[Research progress on the role of microglia in sepsis-associated encephalopathy].

Sepsis-associated encephalopathy (SAE) refers to diffuse brain dysfunction caused by sepsis, which is characterized by decreased attention, directional impairment, being prone to irritation, and in severe cases the patient will experience drowsiness and coma. The pathogenesis of SAE mainly includes neuroinflammation, damage of blood-brain barrier, cerebral vascular dysfunction, and neurometabolic changes, among which neuroinflammation is the core pathological process. Microglia are considered to be important immune cells of the central nervous system and play an important role in neuroinflammation. This article systematically describes the role of microglia in the development of SAE, and discusses the phenotype and related signaling pathways of microglia, in order to clarify the role of microglia in SAE and provide a theoretical basis for clinical treatment of SAE.

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.

Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a severe and frequent complication of sepsis causing delirium, coma, and long-term cognitive dysfunction. We identified microglia and C1q complement activation in hippocampal autopsy tissue of patients with sepsis and increased C1q-mediated synaptic pruning in a murine polymicrobial sepsis model. Unbiased transcriptomics of hippocampal tissue and isolated microglia derived from septic mice revealed an involvement of the innate immune system, complement activation, and up-regulation of lysosomal pathways during SAE in parallel to neuronal and synaptic damage. Microglial engulfment of C1q-tagged synapses could be prevented by stereotactic intrahippocampal injection of a specific C1q-blocking antibody. Pharmacologically targeting microglia by PLX5622, a CSF1-R inhibitor, reduced C1q levels and the number of C1q-tagged synapses, protected from neuronal damage and synapse loss, and improved neurocognitive outcome. Thus, we identified complement-dependent synaptic pruning by microglia as a crucial pathomechanism for the development of neuronal defects during SAE.

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.

Activation of glucagon-like peptide-1 receptor in microglia exerts protective effects against sepsis-induced encephalopathy via attenuating endoplasmic reticulum stress-associated inflammation and apoptosis in a mouse model of sepsis.

Sepsis-induced encephalopathy (SAE) is a detrimental complication in patients with severe sepsis, while there is still no effective treatment. Previous studies have elucidated the neuroprotective effects of glucagon-like peptide-1 receptor (GLP-1R) agonists. However, the role of GLP-1R agonists in the pathological process of SAE is unclear. Here, we found that GLP-1R was up-regulated in the microglia of septic mice. The activation of GLP-1R with Liraglutide could inhibit endoplasmic reticulum stress (ER stress) and associated inflammatory response as well as apoptosis triggered by LPS or tunicamycin (TM) in BV2 cells. In vivo experiments confirmed the benefits of Liraglutide in the regulation of microglial activation, ER stress, inflammation, and apoptosis in the hippocampus of septic mice. Additionally, the survival rate and cognitive dysfunction of septic mice were also improved after Liraglutide administration. Mechanically, cAMP/PKA/CREB signaling is involved in the protection of ER stress-induced inflammation and apoptosis in cultured microglial cells under LPS or TM stimulations. In conclusion, we speculated that GLP-1/GLP-1R activation in microglia might be a potential therapeutic target for the treatment of SAE.

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.

Environmental Enrichment Protects Against Cognition Deficits Caused by Sepsis-Associated Encephalopathy.

BACKGROUND: One of the most serious complications of sepsis is sepsis-associated encephalopathy (SAE), which impairs the cognition ability of survivors. Environmental enrichment (EE) has been demonstrated to alleviate cognition deficits under many kinds of brain injury conditions. However, EE's effects on SAE remain unknown. Therefore, this study aimed to determine EE's effect on cognition disorders under SAE conditions and the underlying mechanism. MATERIALS AND METHODS: Adult male rats, subject to SAE or not, were housed under a standard environment (SE) or EE for 30 days. Subsequently, the rats were subjected to cognitive tests, such as the novel object recognition (NOR) test, the Morris water maze (MWM) test, an Open Field (OF) test, the elevated plus maze (EPM) test, and a sensory neglect (SN) test. Neuroinflammation, apoptosis, and oxidative stress changes in the brain were also detected. RESULTS: The results revealed that SAE impaired somatesthesia, recognition memory, spatial learning and memory, and exploratory activity, which were significantly improved by EE housing. EE also prevented SAE-induced anxiety-like behavior. In addition, EE housing capable induced a decrease in pro-inflammatory cytokines, and an increase in anti-inflammatory cytokines and antioxidant properties in the brain. Moreover, EE housing exerted an anti-apoptosis function by upregulating the level of B-cell lymphoma/leukemia-2 (Bcl-2) level and downregulating the level of p53 level in the hippocampus. CONCLUSIONS: The results of the present study indicated that EE exerts a neuroprotective function on cognitive ability in SAE rats. The effect is achieved by increasing antioxidants, and anti-inflammatory and antiapoptotic capacities. EE can effectively rescue SAE-induced cognitive deficits.

Probiotics Exert Protective Effect against Sepsis-Induced Cognitive Impairment by Reversing Gut Microbiota Abnormalities.

Recent evidence has revealed that probiotics could affect neurodevelopment and cognitive function via regulating gut microbiota. However, the role of probiotics in sepsis-associated encephalopathy (SAE) remained unclear. This study was conducted to assess the effects and therapeutic mechanisms of probiotic Clostridium butyricum (Cb) against SAE in mice. The SAE model mouse was induced by cecal ligation and puncture (CLP) and was given by intragastric administration with Cb for 1 month. A series of behavioral tests, including neurological severity score, tail suspension test, and elevated maze test, were used to assess cognitive impairment. Nissl staining and Fluoro-Jade C (FJC) staining were used to assess neuronal injury. Microglia activation, the release of neuroinflammatory cytokines, and the levels of ionized calcium-binding adapter molecule 1 (Iba-1) and brain-derived neurotrophic factor (BDNF) in the brain were determined. The compositions of the gut microbiota were detected by 16S rRNA sequencing. Our results revealed that Cb significantly attenuated cognitive impairment and neuronal damage. Moreover, Cb significantly inhibited excessive activation of microglia, decreased Iba-1 level, and increased BDNF level in the SAE mice. In addition, Cb improved gut microbiota dysbiosis of SAE mice. These findings revealed that Cb exerted anti-inflammatory effects and improved cognitive impairment in SAE mice, and their neuroprotective mechanisms might be mediated by regulating gut microbiota.

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.

Ethyl pyruvate protects against sepsis-associated encephalopathy through inhibiting the NLRP3 inflammasome.

BACKGROUND: With the advance of antibiotics and life support therapy, the mortality of sepsis has been decreasing in recent years. However, the incidence of sepsis-associated encephalopathy (SAE), a common complication of sepsis, is still high. There are few effective therapies to treat clinical SAE. We previously found that ethyl pyruvate (EP), a metabolite derivative, is able to effectively inhibit the NLRP3 inflammasome activation. Administration of ethyl pyruvate protects mice against polymicrobial sepsis in cecal ligation and puncture (CLP) model. The aim of present study is to investigate if ethyl pyruvate is able to attenuate SAE. METHODS: After CLP, C57BL/6 mice were intraperitoneally or intrathecally injected with saline or ethyl pyruvate using the sham-operated mice as control. New Object Recognition (NOR) and Morris Water Maze (MWM) were conducted to determine the cognitive function. Brain pathology was assessed via immunohistochemistry. To investigate the mechanisms by which ethyl pyruvate prevent SAE, the activation of NLRP3 in the hippocampus and the microglia were determined using western blotting, and cognitive function, microglia activation, and neurogenesis were assessed using WT, Nlrp3-/- and Asc-/- mice in the sublethal CLP model. In addition, Nlrp3-/- and Asc-/- mice treated with saline or ethyl pyruvate were subjected to CLP. RESULTS: Ethyl pyruvate treatment significantly attenuated CLP-induced cognitive decline, microglia activation, and impaired neurogenesis. In addition, EP significantly decreased the NLRP3 level in the hippocampus of the CLP mice, and inhibited the cleavage of IL-1ß induced by NLRP3 inflammsome in microglia. NLRP3 and ASC deficiency demonstrated similar protective effects against SAE. Nlrp3-/- and Asc-/- mice significantly improved cognitive function and brain pathology when compared with WT mice in the CLP models. Moreover, ethyl pyruvate did not have additional effects against SAE in Nlrp3-/- and Asc-/- mice. CONCLUSION: The results demonstrated that ethyl pyruvate confers protection against SAE through inhibiting the NLRP3 inflammasome.

Sepsis Associated Delirium.

Sepsis is a potentially life-threatening condition caused by a systemic dysregulated host response to infection. The brain is particularly susceptible to the effects of sepsis with clinical manifestations ranging from mild confusion to a deep comatose state. Sepsis-associated delirium (SAD) is a cerebral manifestation commonly occurring in patients with sepsis and is thought to occur due to a combination of neuroinflammation and disturbances in cerebral perfusion, the blood brain barrier (BBB) and neurotransmission. The neurological impairment associated with SAD can persist for months or even longer, after the initial septic episode has subsided which may impair the rehabilitation potential of sepsis survivors. Early identification and treatment of the underlying sepsis is key in the management of SAD as once present it can be difficult to control. Through the regular use of validated screening tools for delirium, cases of SAD can be identified early; this allows potentially aggravating factors to be addressed promptly. The usefulness of biomarkers, neuroimaging and electroencephalopathy (EEG) in the diagnosis of SAD remains controversial. The Society of Critical Care Medicine (SCCM) guidelines advise against the use of medications to treat delirium unless distressing symptoms are present or it is hindering the patient's ability to wean from organ support.

Morin exerts protective effects on encephalopathy and sepsis-associated cognitive functions in a murine sepsis model.

Sepsis-associated encephalopathy (SAE) often leads to cognitive impairments in the rest life of septic survivors. The potential pathological changes of SAE are complicated and have not been fully understood. Morin, a flavone compound exhibiting neuroprotective activity and anti-inflammation effect, was employed to treat with CLP-induced septic mice in our study. The data from a novel object recognition test and tail suspension test indicated that morin treatment reversed cognitive dysfunction and relieved depressive-like behaviors in septic mice. Morin down-regulated the expressions of IL-6, MCP-1, TNF-α and IL-10 in serum and diminished microglia activation in septic mice. Additionally, Western blot results showed that morin reduced the phosphokinase GSK3ß activity and elevated the phosphatase PP2A activity, which led to lower tau phosphorylation. Morin reduced Aß deposition and protected the synapse integrity, which might be the possible mechanism of protecting cognitive functions in septic mice. In conclusion, we identified that morin exerted anti-inflammation and anti-neurodegeneration effects in septic mice, and prevented further cognitive impairments.

Maf1 Ameliorates Sepsis-Associated Encephalopathy by Suppressing the NF-kB/NLRP3 Inflammasome Signaling Pathway.

Background: The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been identified as an important mediator of blood-brain-barrier disruption in sepsis-associated encephalopathy (SAE). However, no information is available concerning the critical upstream regulators of SAE. Methods: Lipopolysaccharide (LPS) was used to establish an in vitro model of blood-brain barrier (BBB) disruption and an in vivo model of SAE. Disruption of BBB integrity was assessed by measuring the expression levels of tight-junction proteins. NLRP3 inflammasome activation, pro-inflammatory cytokines levels, and neuroapoptosis were measured using biochemical assays. Finally, the FITC-dextran Transwell assay and Evan's blue dye assay were used to assess the effect of Maf1 on LPS-induced endothelial permeability in vitro and in vivo. Results: We found that Maf1 significantly suppressed the brain inflammatory response and neuroapoptosis induced by LPS in vivo and in vitro. Notably, Maf1 downregulated activation of the NF-κB/p65-induced NLRP3 inflammasome and the expression of pro-inflammatory cytokines. In addition, we found that Maf1 and p65 directly bound to the NLRP3 gene promoter region and competitively regulated the function of NLRP3 in inflammations. Moreover, overexpression of NLRP3 reversed the effects of p65 on BBB integrity, apoptosis, and inflammation in response to LPS. Our study revealed novel role for Maf1 in regulating NF-κB-mediated inflammasome formation, which plays a prominent role in SAE. Conclusions: Regulation of Maf1 might be a therapeutic strategy for SAE and other neurodegenerative diseases associated with inflammation.

Brain Volume Changes in Patients with Acute Brain Dysfunction Due to Sepsis.

BACKGROUND: Sepsis-induced brain dysfunction (SIBD) is often encountered in sepsis patients and is related to increased morbidity. No specific tests are available for SIBD, and neuroimaging findings are often normal. In this study, our aim was to analyze the diagnostic value of volumetric analysis of the brain structures and to find out its significance as a prognostic measure. METHODS: In this prospective observational study, brain magnetic resonance imaging (MRI) sections of 25 consecutively enrolled SIBD patients (17 with encephalopathy and 8 with coma) and 22 healthy controls underwent volumetric evaluation by an automated segmentation method. RESULTS: Ten SIBD patients had normal MRI, and 15 patients showed brain lesions or atrophy. The most prominent volume reduction was found in cerebral and cerebellar white matter, cerebral cortex, hippocampus, and amygdala, whereas deep gray matter regions and cerebellar cortex were relatively less affected. SIBD patients with normal MRI showed significantly reduced volumes in hippocampus and cerebral white matter. Caudate nuclei, putamen, and thalamus showed lower volume values in non-survivor SIBD patients, and left putamen and right thalamus showed a more pronounced volume reduction in coma patients. CONCLUSIONS: Volumetric analysis of the brain appears to be a sensitive measure of volumetric changes in SIBD. Volume reduction in specific deep gray matter regions might be an indicator of unfavorable outcome.

SIRT1 activation by butein attenuates sepsis-induced brain injury in mice subjected to cecal ligation and puncture via alleviating inflammatory and oxidative stress.

Sepsis-induced brain injury is frequently encountered in critically ill patients with severe systemic infection. Butein (3,4,2',4'-tetrahydroxychalcone) has been demonstrated as the neuro-protective agent via reducing inflammation and oxidative stress on neurons. Moreover, activation of silent information regulator 1 (SIRT1) inhibits apoptosis, oxidation and inflammation thus alleviating sepsis-induced multiorgan injuries. In present study, we show that butein administrated intraperitoneally (10 mg/kg) saved mice from sepsis-induced lethality by increasing 7-day survival rate after cecal ligation and puncture (CLP) surgery. Additionally, butein treatment enhanced SIRT1 signaling thus decreasing the Ac-NF-κB, Ac-FOXO1 and Ac-p53 levels, thus attenuating the brain injury of mice after CLP surgery by decreasing cerebral edema, maintaining the blood-brain barrier integrity, inhibiting neuronal apoptosis, and decreasing pro-inflammatory cytokines production (IL-6, TNF-α and IL-1ß) and oxidative stress (downregulation of MDA, and upregulation of SOD and CAT) in both serum and cerebral cortex tissues. Moreover, butein treatment attenuated LPS induced neurological function loss. However, all above mentioned neuro-protective actions of butein were partially inhibited by EX527 co-treatment, one standard SIRT1 inhibitor. Collectively, butein attenuates sepsis-induced brain injury through alleviation of cerebral inflammation, oxidative stress and apoptosis by SIRT1 signaling activation.

Sevoflurane exerts brain-protective effects against sepsis-associated encephalopathy and memory impairment through caspase 3/9 and Bax/Bcl signaling pathway in a rat model of sepsis.

Objective We compared the effects of sevoflurane and isoflurane on systemic inflammation, sepsis-associated encephalopathy, and memory impairment in a rat sepsis model of cecal ligation and puncture (CLP)-induced polymicrobial peritonitis. Methods Twenty-four rats were assigned to sham, CLP, CLP + sevoflurane, and CLP + isoflurane groups. At 72 hours after CLP, the rats underwent behavior tests. Serum cytokines were evaluated. Brain tissue samples were collected for determination of glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase; the wet/dry weight ratio; myeloperoxidase (MPO) and malondialdehyde (MDA); apoptotic gene release; and histologic examinations. Results The MPO level, wet/dry weight ratio, and histopathology scores were lower and the Bcl2a1 and Bcl2l2 expressions were upregulated in both the CLP + sevoflurane and CLP + isoflurane groups compared with the CLP group. The interleukin-6, interleukin-1ß, MDA, and caspase 3, 8, and 9 levels were lower; the GPX, SOD, Bax, Bcl2, and Bclx levels were higher; and non-associative and aversive memory were improved in the CLP + sevoflurane group compared with the CLP + isoflurane group. Conclusion Sevoflurane decreased apoptosis and oxidative injury and improved memory in this experimental rat model of CLP. Sevoflurane sedation may protect against brain injury and memory impairment in septic patients.

Regulation of Sirtuin 3-Mediated Deacetylation of Cyclophilin D Attenuated Cognitive Dysfunction Induced by Sepsis-Associated Encephalopathy in Mice.

The present study aimed to investigate cognitive dysfunction in the hippocampus induced by sepsis-associated encephalopathy (SAE) via acetylation of cyclophilin D (CypD) and opening of mitochondrial permeability transition pore. It also explored whether activating sirtuin 3 (SIRT3) can mediate deacetylation of CypD and prevent the development of SAE. Male mice were randomly assigned to six groups: sham group, cecal ligation puncture group, CypD siRNA transfection (CypD-si) group, CypD control siRNA transfection (CypD-c) group, SIRT3 overexpression vector pcDNA3.1 (SIRT3-p) group, and SIRT3 empty vector pcDNA3.1 (SIRT3-v) group (n = 18). The CypD-si and CypD-c groups were transfected with CypD siRNA and CypD control siRNA, respectively. The SIRT3-p and SIRT3-v groups were injected with SIRT3 pcDNA3.1 and vector pcDNA3.1, respectively. The learning and memory function was assessed using the learning version of the Morris water maze test. Then, cell apoptosis and the levels of CypD, acetylated CypD, SIRT-3, interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and caspase-3 in the hippocampus were determined. The levels of CypD and acetylation of CypD increased in the hippocampus induced by SAE. Increasing SIRT3 and decreasing CypD can attenuate cognitive impairment and neuroapoptosis, and protect the integrity of mitochondrial membrane from damage and restore the protein expressions of IL-6, TNF-α, and caspase-3. Activating SIRT3-mediated deacetylation of CypD attenuated learning and memory dysfunction induced by SAE.

Ginsenoside Rg1 protects against sepsis-associated encephalopathy through beclin 1-independent autophagy in mice.

BACKGROUND: Sepsis-associated encephalopathy (SAE), a commonly complicated syndrome, is associated with increased mortality in patients with sepsis. Currently, no specific diagnostic test or effective intervention exists to improve long-term consequences on cerebral function. Ginsenoside Rg1 (Rg1), a major component in ginseng, was reported to have pleiotropic properties including anti-inflammation and neuroprotection. The aim of our study was to investigate the protective effect of Rg1 on SAE and the potential mechanism. MATERIALS AND METHODS: SAE model was prepared by inducing cecal ligation and puncture (CLP) in mice. Rg1 was injected 1 h before the CLP operation. Survival rate within 7 d after operation was analyzed. Surviving mice were subjected to Morris water maze tests and the brains were collected for histopathologic evaluation and immunohistochemistry. The hippocampus was obtained for Western blot, real time polymerase chain reaction, and enzyme-linked immunosorbent assay analysis. RESULTS: Rg1 improved the postoperative survival rate and protected against sepsis-associated learning and memory impairments (Morris water maze). Besides, Rg1 was able to attenuate brain histopathologic changes (hematoxylin and eosin staining), suppress Iba1 activation, decrease the expressions of inflammatory cytokines (tumor necrosis factor α, interleukin 1ß, and interleukin 6), and reduce neuronal apoptosis (cleaved caspase 3 activation) in hippocampus. Furthermore, the mechanism study showed that Rg1 suppressed the expressions of light chain 3-II and p62 in hippocampus but not beclin 1. CONCLUSIONS: These findings suggested that Rg1 improved the survival rate and ameliorated cognitive impairments partially through regulating cerebral inflammation and apoptosis. In addition, the action mechanism might be noncanonical beclin 1-independent autophagy pathway. Rg1 may be a promising treatment strategy for SAE.

[CLINICAL ASPECTS OF SEPTIC ENCEPHALOPATHY].

Septic encephalopathy is a form of general cerebral dysfunction caused by a systemic inflammatory reaction. Its investigation encounters enormous difficulties for the lack of reliable biological markers of neuronal lesions and methods for the evaluation of consciousness in severely ill patients. Hence, the importance of correct clinical interpretation of the character and magnitude of CNS activity. Examples are presented demonstrating the difficulty of interpreting disorders in CNS activity associated with evere community-acquired pneumonia.

Sepsis-induced brain mitochondrial dysfunction is associated with altered mitochondrial Src and PTP1B levels.

Sepsis-induced brain dysfunction (SIBD) is often the first manifestation of sepsis, and its pathogenesis is associated with mitochondrial dysfunction. In this study, we investigated the roles of the tyrosine kinase Src and protein tyrosine phosphatase 1B (PTP1B) in brain mitochondrial dysfunction using a rat model of lipopolysaccharide (LPS)-induced sepsis. We found that there was a gradual and significant increase of PTP1B levels in the rat brain after sepsis induction. In contrast, brain Src levels were reduced in parallel with the PTP1B increase. Sepsis led to significantly reduced tyrosine phosphorylation of mitochondrial oxidative phosphorylation (OXPHOS) complexes I, II and III. Pretreatment of mitochondrial proteins with active PTP1B significantly inhibited complexes I and III activities in vitro, whereas Src enhanced complexes I, II, and III activities. PTP1B and Src were each co-immunoprecipitated with OXPHOS complexes I and III, suggesting direct interactions between both proteins and complexes I and III. Src also directly interacted with complex II. Furthermore, pretreatment of mitochondrial proteins with active PTP1B resulted in overproduction of reactive oxygen species and decreased mitochondrial membrane potential. Pretreatment with active Src produced the opposite effect. These results suggest that brain mitochondrial dysfunction following LPS-induced sepsis in rats is partly attributed to PTP1B and Src mediated decrease in mitochondrial protein tyrosine phosphorylation.