Serotonergic neurotransmission mediated cognitive dysfunction in two mouse models of sepsis-associated encephalopathy.

BACKGROUND: Patients with sepsis-associated encephalopathy (SAE) often exhibit cognitive impairments. Despite this, the underlying mechanisms of SAE remain largely unexplored. Here, we explored the role of serotonergic neurotransmission in cognitive dysfunction of two mouse models of SAE. METHODS: The mouse models of SAE were established by injection of lipopolysaccharide (LPS, 10 mg/kg, intraperitoneal) and cecal ligation puncture (CLP) respectively. Barnes maze, new object recognition test and open field test were used to evaluate the effects of fluoxetine (selective serotonin reuptake inhibitor) and cyproheptadine (nonselective 5-HT2 receptor antagonist) on cognition and motor activity of mice. Additionally, WAY100635 (5-HT1A receptor antagonist) was co-administered with fluoxetine to explore the mechanism underlying effect of fluoxetine on cognitive impairments of SAE. Enzyme-linked immunosorbent assay (ELISA) was performed to determine 5-HT levels in hippocampus, brainstem and frontal lobe of experimental groups. RESULTS: Both LPS-induced sepsis and CLP induced sepsis resulted in a notable learning deficit. Fluoxetine ameliorated, while cyproheptadine aggravated, cognitive impairment in two classic mouse models of SAE. The cognition-enhancing effect of fluoxetine is reversed by WAY100635. Decreased 5-HT levels in hippocampus, brainstem and frontal lobe were observed in LPS septic model and CLP septic model. Notably, both fluoxetine and cyproheptadine significantly increased 5-HT levels in those brain regions in LPS septic model. Additionally, fluoxetine significantly increased 5-HT levels in frontal lobe of CLP septic model. CONCLUSIONS: Our study demonstrated that serotonergic neurotransmission plays a significant role in mechanisms underlying cognitive impairment in SAE. These findings contribute to identification of novel targets to prevent and arrest cognitive impairment in SAE.

Potential of piperine for neuroprotection in sepsis-associated encephalopathy.

AIMS: Sepsis-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 METHODS: C57BL/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 FINDINGS: Our 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. SIGNIFICANCE: In conclusion, our data demonstrate that piperine exerts a neuroprotective effect on SAE in animals that have undergone CLP.

Elevated Intracranial Pressure Level Is a Risk Factor for Sepsis-associated Encephalopathy: A Prospective Cohort Study.

BACKGROUND/AIM: Cerebral edema is common in patients with sepsis-associated encephalopathy (SAE) and is a major cause of elevated intracranial pressure (ICP); however, the relationship between elevated ICP and SAE is unclear. The aim of this study was to investigate the association between optic nerve sheath diameter (ONSD), a surrogate of ICP, and the incidence of SAE. PATIENTS AND METHODS: A prospective observational study was performed in a medical-surgical adult intensive care unit (ICU). All patients in the ICU who were consecutively diagnosed with sepsis during the study period were evaluated for eligibility. Ultrasound measurements of ONSD were performed within 6 h of enrollment and every two days thereafter until the patient developed SAE. Clinical and blood test data were collected throughout this period. Patients underwent a daily conscious and cognitive assessment. SAE was diagnosed as delirium or Glasgow Coma Scale (GCS) <15 points. Multivariate modified Poisson regression analysis was performed to identify risk factors for SAE. RESULTS: A total of 123 patients with sepsis were included in the analysis. 58 patients (47.2%) developed SAE. The levels of ONSD0 (the first measured value) and ONSDmax (the maximum measured value) in the SAE group were significantly higher than those in the non-SAE group (5.23±0.52 mm vs. 5.85±0.54 mm for ONSD0 and 5.41±0.46 mm vs. 6.09±0.58 mm for ONSDmax, respectively; all p-values <0.001). The area under the curves (AUCs) for the ONSD0 and ONSDmax values in predicting SAE were 0.801 (95%CI=0.723-0.880, p<0.001) and 0.829 (95%CI=0.754-0.903, p<0.001), respectively. A higher ONSD0 level was significantly associated with an increased risk of SAE (adjusted risk ratio 3.241; 95%CI=1.686-6.230, p<0.001). CONCLUSION: The levels of ONSD correlate with risk of SAE, indicating that increased ICP level is an independent risk factor for the development of SAE. Dynamic monitoring of ONSD/ICP has a high predictive value for SAE. Measures to prevent increases in ICP are helpful to reduce the incidence of SAE in sepsis patients.

The spectrum of sepsis-associated encephalopathy: a clinical perspective.

Sepsis-associated encephalopathy is a severe neurologic syndrome characterized by a diffuse dysfunction of the brain caused by sepsis. This review provides a concise overview of diagnostic tools and management strategies for SAE at the acute phase and in the long term. Early recognition and diagnosis of SAE are crucial for effective management. Because neurologic evaluation can be confounded by several factors in the intensive care unit setting, a multimodal approach is warranted for diagnosis and management. Diagnostic tools commonly employed include clinical evaluation, metabolic tests, electroencephalography, and neuroimaging in selected cases. The usefulness of blood biomarkers of brain injury for diagnosis remains limited. Clinical evaluation involves assessing the patient's mental status, motor responses, brainstem reflexes, and presence of abnormal movements. Electroencephalography can rule out non-convulsive seizures and help detect several patterns of various severity such as generalized slowing, epileptiform discharges, and triphasic waves. In patients with acute encephalopathy, the diagnostic value of non-contrast computed tomography is limited. In septic patients with persistent encephalopathy, seizures, and/or focal signs, magnetic resonance imaging detects brain injury in more than 50% of cases, mainly cerebrovascular complications, and white matter changes. Timely identification and treatment of the underlying infection are paramount, along with effective control of systemic factors that may contribute to secondary brain injury. Upon admission to the ICU, maintaining appropriate levels of oxygenation, blood pressure, and metabolic balance is crucial. Throughout the ICU stay, it is important to be mindful of the potential neurotoxic effects associated with specific medications like midazolam and cefepime, and to closely monitor patients for non-convulsive seizures. The potential efficacy of targeted neurocritical care during the acute phase in optimizing patient outcomes deserves to be further investigated. Sepsis-associated encephalopathy may lead to permanent neurologic sequelae. Seizures occurring in the acute phase increase the susceptibility to long-term epilepsy. Extended ICU stays and the presence of sepsis-associated encephalopathy are linked to functional disability and neuropsychological sequelae, underscoring the necessity for long-term surveillance in the comprehensive care of septic patients.

HSPB8 up-regulation alleviates cognitive dysfunction in a mouse model of sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is associated with a higher risk of cognitive deficits; however, its potential mechanisms are still unknow. Recently, researches show that HSPB8, a family of small heat shock proteins, affects cognitive function and ameliorates sepsis-induced dysfunction. However, the role of HSPB8 in SAE-associated cognitive impairment has not been elucidated. In this study, we found that HSPB8 expression was up-regulated in the brain of mice with lipopolysaccharide-induced sepsis. HSPB8 overexpression alleviated cognitive decline in SAE mice. In addition, exogenous HSPB8 exerts neuroprotective effects and salvages synaptic function via regulating NRF1/TFAM-induced mitochondrial biogenesis and DRP1-mediate mitochondrial fission in a lipopolysaccharide-induced mouse model. Furthermore, HSPB8 overexpression inhibits IBA1 and NLRP3 activation in the SAE model. Overexpression of HSPB8 may be an efficient treatment for relieving SAE-related cognitive decline.

Exploring Neuroprotective Agents for Sepsis-Associated Encephalopathy: A Comprehensive Review.

Sepsis is a life-threatening condition resulting from an inflammatory overreaction that is induced by an infectious factor, which leads to multi-organ failure. Sepsis-associated encephalopathy (SAE) is a common complication of sepsis that can lead to acute cognitive and consciousness disorders, and no strict diagnostic criteria have been created for the complication thus far. The etiopathology of SAE is not fully understood, but plausible mechanisms include neuroinflammation, blood-brain barrier disruption, altered cerebral microcirculation, alterations in neurotransmission, changes in calcium homeostasis, and oxidative stress. SAE may also lead to long-term consequences such as dementia and post-traumatic stress disorder. This review aims to provide a comprehensive summary of substances with neuroprotective properties that have the potential to offer neuroprotection in the treatment of SAE. An extensive literature search was conducted, extracting 71 articles that cover a range of substances, including plant-derived drugs, peptides, monoclonal antibodies, and other commonly used drugs. This review may provide valuable insights for clinicians and researchers working in the field of sepsis and SAE and contribute to the development of new treatment options for this challenging condition.

An Fgr kinase inhibitor attenuates sepsis-associated encephalopathy by ameliorating mitochondrial dysfunction, oxidative stress, and neuroinflammation via the SIRT1/PGC-1α signaling pathway.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is characterized by diffuse brain dysfunction, long-term cognitive impairment, and increased morbidity and mortality. The current treatment for SAE is mainly symptomatic; the lack of specific treatment options and a poor understanding of the underlying mechanism of disease are responsible for poor patient outcomes. Fgr is a member of the Src family of tyrosine kinases and is involved in the innate immune response, hematologic cancer, diet-induced obesity, and hemorrhage-induced thalamic pain. This study investigated the protection provided by an Fgr kinase inhibitor in SAE and the underlying mechanism(s) of action. METHODS: A cecal ligation and puncture (CLP)-induced mouse sepsis model was established. Mice were treated with or without an Fgr inhibitor and a PGC-1α inhibitor/activator. An open field test, a novel object recognition test, and an elevated plus maze were used to assess neurobehavioral changes in the mice. Western blotting and immunofluorescence were used to measure protein expression, and mRNA levels were measured using quantitative PCR (qPCR). An enzyme-linked immunosorbent assay was performed to quantify inflammatory cytokines. Mitochondrial membrane potential and morphology were measured by JC-1, electron microscopy, and the MitoTracker Deep Red probe. Oxidative stress and mitochondrial dysfunction were analyzed. In addition, the regulatory effect of Fgr on sirtuin 1 (SIRT1) was assessed. RESULTS: CLP-induced sepsis increased the expression of Fgr in the hippocampal neurons. Pharmacological inhibition of Fgr attenuated CLP-induced neuroinflammation, the survival rate, cognitive and emotional dysfunction, oxidative stress, and mitochondrial dysfunction. Moreover, Fgr interacted with SIRT1 and reduced its activity and expression. In addition, activation of SIRT1/PGC-1α promoted the protective effects of the Fgr inhibitor on CLP-induced brain dysfunction, while inactivation of SIRT1/PGC-1α counteracted the benefits of the Fgr inhibitor. CONCLUSIONS: To our knowledge, this is the first report of Fgr kinase inhibition markedly ameliorating SAE through activation of the SIRT1/PGC-1α pathway, and this may be a promising therapeutic target for SAE.

Sex, sepsis and the brain: defining the role of sexual dimorphism on neurocognitive outcomes after infection.

Sexual dimorphisms exist in multiple domains, from learning and memory to neurocognitive disease, and even in the immune system. Male sex has been associated with increased susceptibility to infection, as well as increased risk of adverse outcomes. Sepsis remains a major source of morbidity and mortality globally, and over half of septic patients admitted to intensive care are believed to suffer some degree of sepsis-associated encephalopathy (SAE). In the short term, SAE is associated with an increased risk of in-hospital mortality, and in the long term, has the potential for significant impairment of cognition, memory, and acceleration of neurocognitive disease. Despite increasing information regarding sexual dimorphism in neurologic and immunologic systems, research into these dimorphisms in sepsis-associated encephalopathy remains critically understudied. In this narrative review, we discuss how sex has been associated with brain morphology, chemistry, and disease, sexual dimorphism in immunity, and existing research into the effects of sex on SAE.

Neurofilament light chains to assess sepsis-associated encephalopathy: Are we on the track toward clinical implementation?

Sepsis is the most common cause of admission to intensive care units worldwide. Sepsis patients frequently suffer from sepsis-associated encephalopathy (SAE) reflecting acute brain dysfunction. SAE may result in increased mortality, extended length of hospital stay, and long-term cognitive dysfunction. The diagnosis of SAE is based on clinical assessments, but a valid biomarker to identify and confirm SAE and to assess SAE severity is missing. Several blood-based biomarkers indicating neuronal injury have been evaluated in sepsis and their potential role as early diagnosis and prognostic markers has been studied. Among those, the neuroaxonal injury marker neurofilament light chain (NfL) was identified to potentially serve as a prognostic biomarker for SAE and to predict long-term cognitive impairment. In this review, we summarize the current knowledge of biomarkers, especially NfL, in SAE and discuss a possible future clinical application considering existing limitations.

PD-L1 promotes GSDMD-mediated NET release by maintaining the transcriptional activity of Stat3 in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE), as shown as acute and long-term cognitive impairment, is associated with increased mortality of sepsis. The causative factors of SAE are diverse and the underlying pathological mechanisms of SAE remain to be fully elucidated. Multiple studies have demonstrated a crucial role of microglia in the development of SAE, but the role of neutrophils and neutrophil extracellular traps (NETs) in SAE is still unclear. Here, we firstly show that in murine sepsis model, neutrophils and NETs promote blood-brain barrier (BBB) disruption, neuronal apoptosis and microglia activation in hippocampus and induce hippocampus-dependent memory impairment. Anti-Gr-1 antibody or DNase I treatment attenuates these sepsis-induced changes. Then, we find that genetic deletion of neutrophil GSDMD or PD-L1 reduces NET release and improves SAE in murine sepsis model. Finally, in human septic neutrophils, p-Y705-Stat3 binds to PD-L1, promotes PD-L1 nuclear translocation and enhances transcription of the gasdermin D (GSDMD) gene. In summary, our findings firstly identify a novel function of PD-L1 in maintaining transcriptional activity of p-Y705-Stat3 to promote GSDMD-dependent NET release in septic neutrophils, which plays a critical role in the development of SAE.

Hydrogen regulates mitochondrial quality to protect glial cells and alleviates sepsis-associated encephalopathy by Nrf2/YY1 complex promoting HO-1 expression.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a complication of the central nervous system in patients with sepsis. Currently, no effective treatment for sepsis is available. Hydrogen plays a protective role in different diseases; however, the detailed mechanism of hydrogen-treated disease remains unclear. The purpose of this study was to investigate the effect of hydrogen on SAE in vitro and in vivo and the mechanism of hydrogen in mitochondrial dynamics and its function in astrocytes and microglia stimulated by lipopolysaccharides (LPSs). METHODS: Animal models of SAE were generated by cecal ligation and puncture, and the SAE model was established by in vitro LPS stimulation. MTT, lactate dehydrogenase (LDH), reactive oxygen species (ROS), heme oxygenase-1 (HO-1) activity, mitochondrial membrane potential (MMP), and cell apoptosis assays were used to determine the effect of hydrogen on astrocytes and microglia stimulated by LPSs. The relationships between nuclear factor erythroid 2-related factor 2 (Nrf2), YY1, and HO-1 were examined by chromatin immunoprecipitation and co-immunoprecipitation. Mitochondrial homeostasis-related proteins in LPS-stimulated glial cells and brain tissues of SAE mice were detected by western blotting. The effects of hydrogen treatment in the SAE mouse model were investigated using Morris water maze and Y-maze analyses. RESULTS: After performing experiments with different concentrations of LPSs in vitro, we selected 1000 ng/ml for subsequent experiments. Hydrogen attenuated the increase in ROS, LDH, and apoptosis and promoted decreases in cell activity and MMP, further promoting an increase in HO-1 expression induced by LPSs in astrocytes and microglia. Moreover, hydrogen further promoted the expression of Nrf2, HO-1, PGC-1α, TFAM, PARKIN, and PINK1, inhibited LPS-induced OPA1 and MFN2 expression in astrocytes and microglia, and downregulated the expression of DRP1 after LPS induction. Intriguingly, hydrogen treatment enhanced the binding between Nrf2 and YY1. However, silencing Nrf2 or YY1 abolished the protective effects of hydrogen on cell activity, LDH, ROS, and MMP; apoptosis; and regulation of Nrf2, HO-1, PGC-1α, TFAM, OPA1, DRP1, MFN2, PARKIN, and PINK1 in microglia. Finally, hydrogen treatment improved the results of behavioral detection, apoptosis, Nrf2, HO-1, PGC-1α, TFAM, OPA1, DRP1, MFN2, PARKIN, PINK1, and cytokines in SAE in vivo. CONCLUSIONS: Hydrogen improved cell injury and mitochondrial quality, which were associated with HO-1 expression promoted by the Nrf2/YY1 complex in vitro. Thus, hydrogen treatment may represent a novel therapeutic method for treating SAE.

CLINICAL PHENOTYPES OF SEPSIS-ASSOCIATED ENCEPHALOPATHY: A RETROSPECTIVE COHORT STUDY.

ABSTRACT: Background: Sepsis-associated encephalopathy (SAE) is a dysfunction of the central nervous system experienced during sepsis with variable clinical and pathophysiologic features. We sought to identify distinct SAE phenotypes in relation to clinical outcomes. Methods: The Medical Information Mart for Intensive Care IV (MIMIC-IV) database and the eICU database were used to conduct a retrospective cohort study. Adult sepsis patients were included and SAE was defined as having a Glasgow Coma Scale (GCS) score ˂15 or delirium. The following our clinical phenotypes were defined as: ischemic-hypoxic, metabolic, mixed (ischemic-hypoxic and metabolic), and unclassified. The primary outcome was in-hospital mortality. Results: The study enrolled 4,120 sepsis patients, 2,239 from MIMIC-IV (including 1,489 patients with SAE, 67%), and 1,881 from eICU (1,291, 69%). For the SAE cohort, 2,780 patients in total were enrolled (median age, 67 years; interquartile range, 56-76.8; 1,589 (57%) were male; median GCS score was 12 [8-14]; median Sequential Organ Failure Assessment score was 6 [4-9]). The SAE phenotype distributions between the MIMIC-IV and eICU cohorts were as follows (39% vs. 35% ischemic-hypoxic, P = 0.043; 38% vs. 40% metabolic, P = 0.239; 15% vs. 15% mixed, P = 0.972; 38% vs. 40% unclassified, P = 0.471). For the overall cohort, the in-hospital mortality for patients with ischemic-hypoxic, metabolic, mixed, or unclassified phenotypes was 33.9% (95% confidence interval, 0.3-0.37), 28.4% (0.26-0.31), 41.5% (0.37-0.46), and 14.2% (0.12-0.16), respectively. In the multivariable logistic analysis, the mixed phenotype was associated with the highest risk of in-hospital mortality after adjusting for age, sex, GCS, and modified Sequential Organ Failure Assessment score (adjusted odds ratio, 2.11; 95% confidence interval, 1.67-2.67; P < 0.001). Conclusions: Four SAE phenotypes had different clinical outcomes. The mixed phenotype had the worst outcomes. Further understanding of these phenotypes in sepsis may improve trial design and targeted SAE management.

Cerebral Blood Flow Alterations in Sepsis-Associated Encephalopathy: A Prospective Observational Study.

BACKGROUND: The timely recognition of sepsis-associated encephalopathy (SAE) remains a challenge. This study aimed to observe the CBF changes via TCD during sepsis and explore their possible predictive value in SAE. METHODS: In this prospective observational study, septic patients were enrolled and classified according to the diagnosis of SAE into two groups: SAE group and non-SAE group. Then SAE patients were further divided into subgroup A (the type with agitation) and subgroup B (the type with depressed consciousness) based on their clinical manifestations. The clinical profiles and TCD parameters within 24 hours of onset were compared between groups and subgroups. RESULTS: Exactly 198 septic patients were enrolled including 65 patients in SAE group (36 male/29 female with a median age of 70) and 133 patients in non-SAE group (75 male/58 female with a median age of 67). Significant elevated peak-systolic velocity (VS; 107 [69-138] cm/s vs 85 [69-101] cm/s, P = .002) of the left middle cerebral artery (MCA) and pulsatility index (PI; left: 0.99 [0.81-1.34] vs 0.89 [0.76-1.00], P < .001; right: 0.99 [0.77-1.21] vs 0.88 [0.78-1.03], P = .007) of bilateral MCAs were found in SAE group compared with non-SAE group. In subgroup analysis, subgroup A (the type with agitation) showed significantly increased VS/VM/VD and lower PI/RI of bilateral MCAs compared with subgroup B (the type with depressed consciousness). The cerebral blood flow volume of subgroup A were obviously higher than subgroup B [858.7 (729.1,876.9) mL/s vs 380.9 (373.3,447.4) mL/s, P < .001]. CONCLUSIONS: This study confirmed the abnormal CBF among SAE and found different types of CBF alterations were related to different clinical features. VS and PI might help clinicians to early identify different types of SAE.

PERK-STING-RIPK3 pathway facilitates cognitive impairment by inducing neuronal necroptosis in sepsis-associated encephalopathy.

AIMS: Sepsis-associated encephalopathy (SAE) is a common but serious complication in septic survivors and often causes long-term cognitive impairments. The role of RIPK3-participated necroptosis in SAE remains obscured. STING is a key molecule in regulating necroptosis and apoptosis. However, there is uncertainty as to the mechanisms of STING in CLP-induced SAE. The aim of this study was to investigate whether STING is involved in the underlying mechanism of SAE. METHODS: The contextual fear conditioning test (CFCT) assesses cognitive impairment. A transmission electron microscope (TEM) was used to notice the necroptosis. Western blotting and immunofluorescence labeling were applied for the observation of related proteins. RESULTS: The phosphorylated STING in the hippocampal neuron of SAE mice was significantly elevated. Knocking down STING inhibited necroptosis and attenuated cognitive impairment in SAE mice. Moreover, RIPK3-/- mice had less cognitive deficit in the SAE model. However, STING overexpression did not deteriorate cognitive impairment in RIPK3-/- mice with SAE, indicating that STING is upstream involved in necroptosis. Furthermore, PERK inhibition ameliorated cognitive deficits through a STING-dependent pathway in SAE mice. CONCLUSION: PERK-STING-RIPK3 pathway facilitates cognitive impairment by inducing neuronal necroptosis in the pathology of SAE, which provided a new therapeutic target in SAE treatment.

What's new on septic encephalopathy? Ten things you need to know.

Sepsis associated encephalopathy (SAE) is a frequent complication of sepsis and is associated with a higher risk of short-term mortality and long-term cognitive impairment. The EEG is a sensitive complement of the clinical examination that can also detect and quantify encephalopathy and identify features with prognostic value, such as lack of reactivity. Moreover, despite their effect on outcome is still debated, the EEG is the only tool to detect non-convulsive seizures which can occur in a septic setting. Understanding the pathophysiology of SAE is fundamental to define potential therapeutic targets. Neuroinflammation plays an important role in the development of SAE and many blood and imaging biomarkers have recently shown a promising ability to distinguish SAE form non-SAE patient. In recent years, some interesting mediators of inflammation were successfully targeted in animal models, with a significant reduction in the neuroinflammation and in sepsis-induced cognitive decline. However, the complexity of the host response to sepsis currently limits the use of immunomodulation therapies in humans. Alteration in regulatory systems of cerebral blood flow, namely cerebral autoregulation (CA) and neurovascular coupling, contribute to SAE development. Nowadays, clinicians have access to different tools to assess them at the bedside and CA-based blood pressure protocols should be implemented to optimize cerebral perfusion. Its inauspicious consequences, its complex physiopathology and the lack of efficacious treatment make of SAE a highly active research subject.

Metabolic Reprogramming of Microglia in Sepsis-Associated Encephalopathy: Insights from Neuroinflammation.

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by sepsis that manifests as a range of brain dysfunctions from delirium to coma. It is a relatively common complication of sepsis associated with poor patient prognosis and mortality. The pathogenesis of SAE involves neuroinflammatory responses, neurotransmitter dysfunction, blood-brain barrier (BBB) disruption, abnormal blood flow regulation, etc. Neuroinflammation caused by hyperactivation of microglia is considered to be a key factor in disease development, which can cause a series of chain reactions, including BBB disruption and oxidative stress. Metabolic reprogramming has been found to play a central role in microglial activation and executive functions. In this review, we describe the pivotal role of energy metabolism in microglial activation and functional execution and demonstrate that the regulation of microglial metabolic reprogramming might be crucial in the development of clinical therapeutics for neuroinflammatory diseases like SAE.

Sepsis and the brain: a review for acute and general physicians.

Sepsis-associated encephalopathy (SAE) describes acute cognitive dysfunction secondary to systemic or peripheral infection occurring outside of the central nervous system (CNS). Symptoms can range from mild confusion to coma and may precede the clinical signs of sepsis. Recognition that SAE is a potential differential diagnosis in patients presenting with delirium is important, as SAE is a diagnosis of exclusion. Physicians should also be aware that severe SAE is associated with a high mortality. Although mortality is often secondary to multiorgan failure rather than neurological sequelae, long-term cognitive and psychological morbidities have been reported in sepsis survivors. Early treatment (which can include prompt identification and source control of the infection) and good supportive care might improve cognitive outcomes. Future work should aim to improve understanding of both acute and chronic SAE with a focus on therapeutic interventions and improving patient outcomes.

[Research Progress in Clinical Electrophysiological Assessment of Patients with Sepsis-Associated Encephalopathy].

Sepsis-associated encephalopathy(SAE) caused by infections outside the central nervous system always presents extensive brain damage.It is common in clinical practice and associated with a poor prognosis.There are problems in the assessing and diagnosing of SAE.Many factors,such as sedation and mechanical ventilation,make it difficult to assess SAE,while electrophysiological examination may play a role in the assessment.We reviewed the studies of electrophysiological techniques such as electroencephalography and somatosensory evoked potentials for monitoring SAE,hoping to provide certain evidence for the clinical evaluation and diagnosis of SAE.

Effects of hydrogen-rich saline in neuroinflammation and mitochondrial dysfunction in rat model of sepsis-associated encephalopathy.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is one of the most common types of sepsis-related organ dysfunction without overt central nervous system (CNS) infection. It is associated with higher mortality, low quality of life, and long-term neurological sequelae in suspected patients. At present there is no specific treatment for SAE rather than supportive therapy and judicious use of antibiotics, which are sometimes associated with adverse effects. Molecular hydrogen (H2) has been reported to play crucial role in regulating inflammatory responses, neuronal injury, apoptosis and mitochondrial dysfunction in adult models of SAE. Here we report the protective effect of hydrogen-rich saline in juvenile SAE rat model and its possible underling mechanism(s). MATERIALS AND METHODS: Rats were challenged with lipopolysaccharide (LPS) at a dose of 8 mg/kg injected intraperitoneally to induce sepsis and hydrogen-rich saline (HRS) administered 1 h following LPS induction at a dose of 5 ml/kg. Rats were divided into: sham, sham + HRS, LPS and LPS + HRS. At 48 h, rats were sacrificed and Nissl staining for neuronal injury, TUNEL assay for apoptotic cells detection, immunohistochemistry, and ELISA protocol for inflammatory cytokines determination, mitochondrial dysfunction parameters, electron microscopy and western blot analysis were studied to examine the effect of HRS in LPS-induced septic rats. RESULTS: Rats treated with HRS improved neuronal injury, improvement in rats' survival rate. ELISA analysis showed decreased TNF-α and IL-1ß and increased IL-10 expression levels in the HRS-treated group. Apoptotic cells were decreased after HRS administration in septic rats. The numbers of GFAP and IBA-1positive cells were attenuated in the HRS-treated group when compared to the LPS group. Subsequently, GFAP and IBA-1 immunoreactivity were decreased after HRS treatment. Mitochondrial membrane potential detected by JC-1 dye and ATP content were decreased in septic rats, which were improved after HRS treatment, while release of ROS was increased in the LPS group reverted by HRS treatment, ameliorating mitochondrial dysfunction. Further analysis by transmission electron microscopy showed decreased number of mitochondria and synapses, and disrupted mitochondrial membrane ultrastructure in the LPS group, while HRS administration increased mitochondria and synapses number. CONCLUSION: These data demonstrated that HRS can improve survival rate, attenuate neuroinflammation, astrocyte and microglial activation, neuronal injury and mitochondrial dysfunction in juvenile SAE rat model, making it a potential therapeutic candidate in treating paediatric SAE.

Identification of sepsis-associated encephalopathy risk factors in elderly patients: a retrospective observational cohort study.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis that affects upwards of half of all sepsis patients. Few studies have examined the etiology and risk factors of SAE among elderly patients. This study was designed to explore the epidemiology of SAE and the risk factors associated with its development in elderly populations. METHODS: This was a retrospective analysis of elderly sepsis patients admitted to our intensive care unit between January 2017 and January 2022. We then compared non-SAE and SAE groups concerning baseline clinicopathological findings, underlying diseases, infection site, disease type, disease severity, biochemical findings, and 28-day mortality. We further stratified patients in the SAE group based on whether or not they survived for 28 days, and we compared the above data between these groups. RESULTS: Of the 222 elderly sepsis patients, 132 (59.46%) had SAE. SAE patients were found to be significantly older than non-SAE patients. Both age and blood sodium concentrations were found to be associated with SAE risk, while elderly sepsis patients without underlying chronic obstructive pulmonary disease (COPD) have a relatively higher risk of developing SAE. The SAE group also had a significantly higher rate of 28-day mortality, and sequential organ failure assessment (SOFA) scores were a risk factor associated with 28-day mortality. DISCUSSION: Among elderly sepsis patients, SAE risk increases with advancing age, higher blood sodium concentrations, and without underlying COPD. SAE incidence is associated with a poorer prognosis, and SOFA scores are independent predictors of increased mortality among elderly SAE patients.