Targeted rescue of synaptic plasticity improves cognitive decline in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a frequent complication of severe systemic infection resulting in delirium, premature death, and long-term cognitive impairment. We closely mimicked SAE in a murine peritoneal contamination and infection (PCI) model. We found long-lasting synaptic pathology in the hippocampus including defective long-term synaptic plasticity, reduction of mature neuronal dendritic spines, and severely affected excitatory neurotransmission. Genes related to synaptic signaling, including the gene for activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and members of the transcription-regulatory EGR gene family, were downregulated. At the protein level, ARC expression and mitogen-activated protein kinase signaling in the brain were affected. For targeted rescue we used adeno-associated virus-mediated overexpression of ARC in the hippocampus in vivo. This recovered defective synaptic plasticity and improved memory dysfunction. Using the enriched environment paradigm as a non-invasive rescue intervention, we found improvement of defective long-term potentiation, memory, and anxiety. The beneficial effects of an enriched environment were accompanied by an increase in brain-derived neurotrophic factor (BDNF) and ARC expression in the hippocampus, suggesting that activation of the BDNF-TrkB pathway leads to restoration of the PCI-induced reduction of ARC. Collectively, our findings identify synaptic pathomechanisms underlying SAE and provide a conceptual approach to target SAE-induced synaptic dysfunction with potential therapeutic applications to patients with SAE.

Early hyperbaric oxygen therapy through regulating the HIF-1α signaling pathway attenuates Neuroinflammation and behavioral deficits in a mouse model of Sepsis-associated encephalopathy.

BACKGROUND: Sepsis-associated encephalopathy (SAE) presents a significant clinical challenge, associated with increased mortality and healthcare expenses. Hyperbaric oxygen therapy (HBOT), involving inhaling pure or highly concentrated oxygen under pressures exceeding one atmosphere, has demonstrated neuroprotective effects in various conditions. However, the precise mechanisms underlying its protective actions against sepsis-associated brain injury remain unclear. This study aimed to determine whether HBOT protects against SAE and to elucidate the impact of the hypoxia-inducible factor-1α (HIF-1α) signaling pathway on SAE. METHODS: The experiment consisted of two parts. In the first part, C57BL/6 J male mice were divided into five groups using a random number table method: control group, sham surgery group, sepsis group, HBOT + sepsis group, and HBOT + sham surgery group. In the subsequent part, C57BL/6 J male mice were divided into four groups: sepsis group, HBOT + sepsis group, HIF-1α + HBOT + sepsis group, and HIF-1α + sepsis group. Sepsis was induced via cecal ligation and puncture (CLP). Hyperbaric oxygen therapy was administered at 1 h and 4 h post-CLP. After 24 h, blood and hippocampal tissue were collected for cytokine measurements. HIF-1α, TNF-α, IL-1ß, and IL-6 expression were assessed via ELISA and western blotting. Microglial expression was determined by immunofluorescence. Blood-brain barrier permeability was quantified using Evans Blue. Barnes maze and fear conditioning were conducted 14 days post-CLP to evaluate learning and memory. RESULTS: Our findings reveal that CLP-induced hippocampus-dependent cognitive deficits coincided with elevated HIF-1α and increased TNF-α, IL-1ß, and IL-6 levels in both blood and hippocampus. Observable activation of microglial cells in the hippocampus and increased blood-brain barrier (BBB) permeability were also evident. HBOT mitigated HIF-1α, TNF-α, IL-1ß, and IL-6 levels, attenuated microglial activation in the hippocampus, and significantly improved learning and memory deficits in CLP-exposed mice. Additionally, these outcomes were corroborated by injecting a lentivirus that overexpressed HIF-1α into the hippocampal region of the mice. CONCLUSION: HIF-1α escalation induced peripheral and central inflammatory factors, promoting microglial activation, BBB impairment, and cognitive dysfunction. However, HBOT ameliorated these effects by reducing HIF-1α levels in Sepsis-Associated Encephalopathy.

Paediatric sepsis-associated encephalopathy (SAE): a comprehensive review.

Sepsis-associated encephalopathy (SAE) is one of the most common types of organ dysfunction without overt central nervous system (CNS) infection. It is associated with higher mortality, low quality of life, and long-term neurological sequelae, its mortality in patients diagnosed with sepsis, progressing to SAE, is 9% to 76%. The pathophysiology of SAE is still unknown, but its mechanisms are well elaborated, including oxidative stress, increased cytokines and proinflammatory factors levels, disturbances in the cerebral circulation, changes in blood-brain barrier permeability, injury to the brain's vascular endothelium, altered levels of neurotransmitters, changes in amino acid levels, dysfunction of cerebral microvascular cells, mitochondria dysfunction, activation of microglia and astrocytes, and neuronal death. The diagnosis of SAE involves excluding direct CNS infection or other types of encephalopathies, which might hinder its early detection and appropriate implementation of management protocols, especially in paediatric patients where only a few cases have been reported in the literature. The most commonly applied diagnostic tools include electroencephalography, neurological imaging, and biomarker detection. SAE treatment mainly focuses on managing underlying conditions and using antibiotics and supportive therapy. In contrast, sedative medication is used judiciously to treat those showing features such as agitation. The most widely used medication is dexmedetomidine which is neuroprotective by inhibiting neuronal apoptosis and reducing a sepsis-associated inflammatory response, resulting in improved short-term mortality and shorter time on a ventilator. Other agents, such as dexamethasone, melatonin, and magnesium, are also being explored in vivo and ex vivo with encouraging results. Managing modifiable factors associated with SAE is crucial in improving generalised neurological outcomes. From those mentioned above, there are still only a few experimentation models of paediatric SAE and its treatment strategies. Extrapolation of adult SAE models is challenging because of the evolving brain and technical complexity of the model being investigated. Here, we reviewed the current understanding of paediatric SAE, its pathophysiological mechanisms, diagnostic methods, therapeutic interventions, and potential emerging neuroprotective agents.

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.

Conservative oxygen therapy in critically ill and perioperative period of patients with sepsis-associated encephalopathy.

Objectives: Sepsis-associated encephalopathy (SAE) patients in the intensive care unit (ICU) and perioperative period are administrated supplemental oxygen. However, the correlation between oxygenation status with SAE and the target for oxygen therapy remains unclear. This study aimed to examine the relationship between oxygen therapy and SAE patients. Methods: Patients diagnosed with sepsis 3.0 in the intensive care unit (ICU) were enrolled. The data were collected from the Medical Information Mart for Intensive Care IV (MIMIC IV) database and the eICU Collaborative Research Database (eICU-CRD) database. The generalized additive models were adopted to estimate the oxygen therapy targets in SAE patients. The results were confirmed by multivariate Logistic, propensity score analysis, inversion probability-weighting, doubly robust model, and multivariate COX analyses. Survival was analyzed by the Kaplan-Meier method. Results: A total of 10055 patients from eICU-CRD and 1685 from MIMIC IV were included. The incidence of SAE patients was 58.43%. The range of PaO2 (97-339) mmHg, PaO2/FiO2 (189-619), and SPO2≥93% may reduce the incidence of SAE, which were verified by multivariable Logistic regression, propensity score analysis, inversion probability-weighting, and doubly robust model estimation in MIMIC IV database and eICU database. The range of PaO2/FiO2 (189-619) and SPO2≥93% may reduce the hospital mortality of SAE were verified by multivariable COX regression. Conclusions: SAE patients in ICU, including perioperative period, require conservative oxygen therapy. We should maintain SPO2≥93%, PaO2 (97-339) mmHg and PaO2/FiO2 (189-619) in SAE patients.

Sepsis-Induced Brain Dysfunction: Pathogenesis, Diagnosis, and Treatment.

Dysregulated host response to infection, which cause life-threatening organ dysfunction, was defined as sepsis. Sepsis can cause acute and long-term brain dysfunction, namely, sepsis-associated encephalopathy (SAE) and cognitive impairment. SAE refers to changes in consciousness without direct evidence of central nervous system infection. It is highly prevalent and may cause poor outcomes in sepsis patients. Cognitive impairment seriously affects the life quality of sepsis patients and increases the medical burden. The pathogenesis of sepsis-induced brain dysfunction is mainly characterized by the interaction of systemic inflammation, blood-brain barrier (BBB) dysfunction, neuroinflammation, microcirculation dysfunction, and brain dysfunction. Currently, the diagnosis of sepsis-induced brain dysfunction is based on clinical manifestation of altered consciousness along with neuropathological examination, and the treatment is mainly involves controlling sepsis. Although treatments for sepsis-induced brain dysfunction have been tested in animals, clinical treat sepsis-induced brain dysfunction is still difficult. Therefore, we review the underlying mechanisms of sepsis-induced brain injury, which mainly focus on the influence of systemic inflammation on BBB, neuroinflammation, brain microcirculation, and the brain function, which want to bring new mechanism-based directions for future basic and clinical research aimed at preventing or ameliorating brain dysfunction.

Central role of microglia in sepsis-associated encephalopathy: From mechanism to therapy.

Sepsis-associated encephalopathy (SAE) is a cognitive impairment associated with sepsis that occurs in the absence of direct infection in the central nervous system or structural brain damage. Microglia are thought to be macrophages of the central nervous system, devouring bits of neuronal cells and dead cells in the brain. They are activated in various ways, and microglia-mediated neuroinflammation is characteristic of central nervous system diseases, including SAE. Here, we systematically described the pathogenesis of SAE and demonstrated that microglia are closely related to the occurrence and development of SAE. Furthermore, we comprehensively discussed the function and phenotype of microglia and summarized their activation mechanism and role in SAE pathogenesis. Finally, this review summarizes recent studies on treating cognitive impairment in SAE by blocking microglial activation and toxic factors produced after activation. We suggest that targeting microglial activation may be a putative treatment for SAE.

Therapeutic effects of human umbilical cord mesenchymal stem cell on sepsis-associated encephalopathy in mice by regulating PI3K/AKT pathway.

Sepsis-associated encephalopathy is a common brain diseases, presenting severe diffuse brain dysfunction. The umbilical cord mesenchymal stem cells have been reported to have protective role for treating diseases, while its role in sepsis-associated encephalopathy remained elusive. This brief report investigated the therapeutic effect of umbilical cord mesenchymal stem cells on sepsis-associated encephalopathy in mice model and uncovering the underlying mechanism. The sepsis-associated encephalopathy mice were injected with 3 mg/kg lipopolysaccharide. An enzyme-linked immunosorbent assay was carried out to determine the production of inflammatory cytokines. Morris water maze test was used to evaluate mice's neurological dysfunction. Cell apoptosis and tissue injury of the cerebral cortex were assessed using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and HE staining. Evans Blue leakage detection was used to examine the blood-brain barrier integrity. The protein levels were determined using Western blot. Results showed that the productions of inflammatory cytokines including interleukin 6 (IL-6), interleukin-1ß (IL-1ß), tumor necrosis factor α (TNF-α), and high mobility group box protein 1 (HMGB1) and activated NF-κB were increased in sepsis-associated encephalopathy mice, which were decreased by umbilical cord mesenchymal stem cells treatment. Besides, umbilical cord mesenchymal stem cells inhibited lipopolysaccharide-induced cell apoptosis and neuron injury of the cerebral cortex in sepsis-associated encephalopathy mice. Moreover, cognitive dysfunction was observed in sepsis-associated encephalopathy mice, which was alleviated by umbilical cord mesenchymal stem cells. Furthermore, umbilical cord mesenchymal stem cells activated PI3K/AKT signaling pathway. In conclusion, umbilical cord mesenchymal stem cells alleviated inflammation, cell apoptosis and neuron injury of the cerebral cortex, and cognitive dysfunction in sepsis-associated encephalopathy animal model in a PI3K/AKT dependent pathway, making them to be a promising therapeutic strategy for treating sepsis-associated encephalopathy.

Non-hepatic Hyperammonemia: A Potential Therapeutic Target for Sepsis-associated Encephalopathy.

Sepsis-Associated Encephalopathy (SAE) is a common complication in the acute phase of sepsis, and patients who develop SAE have a higher mortality rate, longer hospital stay, and worse quality of life than other sepsis patients. Although the incidence of SAE is as high as 70% in sepsis patients, no effective treatment is available for this condition. To develop an effective treatment for SAE, it is vital to explore its pathogenesis. It is known that hyperammonemia is a possible factor in the pathogenesis of hepatic encephalopathy as ammonia is a potent neurotoxin. Furthermore, our previous studies indicate that non-hepatic hyperammonemia seems to occur more often in sepsis patients; it was also found that >50% of sepsis patients with non-hepatic hyperammonemia exhibited encephalopathy and delirium. Substatistical analyses indicate that non-hepatic hyperammonemia is an independent risk factor for SAE. This study updates the definition, clinical manifestations, and diagnosis of SAE; it also investigates the possible treatment options available for non-hepatic hyperammonemia in patients with sepsis and the mechanisms by which non-hepatic hyperammonemia causes encephalopathy.

Sepsis-associated encephalopathy and septic encephalitis: an update.

INTRODUCTION: Sepsis-associated encephalopathy (SAE) and septic encephalitis (SE) are associated with increased mortality, long-term cognitive impairment, and focal neurological deficits. AREAS COVERED: The PUBMED database was searched 2016-2020. The clinical manifestation of SAE is delirium, SE additionally is characterized by focal neurological symptoms. SAE is caused by inflammation with endothelial/microglial activation, increase of permeability of the blood-brain-barrier, hypoxia, imbalance of neurotransmitters, glial activation, axonal, and neuronal loss. Septic-embolic (SEE) and septic-metastatic encephalitis (SME) are characterized by focal ischemia (SEE) and small abscesses (SME). The continuum between SAE, SME, and SEE is documented by imaging techniques and autopsies. The backbone of treatment is rapid optimum antibiotic therapy. Experimental approaches focus on modulation of inflammation, stabilization of the blood-brain barrier, and restoration of membrane/mitochondrial function. EXPERT OPINION: The most promising diagnostic approaches are new imaging techniques. The most important measure to fight delirium remains establishment of daily structure and adequate sensory stimuli. Dexmedetomidine and melatonin appear to reduce the frequency of delirium, their efficacy in SAE and SE remains to be established. Drugs already licensed for other indications or available as food supplements which may be effective in SAE are statins, L-DOPA/benserazide, ß-hydroxybutyrate, palmitoylethanolamide, and tetracyclines or other bactericidal non-lytic antibiotics.

A retrospective study of sepsis-associated encephalopathy: epidemiology, clinical features and adverse outcomes.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a common complication of sepsis that may result in worse outcomes. This study was designed to determine the epidemiology, clinical features, and risk factors of SAE. METHODS: This was a retrospective study of all patients with sepsis who were admitted to the Critical Care Medicine Department of Hangzhou First People's Hospital Affiliated with Zhejiang University School of Medicine from January 2015 to December 2019. RESULTS: A total of 291 sepsis patients were screened, and 127 (43.6%) were diagnosed with SAE. There were significant differences in median age, proportion of underlying diseases such as hypertension, Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, gastrointestinal infections, detection rate of Enterococcus, and 28-day mortality between the SAE and non-SAE groups. Both the SOFA score and APACHE II score were independent risk factors for SAE in patients with sepsis. All 127 SAE patients were divided into survival and non-survival groups. The age, SOFA score, and APACHE II score were independently associated with 28-day mortality in SAE patients. CONCLUSION: In the present retrospective study, nearly half of patients with sepsis developed SAE, which was closely related to poor outcomes. Both the SOFA score and APACHE II score were independent risk factors for predicting the occurrence and adverse outcome of SAE.

Electroacupuncture Improves Cognition in Rats With Sepsis-Associated Encephalopathy.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a common complication of sepsis. Although sepsis is effectively managed with the administration of antibiotics and source control, which may include surgical intervention, SAE usually leads to prolonged cognitive dysfunction affecting the quality of life of the patients. In this study, we investigated the possible effect of electroacupuncture (EA) on cognition in a model of SAE induced by cecal ligation and puncture (CLP). MATERIALS AND METHODS: The rats were randomly divided into four groups: the control group, the CLP group, the CLP with EA treatment group (CLP + EA), and the CLP with sham EA treatment group (CLP + sham EA). EA at DU20, LI11, and ST36 or sham EA was performed 30 min daily for 10 consecutive days starting from 2 days before CLP. Then cognitive function was examined by the Morris water maze test. On day 14 after CLP surgery, the synaptic injury, neuron loss, and oxidative stress were studied. RESULTS: Rats with EA treatment showed improved survival rate, spatial learning, and memory abilities. The dendritic spine density, the synaptic proteins, and the hippocampal neuron number were also increased after EA treatment. Furthermore, EA suppressed oxidative stress through regulating the level of malondialdehyde and superoxide dismutase and enhanced the expression of antioxidant nuclear factor erythroid-2-related factor-2 and hemeoxygenase-1. But sham EA did not have the same effect. CONCLUSIONS: EA may protect against SAE-induced cognitive dysfunction by inhibiting synaptic injury, neuronal loss, and oxidative stress, and the nuclear factor erythroid-2-related factor-2/hemeoxygenase-1 signaling pathway may be involved in this effect.

[Effect of "Tongdu Tiaoshen" needling on cognitive dysfunction in patients with sepsis asso-ciated encephalopathy and its mechanism].

OBJECTIVE: To observe the efficacy of "Tongdu Tiaoshen" (dredging Governor Vessel and regula-ting mind,needling on the cognitive function of patients with sepsis associated encephalopathy (SAE). METHODS: A total of 64 patients with SAE were enrolled in the present study, and randomly and equally divided into a control group and a treatment group. Patients in the control group received conventional medicines and conventional needling treatment. The patients of the treatment group received conventional medicines and "Tongdu Tiaoshen" needling treatment. The treatment was conducted once daily for 10 days. The Montreal Cognitive Assessment (MoCA) scale was used to assess the therapeutic effect after the treatment. Serum interleukin-6 (IL-6) was detected by radioimmunoassay, serum C-reactive protein (CRP) was detected by immuno-scattering method, and arterial blood lactic acid (Lac) content was detected by blood gas analyzer. RESULTS: The effective rate in the treatment group was obviously higher than that in the control group (P<0.01). After the treatment, the MoCA scores were considerably increased in both groups compared with their own pre-treatment (P<0.01), and the MoCA scores in the treatment group were obviously higher than those of the control group in the visual space and executive function, attention and computational power, language, abstraction and delayed recall dimensions (P<0.01). The contents of IL-6, CRP and Lac in both groups were significantly decreased after the treatment relevant to those of their own pre-treatment (P<0.01), and were obviously lower in the treatment group than those in the control group (P<0.01). CONCLUSION: "Tongdu Tiaoshen" needling can significantly improve the cognitive function of SAE patients, which may be associated with its effect in reducing inflammatory reaction of sepsis.

Sepsis-associated encephalopathy: A review of literature.

Sepsis is a leading cause of death in medical and surgical intensive care units (ICUs). Disturbance of consciousness of varying severity is an early warning sign of developing sepsis in the majority of cases. Sepsis-associated encephalopathy (SAE) is the most frequent type of encephalopathy in the ICU and is defined as a state of diffuse cerebral dysfunction caused by the inflammatory response of the body to various infections, where the inflammatory process does not affect the central nervous system (CNS) directly and the primary symptom is a disturbed level of consciousness. The aim of this comprehensive review was to collect the latest scientific knowledge regarding the epidemiology, clinical aspects, pathogenesis, diagnosis, and possible prevention strategies related to SAE.

Sepsis and Septic Shock Strategies.

Three therapeutic principles most substantially improve organ dysfunction and survival in sepsis: early, appropriate antimicrobial therapy; restoration of adequate cellular perfusion; timely source control. The new definitions of sepsis and septic shock reflect the inadequate sensitivity, specify, and lack of prognostication of systemic inflammatory response syndrome criteria. Sequential (sepsis-related) organ failure assessment more effectively prognosticates in sepsis and critical illness. Inadequate cellular perfusion accelerates injury and reestablishing perfusion limits injury. Multiple organ systems are affected by sepsis and septic shock and an evidence-based multipronged approach to systems-based therapy in critical illness results in improve outcomes.

Neuroglobin Protects Rats from Sepsis-Associated Encephalopathy via a PI3K/Akt/Bax-Dependent Mechanism.

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, and has no generally accepted treatment due to its complicated pathophysiology. Previously, we demonstrated the protective role of neuroglobin (Ngb) in SAE rats, but the exact mechanism has not been determined. To investigate the potential neuroprotective roles and mechanisms of Ngb, Sprague-Dawley rats were used. Overexpression of Ngb via intracerebroventricular injection with Ngb plasmids attenuated brain damage assessed by hematoxylin and eosin (HE) staining and neurological dysfunction assessed by Morris water maze test. Western blot analysis also showed that the phosphorylation of Akt increased and the protein level of Bax decreased. Furthermore, the protective effect can be abolished by PI3K/Akt pathway inhibitor LY294002. Our results demonstrate that Ngb can protect rats from SAE via a PI3K/Akt/Bax-dependent mechanism.