Sepsis-associated Encephalopathy Research Articles

Inflammasomes in neurological disorders - mechanisms and therapeutic potential.

Inflammasomes are molecular scaffolds that are activated by damage-associated and pathogen-associated molecular patterns and form a key element of innate immune responses. Consequently, the involvement of inflammasomes in several diseases that are characterized by inflammatory processes, such as multiple sclerosis, is widely appreciated. However, many other neurological conditions, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, stroke, epilepsy, traumatic brain injury, sepsis-associated encephalopathy and neurological sequelae of COVID-19, all involve persistent inflammation in the brain, and increasing evidence suggests that inflammasome activation contributes to disease progression in these conditions. Understanding the biology and mechanisms of inflammasome activation is, therefore, crucial for the development of inflammasome-targeted therapies for neurological conditions. In this Review, we present the current evidence for and understanding of inflammasome activation in neurological diseases and discuss current and potential interventional strategies that target inflammasome activation to mitigate its pathological consequences.

A simple nomogram for predicting the mortality of PICU patients with sepsis-associated encephalopathy: a multicenter retrospective study.

As one of the serious complications of sepsis in children, sepsis-associated encephalopathy (SAE) is associated with significantly poor prognosis and increased mortality. However, predictors of outcomes for pediatric SAE patients have yet to be identified. The aim of this study was to develop nomograms to predict the 14-day and 90-day mortality of children with SAE, providing early warning to take effective measures to improve prognosis and reduce mortality. In this multicenter, retrospective study, we screened 291 patients with SAE admitted to the PICU between January 2017 and September 2022 in Shandong Province. A least absolute shrinkage and selector operation (LASSO) method was used to identify the optimal prognostic factors predicting the outcomes in pediatric patients with SAE. Then, multivariable logistic regression analysis was performed based on these variables, and two nomograms were built for visualization. We used the area under the curve (AUC), calibration curves and decision curves to test the accuracy and discrimination of the nomograms in predicting outcomes. There were 129 patients with SAE in the training cohort, and there were 103 and 59 patients in the two independent validation cohorts, respectively. Vasopressor use, procalcitonin (PCT), lactate and pediatric critical illness score (PCIS) were independent predictive factors for 14-day mortality, and vasopressor use, PCT, lactate, PCIS and albumin were independent predictive factors for 90-day mortality. Based on the variables, we generated two nomograms for the early identification of 14-day mortality (AUC 0.853, 95% CI 0.787-0.919, sensitivity 72.4%, specificity 84.5%) and 90-day mortality (AUC 0.857, 95% CI 0.792-0.923, sensitivity 72.3%, specificity 90.6%), respectively. The calibration plots for nomograms showed excellent agreement of mortality probabilities between the observed and predicted values in both training and validation cohorts. Decision curve analyses (DCA) indicated that nomograms conferred high clinical net benefit. The nomograms in this study revealed optimal prognostic factors for the mortality of pediatric patients with SAE, and individualized quantitative risk evaluation by the models would be practical for treatment management.

Prognostic values of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and neuron-specific enolase in patients with sepsis-associated encephalopathy

Background/Aim. Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, characterized by brain dysfunction and associated with a poor prognosis. SAE has a complex pathogenesis, and its severity is in close association with the levels of various serum factors. The aim of the study was to investigate the correlation of tumor necrosis factor (TNF)-?, monocyte chemoattractant protein (MCP)-1, and neuron-specific enolase (NSE) levels with the severity of SAE and to analyze the prognostic values of the three parameters. Methods. This prospective study enrolled 126 patients treated for SAE from June 2020 to June 2022. The levels of TNF-?, MCP-1, and NSE were measured, and the severity of SAE was evaluated using the Sequential Organ Failure Assessment (SOFA) score. Based on the SOFA score, the patients were assigned to two groups: a group with a bad prognosis and a group with a good prognosis. The correlations of TNF-?, MCP-1, and NSE levels with the severity of SAE were analyzed, and their prognostic values were evaluated during a 28-day follow-up. Results. The mean levels of TNF-?, MCP-1, and NSE and the SOFA score of the 126 patients with SAE were 6.52 ? 1.48 pg/mL, 62.53 ? 18.49 pg/mL, 8.61 ? 2.17 ng/mL, and 10.24 ? 2.86 points, respectively. Pearson?s analysis demonstrated significant correlations be-tween TNF-?, MCP-1, and NSE levels and the SOFA score of patients with SAE (r > 0, p < 0.05). Of the 126 patients, 61 (48.4%) had a poor prognosis, while 65 (51.6%) had a good prognosis. Increased serum TNF-?, MCP-1, and NSE levels were risk factors for the poor prognosis of patients with SAE [odds ratio (OR) > 1, p < 0.05]. The areas under the receiver operating characteristic (ROC) curves of serum TNF-?, MCP-1, and NSE levels were all > 0.7, suggesting high predictive values of these parameters. Conclusion. Serum TNF-?, MCP-1, and NSE levels are closely correlated with the severity of SAE and may work as valuable predictors of treatment outcome.

Dynamic A-to-I RNA editing during acute neuroinflammation in sepsis-associated encephalopathy.

The activation of cerebral endothelial cells (CECs) has recently been reported to be the earliest acute neuroinflammation event in the CNS during sepsis-associated encephalopathy (SAE). Importantly, adenosine-to-inosine (A-to-I) RNA editing mediated by ADARs has been associated with SAE, yet its role in acute neuroinflammation in SAE remains unclear. Our current study systematically analyzed A-to-I RNA editing in cerebral vessels, cerebral endothelial cells (CECs), and microglia sampled during acute neuroinflammation after treatment in a lipopolysaccharide (LPS)-induced SAE mouse model. Our results showed dynamic A-to-I RNA editing activity changes in cerebral vessels during acute neuroinflammation. Differential A-to-I RNA editing (DRE) associated with acute neuroinflammation were identified in these tissue or cells, especially missense editing events such as S367G in antizyme inhibitor 1 (Azin1) and editing events in lincRNAs such as maternally expressed gene 3 (Meg3), AW112010, and macrophage M2 polarization regulator (Mm2pr). Importantly, geranylgeranyl diphosphate synthase 1 (Ggps1) and another three genes were differentially edited across cerebral vessels, CECs, and microglia. Notably, Spearman correlation analysis also revealed dramatic time-dependent DRE during acute neuroinflammation, especially in GTP cyclohydrolase1 (Gch1) and non-coding RNA activated by DNA damage (Norad), both with the editing level positively correlated with both post-LPS treatment time and edited gene expression in cerebral vessels and CECs. The findings in our current study demonstrate substantial A-to-I RNA editing changes during acute neuroinflammation in SAE, underlining its potential role in the disease.

Treatment of a teenager with fall from height and high-voltage electrical injury complicated by sepsis-associated encephalopathy

Treatment of a teenager with fall from height and high-voltage electrical injury complicated by sepsis-associated encephalopathy

Acute Encephalopathies in SARS-CoV-2 Infection: A Clinical and Neuroimaging Perspective.

Neurological manifestations are frequent in patients with SARS-CoV-2 infection and can be correlated with different pathogenic mechanisms which can be divided into two categories: direct invasion of the central nervous system by the virus and indirect effects deriving from the severity of the systemic infection and by the inflammatory response correlated with cytokine storm. Among the neurological manifestations, acute encephalopathy is very frequent and its nomenclature has recently been updated. The occurrence of a condition of altered mental status, reduced consciousness, delirium up to coma represents an element associated with a greater severity of the infection and mortality both in an Intensive Care Unit setting and in an Emergency Department setting. The tissue damage mechanisms found in COVID-19 patients' encephalopathy and neuroimaging patterns, as well as histopathology, are similar to those described in sepsis-associated encephalopathy, further confirming the role of indirect mechanisms, with no CNS invasion by the virus. The available data have some limitations, notably the underuse of diagnostic neuroimaging techniques in severely affected patients, particularly in the first wave of the pandemic.

Status Epilepticus Following Labor in a Remote Area: A Case Report of Puerperal Sepsis

Background: Puerperal sepsis is one of the five leading causes of maternal mortality worldwide, commonly occurs in low to middle income countries. Higher incidence is observed in rural areas where diagnostic and therapeutic interventions may be limited.Case: A a 21-year-old woman who developed a fever, abdominal pain, and foul-smelling vaginal discharge five days after giving birth. The patient convulsed five times in total before being admitted. She was diagnosed with status epilepticus caused by sepsis-associated encephalopathy and puerperal sepsis, which was successfully treated with antibiotics and supportive care.Discussion: Pregnancy and the puerperium period involve significant changes in maternal physiology and immune function. The Society of Obstetric Medicine Australia and New Zealand (SOMANZ) has proposed Obstetric-modified quick sepsis related organ failure assessment (omqSOFA) for early recognition of maternal sepsis. An score of 2 or higher has predictive value for maternal sepsis.Conclusion: Early recognition, appropriate treatment, and close monitoring are crucial for improving outcomes in patients with puerperal sepsis.

Down-regulating nuclear factor of activated T cells 1 alleviates cognitive deficits in a mouse model of sepsis-associated encephalopathy, possibly by stimulating hippocampal neurogenesis

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, and has been associated with increased morbidity and mortality. Nuclear factor of activated T cells (NFATs) 1, a transcriptional factor that regulates T cell development, activation and differentiation, has been implicated in neuronal plasticity. Here we examined the potential role of NFAT1 in sepsis-associated encephalopathy in mice. Adult male C57BL/6J mice received intracerebroventricular injections of short interfering RNA against NFAT1 or sex-determining region Y-box 2 (SOX2), or a scrambled control siRNA prior to cecal ligation and perforation (CLP). A group of mice receiving sham surgery were included as an additional control. CLP increased escape latency and decreased the number of crossings into, and total time spent within, the target quadrant in the Morris water maze test. CLP also decreased the freezing time in context-dependent, but not context-independent, fear conditioning test. Knockdown of either NFAT1 or SOX2 attenuated these behavioral deficits. NFAT1 knockdown also attenuated CLP-induced upregulation of SOX2, increased the numbers of nestin-positive cells and newborn astrocytes, reduced the number of immature newborn neurons, and promoted the G1 to S transition of neural stem cells in hippocampus. These findings suggest that NFAT1 may contribute to sepsis-induced behavioral deficits, possibly by promoting SOX2 signaling and neurogenesis.

Palmatine ameliorated lipopolysaccharide-induced sepsis-associated encephalopathy mice by regulating the microbiota-gut-brain axis

BackgroundSepsis-associated encephalopathy (SAE), a common neurological complication from sepsis, is widespread among patients in intensive care unit and is linked to substantial morbidity and mortality rates, thus posing a substantial menace to human health. Due to the intricate nature of SAE's pathogenesis, there remains a dearth of efficacious therapeutic protocols, encompassing pharmaceutical agents and treatment modalities, up until the present time. Palmatine exhibits distinctive benefits in the regulation of inflammation for the improvement of sepsis. Nevertheless, the precise functions of palmatine in treating SAE and its underlying mechanism have yet to be elucidated. PurposeThis study aimed to evaluate efficiency of palmatine in SAE mice and its underlying mechanisms. Study design and methodsBehavioral experiments, percent survival rate analysis, histological analysis, immunofluorescence staining, ELISA analysis, were performed to evaluate the efficiency of palmatine in SAE mice. Quantibody® mouse inflammation array glass chip was performed to observe the effects of palmatine on inflammation storm in SAE mice. Real-time quantitative and western blotting analyzes were employed to examine the expression of relevant targets in the Notch1/nuclear factor-kappa B (NF-κB) pathway. Finally, brain tissues metabolomics-based analyzes were performed to detect the differentially expressed metabolites and metabolic pathways. The fecal samples were subjected to microbial 16S rRNA analysis and untargeted metabolomics analysis in order to identify the specific flora and metabolites associated with SAE, thereby further investigating the mechanism of palmatine in SAE mice. ResultsOur results showed that palmatine significantly improved nerve function, reduced cell apoptosis in brain tissue, and decreased inflammatory cytokine levels in SAE induced-LPS mice. Meanwhile, our results demonstrate the potential of palmatine in modulating key components of the Notch1/NF-κB pathway, enhancing the expression of tight junction proteins, improving intestinal permeability, promoting the growth of beneficial bacteria (such as Lachnospiraceae_NK4A136_group), inhibiting the proliferation of harmful bacteria (such as Escherichia-Shigella), and mitigating metabolic disorders. Ultimately, these observed effects contribute to the therapeutic efficacy of palmatine in treating SAE. ConclusionThe findings of our study have provided confirmation regarding the efficacy of palmatine in the treatment of SAE, thereby establishing a solid foundation for further exploration into SAE therapy and the advancement and investigation of palmatine.

ROLE OF MICROGLIA IN SEPSIS-ASSOCIATED ENCEPHALOPATHY PATHOGENESIS: AN UPDATE.

Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis, which is characterized by cognitive dysfunction, a poor prognosis, and high incidences of morbidity and mortality. Substantial levels of systemic inflammatory factors induce neuroinflammatory responses during sepsis, ultimately disrupting the central nervous system's (CNS) homeostasis. This disruption results in brain dysfunction through various underlying mechanisms, contributing further to SAE's development. Microglia, the most important macrophage in the CNS, can induce neuroinflammatory responses, brain tissue injury, and neuronal dysregulation, resulting in brain dysfunction. They serve an important regulatory role in CNS homeostasis and can be activated through multiple pathways. Consequently, activated microglia are involved in several pathogenic mechanisms related to SAE and play a crucial role in its development. This article discusses the role of microglia in neuroinflammation, dysfunction of neurotransmitters, disruption of the blood-brain barrier, abnormal control of cerebral blood flow, mitochondrial dysfunction, and reduction in the number of good bacteria in the gut as main pathogenic mechanisms of SAE and focuses on studies targeting microglia to ameliorate SAE to provide a theoretical basis for targeted microglial therapy for SAE.

The Role of Iron Metabolism in Sepsis-associated Encephalopathy: a Potential Target.

Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction secondary to infection, and the severity can range from mild delirium to deep coma. Disorders of iron metabolism have been proven to play an important role in a variety of neurodegenerative diseases by inducing cell damage through iron accumulation in glial cells and neurons. Recent studies have found that iron accumulation is also a potential mechanism of SAE. Systemic inflammation can induce changes in the expression of transporters and receptors on cells, especially high expression of divalent metal transporter1 (DMT1) and low expression of ferroportin (Fpn) 1, which leads to iron accumulation in cells. Excessive free Fe2+ can participate in the Fenton reaction to produce reactive oxygen species (ROS) to directly damage cells or induce ferroptosis. As a result, it may be of great help to improve SAE by treatment of targeting disorders of iron metabolism. Therefore, it is important to review the current research progress on the mechanism of SAE based on iron metabolism disorders. In addition, we also briefly describe the current status of SAE and iron metabolism disorders and emphasize the therapeutic prospect of targeting iron accumulation as a treatment for SAE, especially iron chelator. Moreover, drug delivery and side effects can be improved with the development of nanotechnology. This work suggests that treating SAE based on disorders of iron metabolism will be a thriving field.

Potential of piperine for neuroprotection in sepsis-associated encephalopathy

AimsSepsis-associated encephalopathy (SAE) is a common complication that increases mortality and leads to long-term cognitive impairment in sepsis survivors. However, no specific or effective therapy has been identified for this complication. Piperine is an alkaloid known for its anti-inflammatory, antioxidant, and neuroprotective properties, which are important characteristics for treatment of SAE. The objective of this study was to evaluate the neuroprotective effect of piperine on SAE in C57BL/6 mice that underwent cecum ligation and perforation surgery (CLP). Main methodsC57BL/6 male mice were randomly assigned to groups that underwent SHAM surgery or CLP. Mice in the CLP group were treated with piperine at doses of 20 or 40 mg/kg for short- (5 days) or long-term (10 days) periods after CLP. Key findingsOur results revealed that untreated septic animals exhibited increased concentrations of IL-6, TNF, VEGF, MMP-9, TBARS, and NLRP3, and decreased levels of BDNF, sulfhydryl groups, and catalase in the short term. Additionally, the levels of carbonylated proteins and degenerated neuronal cells were increased at both time points. Furthermore, short-term and visuospatial memories were impaired. Piperine treatment reduced MMP-9 activity in the short term and decreased the levels of carbonylated proteins and degenerated neuronal cells in the long term. It also lowered IL-6 and TBARS levels at both time points evaluated. Moreover, piperine increased short-term catalase and long-term BDNF factor levels and improved memory at both time points. SignificanceIn conclusion, our data demonstrate that piperine exerts a neuroprotective effect on SAE in animals that have undergone CLP.

Factor analysis based on SHapley Additive exPlanations for sepsis-associated encephalopathy in ICU mortality prediction using XGBoost - a retrospective study based on two large database.

Sepsis-associated encephalopathy (SAE) is strongly linked to a high mortality risk, and frequently occurs in conjunction with the acute and late phases of sepsis. The objective of this study was to construct and verify a predictive model for mortality in ICU-dwelling patients with SAE. The study selected 7,576 patients with SAE from the MIMIC-IV database according to the inclusion criteria and randomly divided them into training (n = 5,303, 70%) and internal validation (n = 2,273, 30%) sets. According to the same criteria, 1,573 patients from the eICU-CRD database were included as an external test set. Independent risk factors for ICU mortality were identified using Extreme Gradient Boosting (XGBoost) software, and prediction models were constructed and verified using the validation set. The receiver operating characteristic (ROC) and the area under the ROC curve (AUC) were used to evaluate the discrimination ability of the model. The SHapley Additive exPlanations (SHAP) approach was applied to determine the Shapley values for specific patients, account for the effects of factors attributed to the model, and examine how specific traits affect the output of the model. The survival rate of patients with SAE in the MIMIC-IV database was 88.6% and that of 1,573 patients in the eICU-CRD database was 89.1%. The ROC of the XGBoost model indicated good discrimination. The AUCs for the training, test, and validation sets were 0.908, 0.898, and 0.778, respectively. The impact of each parameter on the XGBoost model was depicted using a SHAP plot, covering both positive (acute physiology score III, vasopressin, age, red blood cell distribution width, partial thromboplastin time, and norepinephrine) and negative (Glasgow Coma Scale) ones. A prediction model developed using XGBoost can accurately predict the ICU mortality of patients with SAE. The SHAP approach can enhance the interpretability of the machine-learning model and support clinical decision-making.

Effect of esketamine pretreatment on acute sepsis-associated encephalopathy

PurposeEsketamine, the S(+) enantiomer of ketamine, exhibits good anesthetic efficacy and controllability; however, its potential clinical applications, particularly in sepsis-associated encephalopathy (SAE), remain underexplored. SAE involves the development of diffuse brain dysfunction after sepsis, leading to markedly increased sepsis-related disability and mortality. In this study, we investigated the effects of esketamine pretreatment on acute SAE. MethodsMice were randomly divided into four groups: control (C, n = 22), acute SAE (L, n = 22), esketamine pretreatment + acute SAE (EL, n = 22), and nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor (ML385) + esketamine pretreatment + acute SAE (N + EL, n = 22). Acute SAE was established using intraperitoneal (i.p.) injection of lipopolysaccharide (LPS; 10 mg/kg), while controls received equal amounts of saline. The EL group received daily i.p. injections of esketamine (10 mg/kg) for 5 consecutive days, followed by LPS on day 6. The N + EL group received i.p. injections of ML385 (30 mg/kg) 1 h before esketamine pretreatment. The remainder of treatment followed the same protocol as the EL group. Behavioral tests were performed 24 h post-LPS injection, and whole blood and brain tissues were collected for further analysis. ResultsEsketamine improved sepsis symptoms, 7-day survival, and spatial cognitive impairment, without altering locomotor activity. Moreover, esketamine reversed the LPS-induced increase in serum S100 calcium-binding protein β and neuron-specific enolase levels and reduced hippocampal neuroinflammation, oxidative stress, and neuronal apoptosis in the EL group. However, these neuroprotective effects of esketamine were reversed by ML385. ConclusionThe results of our study suggest that esketamine pretreatment mitigates acute SAE, highlighting the involvement of the Nrf2/heme oxygenase-1 pathway in mediating its neuroprotective effects.

Hyperbaric oxygen therapy as a possible therapeutic candidate for sepsis-associated encephalopathy: A novel hypothesis

Hyperbaric oxygen therapy (HBOT) is being increasingly recognized as a potential therapeutic modality with favorable mechanisms in various diseases. HBOT has demonstrated anti-inflammatory and antiapoptotic effects as well as increased the oxygenation capacity of oxygen-deprived tissues, thus contributing to tissue homeostasis. Focusing on these mechanisms, HBOT could be applied for sepsis-associated encephalopathy (SAE), which is a serious sepsis-related complication. Two vital mechanisms in the pathogenesis of SAE are: (1) neuroinflammation mainly induced by microglia and (2) cerebral ischemia/hypoperfusion caused by cerebral microcirculatory abnormalities. Herein, we highlight the mechanisms of the neuroprotective effects of HBOT and its potential application as a therapeutic modality for SAE. We also discuss the caveats and limitations of applying HBOT in sepsis.

Mechanism of myeloid differentiation factor 2 on mediating sepsis-associated encephalopathy

To investigate the role and underlying mechanism of human myeloid differentiation protein 2 (MD2) in the process of neuronal death induced by lipopolysaccharide (LPS) by establishing an in vitro model of sepsis-associated encephalopathy (SAE) by LPS. Healthy C57BL/6J mice at 14-18 days of gestation were selected, and brain cortical tissue was taken from fetal mice. Neurons were stimulated with 0 (control), 1, 5 and 10 g/L of LPS for 24 hours. The release of lactate dehydrogenase (LDH) was detected and the death of neurons was observed. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of inflammatory factors interleukins (IL-6, IL-1β), in order to determine the optimal dose of LPS for establishing an in vitro neuroinflammation model of SAE. The cells were divided into blank control group and LPS group. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) was used to discover apoptosis. Western blotting was used to detect the expression of the relevant protein markers activated caspase-3, necroptosis-associated protein neuronal receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and phosphorylated RIPK3 (p-RIPK3). Immunofluorescence chemical staining was used to detect the expressions of p-RIPK3 and microtubule-associated protein 2 (MAP2) to evaluate the type of cell death and the degree of neuronal death. Western blotting was used to detect MD2 expression. Immunofluorescence chemical staining was performed to observe the expression and distribution of p-RIPK3 and MD2 in neurons to assess whether MD2 was involved in the inflammatory response promoting neuronal death. In addition, the cells were divided into blank control group, LPS group, and MD2 interfering peptide group (LPS+TC group), and the levels of IL-6, IL-1β and LDH were detected to evaluate whether interfering with MD2 can alleviate LPS induced neuroinflammation. 10 g/L LPS induced notable neuronal death, and the release of LDH in neurons stimulated with this concentration for 24 hours was significantly higher than that in the blank control group (relative release: 1.45±0.04 vs. 1.00±0.00, P < 0.01), indicating apoptosis and necroptosis occurred in neurons, and the levels of inflammatory factors IL-6 and IL-1β were remarkable increased [IL-6 (relative level): 1.94±0.04 vs. 1.00±0.00, IL-1β (relative level): 1.53±0.09 vs. 1.00±0.00, both P < 0.01]. Compared with the blank control group, the apoptosis of cells, cleaved-caspase-3 expression, the p-RIPK3/RIPK3 ratio, and p-RIPK3 expression around neurons in the LPS group were significantly increased [cleaved-caspase-3/GAPDH: 1.55±0.10 vs. 1.00±0.00, P < 0.01; p-RIPK3/RIPK3 ratio (relative value): 1.54±0.06 vs. 1.00±0.00, P < 0.05], which suggested that typical apoptosis and necroptosis apoptosis occurred in neurons in the septic environment. Furthermore, MD2 expression was significantly increased in the LPS group compared with the blank control group (MD2/GAPDH: 1.91±0.07 vs. 1.00±0.00, P < 0.01), and MD2 expression around neurons was increased, indicating that LPS-induced MD2 upregulation may play a key role in neuroinflammation and induction of neuronal death in sepsis. In addition, compared with the LPS group, the MD2-interfering peptide could reduce the expression levels of inflammatory factors IL-6 and IL-1β [IL-6 (relative level): 1.16±0.08 vs. 1.94±0.04, IL-1β (relative level): 1.15±0.05 vs. 1.75±0.09, both P < 0.01] and decrease LDH release (relative release: 1.09±0.01 vs. 1.44±0.04, P < 0.05). LPS induced neuronal inflammatory responses via MD2, which ultimately leads to apoptosis and necroptosis. Interfering with MD2 reduces inflammation and inhibits neuronal death.

Neuroprotective potential of phenolic rich fractions of Solanum nigrum leaves on oxidative and inflammatory reactions in a cecal ligation and puncture (CLP) induced sepsis model in experimental animal

ObjectiveThe present work aimed to investigate the neuroprotective effect of Solanum nigrum leaves against CLP-induced septic encephalopathy in rats. The study was designed to evaluate the effect of Solanum nigrum leaves on behavioral and biochemical changes that occur during septic encephalopathy. MethodsAdult male Wistar rats were distributed into five experimental groups and subjected to caecal ligation and puncture, while the control animals were subjected to a sham operation. Solanum nigrum leaf aqueous extract (doses of 200 mg/kg and 400 mg/kg), ethanolic extract (doses of 200 mg/kg and 400 mg/kg), and vehicle, given orally, were administered for one week after the surgery procedure. Behavioral parameters like anxiety, depressive behavior, and nonaversive memory were evaluated. Anti-inflammatory activity was measured by the membrane stabilization method. At the end of the study, animals were sacrificed and their brains removed. Brain homogenates were prepared to assess antioxidant activity (SOD, CAT, MDA, and GSH). Brain tissue sections were stained by hematoxylin and eosin to examine the histopathologic changes such as neuron degeneration, and perinuclear spaces in the brain. ResultsAqueous and ethanolic extracts at doses of 200 mg/kg and 400 mg/kg, showed significant improvement in behavioral parameters, prevention of oxidative stress, neuron degeneration, and perinuclear edema respectively. Aqueous extract and ethanolic fraction at a concentration of 200μg/mL significantly protected the lysis of the erythrocyte membrane induced by the hypotonic solution. ConclusionCollectively, these results demonstrate that Solanum nigrum leaf aqueous extract and ethanolic extract could be used for the prevention of sepsis-associated encephalopathy.

Association between the first 24 hours PaCO2 and all-cause mortality of patients suffering from sepsis-associated encephalopathy after ICU admission: A retrospective study.

The relationship between the levels of the first 24-h PaCO2 and the prognosis of sepsis-associated encephalopathy (SAE) remains unclear, and the first 24-h optimal target for PaCO2 is currently inconclusive. This study was performed to investigate the correlation between PaCO2 and all-cause mortality for SAE patients, establish a reference range of the initial 24-hour PaCO2 for clinicians in critical care, and explain the possible pathophysiological mechanisms of abnormal PaCO2 levels as a higher mortality risk factor for SAE. The baseline information and clinical data of patients were extracted from the fourth edition Medical Information Mart for Intensive Care database (MIMIC-IV 2.0). Multivariate logistic regressions were performed to assess the relationship between PaCO2 and all-cause mortality of SAE. Additionally, restricted cubic splines, Kaplan-Meier Survival analyses, propensity score matching (PSM) analyses, and subgroup analyses were conducted. A total of 5471 patients were included in our cohort. In the original and matched cohort, multivariate logistic regression analysis showed that normocapnia and mild hypercapnia may be associated with a more favorable prognosis of SAE patients, and survival analysis supported the findings. In addition, a U-shaped association emerged when examining the initial 24-hour PaCO2 levels in relation to 30-day, 60-day, and 90-day mortality using restricted cubic splines, with an average cut-off value of 36.3mmHg (P for nonlinearity<0.05). Below the cut-off value, higher PaCO2 was associated with lower all-cause mortality, while above the cut-off value, higher PaCO2 was associated with higher all-cause mortality. Subsequent subgroup analyses revealed similar results for the subcohort of GCS≤8 compared to the original cohort. Additionally, when examining the subcohort of GCS>8, a L-shaped relationship between PaCO2 and the three clinical endpoints emerged, in contrast to the previously observed U-shaped pattern. The findings from the subcohort of GCS>8 suggested that patients experiencing hypocapnia had a more unfavorable prognosis, which aligns with the results obtained from corresponding multivariate logistic regression analyses. The retrospective study revealed the association between the first 24-h PaCO2 and all-cause mortality risk (30-day, 60-day, and 90-day) for patients with SAE in ICU. The range (35mmHg-50mmHg) of PaCO2 may be the optimal target for patients with SAE in clinical practice.

Aspects of the formation of encephalopathy and myocardiopathy in sepsis

Relevance. The severe brain damage in most cases leads the patient to a long-term chronic critical condition (CCS). Regardless of the underlying disease that led to CCS, patients will have a certain imbalance of neurohumoral regulation and characteristic cognitive, muscle-reflex disorders. This cohort of patients is characterized not only by a cascade of typical pathological processes in the brain, but also by the consistent involvement of the cardiovascular system, respiratory organs, digestive organs, water metabolism, hormonal regulation, immunity, the addition of infectious-septic complications closes the circle of pathological processes, which often leads to death. Materials and methods. The search for domestic publications was carried out in the database on the RSCI website, foreign – in the PubMed, Google Scholar databases in the period 2000–2023. When analyzing the PubMed database, the query «sepsis neuroinflammation» found 5272 links. We also studied works on the following keywords: «neurotransmitters and sepsis». Publications describing the clinical picture, diagnosis, and sepsis were analyzed. A total of 40 articles were analyzed Such systems as immune, nervous and endocrine are interconnected due to regulatory peptides. Stable functioning of the central nervous system (CNS), or rather adequate secretion of neuropeptides are necessary for a normal immune response. Neuronal anti-inflammatory regulation of tissue macrophages is characterized by a local, rapid response to the pathogen through neuromediators.Confirmation of the neuropeptide theory of immunity regulation is the verification of neuropeptide receptors on peripheral blood lymphocytes and monocytes. These results indicate a possible mechanism of a «vicious» circle that occurs in infectious-septic complications and leads to damage to vital organs.To date, there are no widely available means for accurate monitoring of brain function at the patient’s bedside. There is no evidence or recommendations to support monitoring of cerebral perfusion or function in sepsis patients. At the same time, modern research on the phenotyping of patients taking into account brain dysfunction (sepsis associated encephalopathy) is based on the basic postulates of the pathophysiology and biochemistry of sepsis, but does not offer any methods of instrumental diagnosis of this condition, except for the use of validated delirium, coma scales (Glasgow coma scale, FOUR, CAM-ICU, etc.). Despite the described pathogenesis, there is currently no single definition of cardiac cardiomyopathy. However, most authors describe the fundamental features of this pathology: acute reversible one- or two-ventricular systolic or diastolic dysfunction with reduced contractility, not due to coronary heart disease. Primary cellular myocardial dysfunction in sepsis can manifest in several ways, including impaired function of the left and/or right ventricles during systole or diastole, as well as with insufficient cardiac output (CO) and oxygen delivery. To explain the changes in myocardial contractility associated with sepsis, several mechanisms have been proposed taking into account the host response. Since most of the parameters of the echo signal depend on the conditions of the volemic status, the evaluation of the echo signal should be repeated at several time points and supplemented with the definition of cardiac biomarkers. Conclusion. Analyzing the literature data on sepsis-associated encephalopathy and septic cardiomyopathy, it is possible to judge the interconnectedness of these events indirectly through damage to neurons during infectious-septic complications. Especially neuro-humoral mechanisms of regulation of the response to an infectious agent should be evaluated in patients with CCS, not only relying on laboratory diagnostics, but also using instrumental methods of visualization of brain, heart, and kidney damage. Such methods include magnetic resonance imaging (MRI), electroencephalogram (EEG), cerebral oximetry (CMRO2), echocardiography, ultrasound examination of the kidneys, etc

Memantine Attenuates Cognitive and Emotional Dysfunction in Mice with Sepsis-Associated Encephalopathy

Memantine Attenuates Cognitive and Emotional Dysfunction in Mice with Sepsis-Associated Encephalopathy