Metformin attenuates sepsis-induced neuronal injury and cognitive impairment.
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ABSTRACT: Background
Sepsis is considered to be a high-risk factor for cognitive impairment in the brain. The purpose of our study is to explore whether sepsis causes cognitive impairment and try to evaluate the underlying mechanisms and intervention measures.Methods
Here, we used cecum ligation and puncture (CLP) to simulate sepsis. Open field, Novel Objective Recognition, and Morris Water Maze Test were used to detect cognitive function, long-term potentiation was used to assess of synaptic plasticity, and molecular biological technics were used to assess synaptic proteins, ELISA kits were used to detect inflammatory factors. Metformin was injected into the lateral ventricle of SD rats, and we evaluated whether metformin alleviated CLP-mediated cognitive impairment using behavioral, electrophysiological and molecular biological technology experiments.Results
Here we report hippocampal-dependent cognitive deficits and synaptic dysfunction induced by the CLP, accompanied by a significant increase in inflammatory factors. At the same time, metformin was able to improve cognitive impairment induced by CLP in adult male rats.Conclusion
These findings highlight a novel pathogenic mechanism of sepsis-related cognitive impairment through activation of inflammatory factors, and these are blocked by metformin to attenuate sepsis-induced neuronal injury and cognitive impairment.
SUBMITTER: Qin Z
PROVIDER: S-EPMC8675518 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundNeuroinflammatory response is considered to be a high-risk factor for cognitive impairments in the brain. Lipopolysaccharides (LPS) is an endotoxin that induces acute inflammatory responses in injected bodies. However, the molecular mechanisms underlying LPS-associated cognitive impairments still remain unclear.MethodsHere, primary hippocampal neurons were treated with LPS, and western blotting and immunofluorescence were used to investigate whether LPS induces neurons damage. At the same time, SD rats were injected with LPS (830 μg/Kg) intraperitoneally, and Open field test, Novel Objective Recognition test, Fear condition test were used to detect cognitive function. LTP was used to assess synaptic plasticity, and molecular biology technology was used to assess the NF-κB pathway, while ELISA was used to detect inflammatory factors. In addition, metformin was used to treat primary hippocampal neurons, and intraventricularly administered to SD rats. The same molecular technics, behavioral and electrophysiological tests were used to examine whether metformin could alleviate the LPS-associated neuronal damage, as well as synaptic plasticity, and behavioral alterations in SD rats.ResultsAltogether, neuronal damage were observed in primary hippocampal neurons after LPS intervention, which were alleviated by metformin treatment. At the same time, LPS injection in rat triggers cognitive impairment through activation of NF-κB signaling pathway, and metformin administration alleviates the LPS-induced memory dysfunction and improves synaptic plasticity.ConclusionThese findings highlight a novel pathogenic mechanism of LPS-related cognitive impairments through activation of NF-κB signaling pathway, and accumulation of inflammatory mediators, which induces neuronal pathologic changes and cognitive impairments. However, metformin attenuates LPS-induced neuronal injury and cognitive impairments by blocking NF-κB pathway.
| S-EPMC8626880 | biostudies-literature
Project description:IntroductionDiabetic patients may develop acute lung injury less often than non-diabetics; a fact that could be partially ascribed to the usage of antidiabetic drugs, including metformin. Metformin exhibits pleiotropic properties which make it potentially beneficial against lung injury. We hypothesized that pretreatment with metformin preserves alveolar capillary permeability and, thus, prevents ventilator-induced lung injury.MethodsTwenty-four rabbits were randomly assigned to pretreatment with metformin (250 mg/Kg body weight/day per os) or no medication for two days. Explanted lungs were perfused at constant flow rate (300 mL/min) and ventilated with injurious (peak airway pressure 23 cmH?O, tidal volume ?17 mL/Kg) or protective (peak airway pressure 11 cmH?O, tidal volume ?7 mL/Kg) settings for 1 hour. Alveolar capillary permeability was assessed by ultrafiltration coefficient, total protein concentration in bronchoalveolar lavage fluid (BALF) and angiotensin-converting enzyme (ACE) activity in BALF.ResultsHigh-pressure ventilation of the ex-vivo lung preparation resulted in increased microvascular permeability, edema formation and microhemorrhage compared to protective ventilation. Compared to no medication, pretreatment with metformin was associated with a 2.9-fold reduction in ultrafiltration coefficient, a 2.5-fold reduction in pulmonary edema formation, lower protein concentration in BALF, lower ACE activity in BALF, and fewer histological lesions upon challenge of the lung preparation with injurious ventilation. In contrast, no differences regarding pulmonary artery pressure and BALF total cell number were noted. Administration of metformin did not impact on outcomes of lungs subjected to protective ventilation.ConclusionsPretreatment with metformin preserves alveolar capillary permeability and, thus, decreases the severity of ventilator-induced lung injury in this model.
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Project description:ObjectiveTo determine the association between olfactory function and cognition in patients and rodents.BackgroundPerioperative neurocognitive disorders include delayed neurocognitive recovery (dNCR). The contribution of olfactory function to dNCR remains undetermined. It is unknown whether odor enrichment could mitigate dNCR.MethodsWe performed a prospective observational cohort study to determine potential association between olfactory impairment and dNCR in patients. We assessed the effects of anesthesia/surgery on olfactory and cognitive function in mice using the block test and Barnes maze. We measured interleukin-6 (IL-6), olfactory mature protein, growth-associated protein 43, mature and premature olfactory neurons, postsynaptic density 95, and synaptophysin in blood, nasal epithelium, and hippocampus of mice. Odor enrichment, IL-6 antibody, and knockout of IL-6 were used in the interaction experiments.ResultsPatients with dNCR had worse odor identification than the patients without dNCR [preoperative: 7 (1.25, 9) vs 10 (8, 11), median (interquartile range), P <0.001; postoperative: 8 (2.25, 10) vs 10 (8, 11), P <0.001]. Olfactory impairment associated with dNCR in patients before and after adjusting age, sex, education, preoperative mini-mental state examination score, and days of the neuropsychological tests. Anesthesia/surgery induced olfactory and cognitive impairment, increased levels of IL-6 in blood and nasal epithelium, decreased amounts of olfactory receptor neurons and their markers in the nasal epithelium, and reduced amounts of synapse markers in the hippocampus of mice. These changes were attenuated by odor enrichment and IL-6 antibody.ConclusionThe anesthesia/surgery-induced olfactory impairment may contribute to dNCR in patients and postoperative cognitive impairment in mice. Odor enrichment could be a potential intervention.
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Project description:RationaleChemotherapy-induced cognitive impairment, also known as 'chemobrain', is now widely recognized as a frequent adverse side effect of cancer treatment that often persists into survivorship. There are no drugs available to prevent or treat chemotherapy-induced cognitive deficits. The aim of this study was to establish a mouse model of cisplatin-induced cognitive deficits and to determine the potential preventive effects of the anti-diabetic drug metformin.ResultsTreatment of C57/BL6J mice with cisplatin (cumulative dose 34.5 mg/kg) impaired performance in the novel object and place recognition task as well as in the social discrimination task indicating cognitive deficits. Co-administration of metformin prevented these cisplatin-induced cognitive impairments. At the structural level, we demonstrate that cisplatin reduces coherency of white matter fibers in the cingulate cortex. Moreover, the number of dendritic spines and neuronal arborizations as quantified on Golgi-stained brains was reduced after cisplatin treatment. Co-administration of metformin prevented all of these structural abnormalities in cisplatin-treated mice. In contrast to what has been reported in other models of chemobrain, we do not have evidence for persistent microglial or astrocyte activation in the brains of cisplatin-treated mice. Finally, we show that co-administration of metformin also protects against cisplatin-induced peripheral neuropathy.ConclusionIn summary, we show here for the first time that treatment of mice with cisplatin induces cognitive deficits that are associated with structural abnormalities in the brain. Moreover, we present the first evidence that the widely used and safe anti-diabetic drug metformin protects against these deleterious effects of cancer treatment. In view of the ongoing clinical trials to examine the potential efficacy of metformin as add-on therapy in patients treated for cancer, these findings should allow rapid clinical translation.
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Project description:Sepsis?induced cardiomyopathy (SIC) is a complication of severe sepsis and septic shock characterized by an invertible myocardial depression. This study sought to explore the potential effects and mechanism of luteolin, a flavonoid polyphenolic compound, in lipopolysaccharide (LPS)?induced myocardial injury. Experimental mice were randomly allocated into 3 groups (25 mice in each group): The control group (NC), the LPS group (LPS) and the LPS + luteolin group (LPS + Lut). Before the SIC model was induced, luteolin was dissolved in DMSO and injected intraperitoneally for 10 days into LPS + Lut group mice. NC group and LPS group mice received an equal volume of DMSO for 10 days. On day 11, the animal model of sepsis?induced cardiac dysfunction was induced by intraperitoneal injection of LPS. A total of 12 h after LPS injection, measurements and comparisons were made among the groups. Luteolin administration improved cardiac function, attenuated the inflammatory response, alleviated mitochondrial injury, decreased oxidative stress, inhibited cardiac apoptosis and enhanced autophagy. In addition, luteolin significantly decreased the phosphorylation of AMP?activated protein kinase (AMPK) in septic heart tissue. The protective effect of luteolin was abolished by 3?methyladenine (an autophagy inhibitor) and dorsomorphin (compound C, an AMPK inhibitor), as evidenced by decreased autophagic activity, destabilized mitochondrial membrane potential and increased apoptosis in LPS?treated cardiomyocytes, but was mimicked by 5?aminoimidazole?4?carboxamide ribonucleotide (an AMPK activator), suggesting that luteolin attenuates LPS?induced myocardial injury by increasing autophagy through AMPK activation. Luteolin may be a promising therapeutic agent for treating SIC.
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Project description:It is important to maintain cognitive integrity during underwater operations, which may also trigger cognitive alterations. Cognitive effect of underwater operations and the underlying mechanism remain elusive. Here, we found a single underwater operation affects cognition in a time-dependent model. Prolonged exposure elicits significant cognitive impairment and hippocampal dysfunction, which was accompanied by activation of microglia and upregulation of pro-inflammatory cytokines. RNA-sequencing supported the involvement of neuroinflammation and indicated the critical role of CCR3. Knockdown of CCR3 significantly rescued cognitive impairment and hippocampal dysfunction. Furthermore, the upregulation of pro-inflammatory cytokines was also reversed. Mechanistically, CCR3 knockdown switched the activated microglia from a pro-inflammatory to neuroprotective phenotype. Taken together, these results highlighted the time-dependent effects of a single underwater operation on cognitive function. Knocking down CCR3 can attenuate neuroinflammation by regulating polarization of activated microglia, thereby alleviating prolonged underwater operation-induced cognitive impairment.
2024-05-20 | GSE247651 | GEO
Project description:AimsSepsis-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.MethodsThe 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.ResultsThe 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.ConclusionPERK-STING-RIPK3 pathway facilitates cognitive impairment by inducing neuronal necroptosis in the pathology of SAE, which provided a new therapeutic target in SAE treatment.
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Project description:BACKGROUND & AIMS:The severity of sepsis can be linked to excessive inflammatory responses resulting in hepatic injury. P2X7 receptor activation by extracellular ATP (eATP) exacerbates inflammation by augmenting cytokine production; while CD39 (ENTPD1) scavenges eATP to generate adenosine, thereby limiting P2X7 activation and resulting in A2A receptor stimulation. We aim to determine how the functional interaction of P2X7 receptor and CD39 control the macrophage response, and consequently impact on sepsis and liver injury. METHODS:Sepsis was induced by cecal ligation and puncture in C57BL/6 wild-type (WT) and CD39-/- mice. Several in vitro assays were performed using peritoneal or bone marrow derived macrophages to determine CD39 ectonucleotidase activity and its role in sepsis-induced liver injury. RESULTS:CD39 expression in macrophages limits ATP-P2X7 receptor pro-inflammatory signaling. P2X7 receptor paradoxically boosts CD39 activity. Inhibition and/or deletion of P2X7 receptor in LPS-primed macrophages attenuates cytokine production and inflammatory signaling as well as preventing ATP-induced increases in CD39 activity. Septic CD39-/- mice exhibit higher levels of inflammatory cytokines and show more pronounced liver injury than WT mice. Pharmacological P2X7 blockade largely prevents tissue damage, cell apoptosis, cytokine production, and the activation of inflammatory signaling pathways in the liver from septic WT, while only attenuating these outcomes in CD39-/- mice. Furthermore, the combination of P2X7 blockade with adenosine A2A receptor stimulation completely inhibits cytokine production, the activation of inflammatory signaling pathways, and protects septic CD39-/- mice against liver injury. CONCLUSIONS:CD39 attenuates sepsis-associated liver injury by scavenging eATP and ultimately generating adenosine. We propose boosting of CD39 would suppress P2X7 responses and trigger adenosinergic signaling to limit systemic inflammation and restore liver homeostasis during the acute phase of sepsis. Lay summary: CD39 expression in macrophages limits P2X7-mediated pro-inflammatory responses, scavenging extracellular ATP and ultimately generating adenosine. CD39 genetic deletion exacerbates sepsis-induced experimental liver injury. Combinations of a P2X7 antagonist and adenosine A2A receptor agonist are hepatoprotective during the acute phase of abdominal sepsis.
| S-EPMC5875702 | biostudies-literature
Project description:IntroductionSepsis refers to severe systemic inflammation leading to acute lung injury (ALI) and death. Introducing novel therapies can reduce the mortality in ALI. Osteopontin (OPN), a secretory glycoprotein produced by immune reactive cells, plays a deleterious role in various inflammatory diseases. However, its role in ALI caused by sepsis remains unexplored. We hypothesize that treatment with an OPN-neutralizing antibody (anti-OPN Ab) protects mice against ALI during sepsis.MethodsSepsis was induced in 8-week-old male C57BL/6 mice by cecal ligation and puncture (CLP). Anti-OPN Ab or non-immunized IgG as control, at a dose of 50 μg/mouse, was intravenously injected at the time of CLP. After 20 hours, the expression of OPN and proinflammatory cytokines in tissues and plasma was examined by real-time PCR, Western blot, and ELISA. Plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) and the lung myeloperoxidase (MPO) levels were determined by colorimetric assays. Lung damage and neutrophil infiltrations were determined by histological H&E and Gr-1 staining, respectively. The effect of recombinant mouse OPN (rmOPN) on human neutrophil-like cell (HL-60) migration was performed by Boyden chamber assays and the involvement of intracellular signaling molecules in HL-60 cells was revealed by Western blot.ResultsAfter 20 hours of sepsis, mRNA and protein levels of OPN were significantly induced in lungs, spleen, and plasma. Treatment with an anti-OPN Ab in septic mice significantly reduced the plasma levels of ALT, AST, and LDH, and the proinflammatory cytokines IL-6, IL-1β and the chemokine MIP-2, compared with the vehicle group. Similarly, the lung mRNA and protein expressions of proinflammatory cytokines and chemokine were greatly reduced in anti-OPN Ab-treated animals. The lung histological architecture, MPO and neutrophil infiltration were significantly improved in anti-OPN Ab-treated mice compared with the vehicle animals. Treatment of rmOPN in HL-60 cells significantly increased their migration, in vitro. The neutrophils treated with rmOPN remarkably increased the levels of phospho focal adhesion kinase (pFAK), phospho extracellular signal-regulated kinase (pERK) and phospho p38.ConclusionsOur findings clearly demonstrate the beneficial outcomes of anti-OPN Ab treatment in protecting against ALI, implicating a novel therapeutic strategy in sepsis.
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Project description:Acute lung injury is one of major complications associated with sepsis, responsible for morbidity and mortality. Patients who suffer from acute lung injury often require respiratory support under sedations, and it would be important to know the role of sedatives in lung injury. We examined volatile anesthetic isoflurane, which is commonly used in surgical setting, but also used as an alternative sedative in intensive care settings in European countries and Canada. We found that isoflurane exposure attenuated neutrophil recruitment to the lungs in mice suffering from experimental polymicrobial abdominal sepsis. We found that isoflurane attenuated one of major neutrophil chemoattractants LTB4 mediated response via its receptor BLT1 in neutrophils. Furthermore, we have shown that isoflurane directly bound to BLT1 by a competition assay using newly developed labeled BLT1 antagonist, suggesting that isoflurane would be a BLT1 antagonist.
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