instrumental procedure (one-trial inhibitory avoidance). Fear memory is formed in the hippocampus (contextual conditioning and inhibitory avoidance), in the basolateral amygdala (inhibitory avoidance), and in the lateral amygdala (conditioning to a tone). The circuitry involves, in addition, the pre- and infralimbic ventromedial prefrontal cortex, the central amygdala subnuclei, and the dentate gyrus. Fear learning models, notably inhibitory avoidance, have also been very useful for the analysis of the biochemical mechanisms of memory consolidation as a whole. These studies have capitalized on in vitro observations on long-term potentiation and other kinds of plasticity. The effect of a very large number of drugs on fear learning has been intensively studied, often as a prelude to the investigation of effects on anxiety. The extinction of fear learning involves to an extent a reversal of the flow of information in the mentioned structures and is used in the therapy of posttraumatic stress disorder and fear memories in general. Copyright © 2016 the American Physiological Society.

For several decades, one-trial inhibitory avoidance (IA) tasks have been used in the study of memory processing. In the present work, the effects of diazepam (DZP) (0.5mg/kg) and picrotoxin (PIC) (0.3mg/kg) on memory retrieval were assessed using two variants of a step-through IA situation in CF-1 mice. In the first variant, animals get into a dark compartment from an open illuminated platform (platform), whereas in the other, from an enclosed illuminated one (box). PIC impaired retention performance in the "platform-type" IA, but not in the "box-type". DZP enhanced retention performance in both types of IA task. These results evidence critical differences between the two step-through inhibitory avoidance tasks used, that might be relevant not only for retention performance during memory retrieval, but also for the theoretical interpretations and conclusions obtained from behavioral results.

Sepsis is a potentially fatal disease characterized by acute organ failure that affects more than 30 million people worldwide. Inflammation is strongly associated with sepsis, and patients can experience impairments in memory, concentration, verbal fluency, and executive functioning after being discharged from the hospital. We hypothesize that sepsis disrupts the microbiota–gut–brain axis homeostasis triggering cognitive impairment. This immune activation persists during treatment, causing neurological dysfunction in sepsis survivors.

Sepsis is a life-threatening clinical condition caused by a dysregulated host response to infection. Sepsis-associated encephalopathy (SAE) is a common but poorly understood neurological complication of sepsis, which is associated with increased morbidity and mortality. SAE clinical presentation may range from mild confusion and delirium to severe cognitive impairment and deep coma. Important mechanisms associated with SAE include excessive microglial activation, impaired endothelial barrier function, and blood-brain barrier (BBB) dysfunction. Endotoxemia and pro-inflammatory cytokines produced systemically during sepsis lead to microglial and brain endothelial cell activation, tight junction downregulation, and increased leukocyte recruitment. The resulting neuroinflammation and BBB dysfunction exacerbate SAE pathology and aggravate sepsis-induced brain dysfunction. In this mini-review, recent literature surrounding some of the mediators of BBB dysfunction during sepsis is summarized. Modulation of microglial activation, endothelial cell dysfunction, and the consequent prevention of BBB permeability represent relevant therapeutic targets that may significantly impact SAE outcomes.© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Microglial polarization in response to brain inflammatory conditions is a crescent field in neuroscience. However, the effect of systemic inflammation, and specifically sepsis, is a relatively unexplored field that has great interest and relevance. Sepsis has been associated with both early and late harmful events of the central nervous system, suggesting that there is a close link between sepsis and neuroinflammation. During sepsis evolution it is supposed that microglial could exert both neurotoxic and repairing effects depending on the specific microglial phenotype assumed. In this context, here it was reviewed the role of microglial polarization during sepsis-associated brain dysfunction.Copyright © 2017 Elsevier B.V. All rights reserved.

Early diagnosis of sepsis-associated encephalopathy (SAE) is essential for the treatment and prognosis of septic patients. Static PET and MRI have shown promise for early diagnosis, while pharmacokinetic parameters from dynamic PET may provide better quantification for SAE. This study aims to compare the performance of dynamic 2-deoxy-2-[F]fluoro-D-glucose ([F]F-FDG) PET and multiparametric MRI in early imaging SAE with a view to providing guidance for the early diagnosis of SAE.Dynamic [F]F-FDG-PET/CT scans and multiparametric MRI were performed in SAE mice induced by LPS. Standardized uptake value (SUV) was measured in static scan images and [F]F-FDG pharmacokinetic parameters were analyzed with two-tissue compartment model and Patlak plot. MRI relative signal intensity (rT1) derived from T1-weighted images (pre and post contrast) and 4 parameters originating from diffusion-weighted data were measured.Both SUV and dephosphorylation rate constant (k) increased in SAE model as early as 6 h post sepsis induction, while k increased with the relative value (SAE/normal) significantly stronger than that of SUV. Moreover, the net influx constant (K) showed significant decrease in SAE as early as 6 h compared with normal mice. Increased signal intensity was identified in T1-weighted contrast enhanced images and rT1 value increased at 12 h post induction. Diffusion tensor imaging (DTI) revealed fractional anisotropy (FA) decreased at 12 h and 24 h in external capsule (ec) and declined axial diffusivity (AD) was shown in white matter at 24 h.The dynamic PET (k) was more sensitive than static PET (SUV) for early diagnosis of SAE and declined K was firstly found in murine SAE, which indicated the advantage of dynamic PET/CT in early detection and differential diagnosis of SAE. While MRI has a higher soft tissue resolution than PET/CT and can classify more subtle brain areas, the comprehensive utilization of the two modalities is helpful for managing SAE.© 2022. World Molecular Imaging Society.

The purpose of this study was to evaluate a set of widely used nuclear medicine imaging agents as possible methods to study the early effects of systemic inflammation on the living brain in a mouse model of sepsis-associated encephalopathy (SAE). The lipopolysaccharide (LPS)-induced murine systemic inflammation model was selected as a model of SAE.C57BL/6 mice were used. A multimodal imaging protocol was carried out on each animal 4 h following the intravenous administration of LPS using the following tracers: [Tc][2,2-dimethyl-3-[(3E)-3-oxidoiminobutan-2-yl]azanidylpropyl]-[(3E)-3-hydroxyiminobutan-2-yl]azanide ([Tc]HMPAO) and ethyl-7-[I]iodo-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate ([I]iomazenil) to measure brain perfusion and neuronal damage, respectively; 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) to measure cerebral glucose uptake. We assessed microglia activity on another group of mice using 2-[6-chloro-2-(4-[I]iodophenyl)-imidazo[1,2-a]pyridin-3-yl]-N-ethyl-N-methyl-acetamide ([I]CLINME). Radiotracer uptakes were measured in different brain regions and correlated. Microglia activity was also assessed using immunohistochemistry. Brain glutathione levels were measured to investigate oxidative stress.Significantly reduced perfusion values and significantly enhanced [F]FDG and [I]CLINME uptake was measured in the LPS-treated group. Following perfusion compensation, enhanced [I]iomazenil uptake was measured in the LPS-treated group's hippocampus and cerebellum. In this group, both [F]FDG and [I]iomazenil uptake showed highly negative correlation to perfusion measured with ([Tc]HMPAO uptake in all brain regions. No significant differences were detected in brain glutathione levels between the groups. The CD45 and P2Y12 double-labeling immunohistochemistry showed widespread microglia activation in the LPS-treated group.Our results suggest that [I]CLINME and [Tc]HMPAO SPECT can be used to detect microglia activation and brain hypoperfusion, respectively, in the early phase (4 h post injection) of systemic inflammation. We suspect that the enhancement of [F]FDG and [I]iomazenil uptake in the LPS-treated group does not necessarily reflect neural hypermetabolism and the lack of neuronal damage. They are most likely caused by processes emerging during neuroinflammation, e.g., microglia activation and/or immune cell infiltration.

Sepsis and its complications are the leading causes of mortality in intensive care units, accounting for 10-50% of deaths. Intensive care unit survivors present long-term cognitive impairment, including alterations in memory, attention, concentration, and/or global loss of cognitive function. In the present study, we investigated behavioral alterations in sepsis-surviving rats. One hundred and ten male Wistar rats (3-4 months, 250-300 g) were submitted to cecal ligation and puncture (CLP), and 44 were submitted to sham operation. Forty-four rats (40%) survived after CLP, and all sham-operated animals survived and were used as control. Twenty animals of each group were used in the object recognition task (10 in short-term memory and 10 in long-term memory), 12 in the plus-maze test and 12 in the forced swimming test. Ten days after surgery, the animals were submitted individually to an object recognition task, plus-maze and forced swimming tests. A significant impairment of short- and long-term recognition memory was observed in the sepsis group (recognition index 0.75 vs 0.55 and 0.74 vs 0.51 for short- and long-term memory, respectively (P < 0.05). In the elevated plus-maze test no difference was observed between groups in any of the parameters assessed. In addition, sepsis survivors presented an increase in immobility time in the forced swimming test (180 vs 233 s, P < 0.05), suggesting the presence of depressive-like symptoms in these animals after recovery from sepsis. The present results demonstrated that rats surviving exposure to CLP, a classical sepsis model, presented recognition memory impairment and depressive-like symptoms but not anxiety-like behavior.

Background: We aim to demonstrate behavioral alterations in a sepsis model using intravenous (IV) immunoglobulin G (IgG) and immunoglobulins enriched with IgA and IgM (IgGAM). Methods: We divided 48 Wistar albino rats into five groups: control group, sham-operated group (only antibiotic treatment), cecal ligation and puncture (CLP) group (CLP plus antibiotic treatment), IgG group (250 mg/kg IV IgG) and IgGAM group (250 mg/kg IV IgGAM). Intravenous immunoglobulins were given 5 min after the CLP procedure. Experimental animals put into three behavioral tasks 10, 30 and 60 days after the surgery; to evaluate the locomotor activity, an open field test was performed, elevated plus maze test was used to measure anxiety levels, and depressive state was assessed by forced swimming test. The effects of therapy which were acquired from the results of these tests were used to estimate the behavioral changes after CLP. Results: The mortality rate of 50% in the septic rats decreased to 30 and 20% with the administration of IgG and IgGAM, respectively. Significant changes on locomotor activity and depressive-like behavior were reported in the sepsis group; on the other hand, the treatment with immunoglobulins reduced the symptoms. Treatment with immunoglobulins attenuated the sepsis-related anxiogenic-like responses. Behavioral alterations returned to normal on day 60 in all groups. Conclusions: Sepsis caused deterioration on behavioral parameters. Immunoglobulin treatments alleviated the symptoms of functional disturbances and caused early reversal of behavioral deficits in septic animals.

Activation of microglia and mitochondrial dysfunction are two major contributors to the pathogenesis of sepsis-associated brain dysfunction. Mitochondrial dysfunction can alter the immunological profile of microglia favoring to a pro-inflammatory phenotype. Mitochondrial transplantation, as an emerging mitochondria-targeted therapy, possesses considerable therapeutic potential in various central nervous system injuries or diseases. However, the effects of mitochondrial transplantation on microglial polarization and neuroprotection after sepsis remain unclear. In this study, lipopolysaccharide (LPS)/interferon-γ (IFN-γ) and interleukin-4 (IL-4)/interleukin-13 (IL-13) were used to induce different phenotypes of BV2 microglial cells. We observed that mitochondrial content and function were enhanced in IL-4-/IL-13-stimulated microglia. In vitro, mitochondria treatment conferred neuroprotection by enhancing microglial polarization from the M1 phenotype to the M2 phenotype and suppressing microglial-derived inflammatory cytokine release. Furthermore, microglial phenotypes and behavior tests were assessed after mice were subjected to sepsis by cecal ligation and puncture (CLP) followed by intracerebroventricular injection of exogenous functional mitochondria. We found that mitochondrial transplantation induced microglial M2 rather than M1 response 24 h after sepsis. Mitochondrial transplantation improved behavioral deficits by increasing the latency time in inhibitory avoidance test and decreasing the number of crossing and rearing in the test session of open field test 10 days after CLP onset. These findings indicate that mitochondrial transplantation promotes the phenotypic conversion of microglia and improves cognitive impairment in sepsis survivors, supporting the potential use of exogenous mitochondrial transplantation therapy that may be a potential therapeutic opportunity for sepsis-associated brain dysfunction.

Sepsis survivors present long-term cognitive deficits. The present study was to investigate the effect of early administration of high-dose vitamin C on cognitive function in septic rats and explore its possible cerebral protective mechanism. Rat sepsis models were established by cecal ligation and puncture (CLP). Ten days after surgery, the Morris water maze test was performed to evaluate the behavior and cognitive function. Histopathologic changes in the hippocampus were evaluated by nissl staining. The inflammatory cytokines, activities of antioxidant enzymes (superoxide dismutase or SOD) and oxidative products (malondialdehyde or MDA) in the serum and hippocampus were tested 24 h after surgery. The activity of matrix metalloproteinase-9 (MMP-9) and expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) in the hippocampus were measured 24 h after surgery. Compared with the sham group in the Morris water maze test, the escape latency of sepsis rats was significantly (P = 0.001) prolonged in the navigation test, whereas the frequency to cross the platform and the time spent in the target quadrant were significantly (P = 0.003) reduced. High-dose vitamin C significantly decreased the escape latency (P = 0.01), but increased the time spent in the target quadrant (P = 0.04) and the frequency to cross the platform (P = 0.19). In the CLP+ saline group, the pyramidal neurons were reduced and distributed sparsely and disorderly, the levels of inflammatory cytokines of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 in the serum and hippocampus were significantly increased (P = 0.000), the blood brain barrier (BBB) permeability in the hippocampus was significantly (P = 0.000) increased, the activities of SOD in the serum and hippocampus were significantly (P = 0.000 and P = 0.03, respectively) diminished while the levels of MDA in the serum and hippocampus were significantly (P = 0.007) increased. High-dose vitamin C mitigated hippocampus histopathologic changes, reduced systemic inflammation and neuroinflammation, attenuated BBB disruption, inhibited oxidative stress in brain tissue, and up-regulated the expression of nuclear and total Nrf2 and HO-1. High-dose vitamin C significantly (P < 0.05) decreased the levels of tumor necrosis factor- (TNF)-α, interleukin-6 (IL-6), MDA in the serum and hippocampus, and the activity of MMP-9 in the hippocampus, but significantly (P < 0.05) increased the levels of SOD, the anti-inflammatory cytokine (IL-10) in the serum and hippocampus, and nuclear and total Nrf2, and HO-1 in the hippocampus. In conclusion, high-dose vitamin C can improve cognition impairment in septic rats, and the possible protective mechanism may be related to inhibition of inflammatory factors, alleviation of oxidative stress, and activation of the Nrf2/HO-1 pathway.© 2021. The Author(s).

Sepsis-associated encephalopathy (SAE) increases not only morbidity and mortality but has been associated with long-lasting mental impairment after hospital discharge in septic patients. Recently, studies have shown that these mental impairments are caused by infection-induced neuroinflammation. However, the role of T cells in the pathogenesis of SAE and mental impairments remains unclear. Thus, in this study, we aimed to clarify how immune cells, especially T cells, influence the development and recovery of these disorders. In the cecal slurry (CS)-induced septic mouse model, we performed three different kinds of behavioral tests, open-field test, marble burying test, and forced swimming test, and observed anxiety-like behavior in septic mice. Additionally, increased interleukin (IL)-1β and IL-6 expression levels, and infiltration of neutrophils and T cells were examined in the brain of septic mice, 10 days after sepsis onset. Twenty days after sepsis onset, the septic mice could recover the number of astrocytes. At day 30, expression levels of IL-1β and tumor necrosis factor (TNF)-α returned to normal levels in the cerebral cortex of septic mice. Interestingly, resolution of neuroinflammation and alleviation of depression were delayed in septic mice treated with FTY720, which inhibits sphingosine-1-phosphate (S1P)-dependent lymphocyte egress from lymph nodes. On analyzing the brain T cells with or without FTY720 in septic mice, the FTY720 untreated mice presented increased regulatory T cells (Treg) and Th2 cells in the brain, whereas the FTY720 treated mice demonstrated increased Th17 in the brain at day 30. Furthermore, in FTY720 treated septic mice, the number of astrocytes in the cerebral cortex remained reduced at day 30. These results suggest that infiltrated Treg and Th2 cells contribute to the attenuation SAE and alleviate SAE-induce mental disorder by resolving neuroinflammation in the chronic phase of sepsis.Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.