GluR2 can Drive Neuroinflammation and Cognitive Impairments Following Peripherally Repeated Lipopolysaccharide Exposures.

Neuroinflammation is being increasingly recognized as a vital factor in the development of various neurological and neuropsychiatric diseases. Lipopolysaccharides (LPS), an outer membrane component of gram-negative bacteria, can trigger innate immune responses, resulting in neuroinflammation and subsequent cognitive deficits. The expression of glutamate receptors (GluRs) on glial cells can induce glial activation. Therefore, we hypothesized that repeated LPS exposure can increase GluR levels, promoting microglial activation and ultimately affecting synaptic plasticity and cognitive function. In this study, C57/BL6 mice were repeatedly exposed to LPS to construct a neuroinflammation animal model. The levels of GluRs, inflammatory cytokines, ionized calcium-binding adaptor molecule 1, postsynaptic density protein 95, synaptophysin 38, NMDA receptor 2 A, and NMDA receptor 2B (GluN2B) were measured in the hippocampi. Furthermore, dendritic spine density in the CA1 hippocampal region was determined. Repeated LPS exposure induced cognitive impairments and microglial activation and increased GluR1 and GluR2 levels. This was accompanied by a significant decrease in GluN2B expression and dendritic spine density in the hippocampi. However, CFM-2, an α-amino-3- hydroxy-5-methyl-4-isoxazolepropionate receptor antagonist, reversed these anomalies. Furthermore, minocycline, a microglial inhibitor, reversed these anomalies and downregulated GluR2 but not GluR1 expression. In summary, we demonstrated that GluR2 plays an essential role in microglia-induced neuroinflammation, resulting in synaptic plasticity and cognitive impairment induced by repeated exposure to LPS.

Liraglutide ameliorates delirium-like behaviors of aged mice undergoing cardiac surgery by mitigating microglia activation via promoting mitophagy.

OBJECTIVE: Postoperative delirium (POD) is a prevalent complication in cardiac surgery patients, particularly the elderly, with neuroinflammation posited as a crucial contributing factor. We investigated the prophylactic effects of liraglutide, a GLP-1 analog, on delirium-like behaviors in aged mice undergoing cardiac surgery and explored the underlying mechanisms focusing on neuroinflammation, mitochondrial dysfunction, and synaptic plasticity. METHODS: Using a cardiac ischemia-reperfusion animal model to mimic cardiac surgery, we assessed delirium-like behaviors, microglial activation, NLRP3 inflammasome activation, mitophagy, synaptic engulfment, and synaptic plasticity. RESULTS: Cardiac surgery triggered delirium-like behaviors, concomitant with heightened microglial and NLRP3 inflammasome activation and impaired mitochondrial function and synaptic plasticity. Pretreatment with liraglutide ameliorated these adverse outcomes. Mechanistically, liraglutide enhanced mitophagy, thereby inhibiting NLRP3 inflammasome activation and subsequent microglial activation. Furthermore, liraglutide counteracted surgery-induced synaptic loss and impairment of synaptic plasticity. CONCLUSION: Liraglutide exerts protective effects against delirium-like behaviors in aged mice post-cardiac surgery, potentially through bolstering microglia mitophagy, curtailing neuroinflammation, and preserving synaptic integrity. This highlights the potential of liraglutide as a promising perioperative strategy for delirium prevention in cardiac surgery patients.

Complement C1q drives microglia-dependent synaptic loss and cognitive impairments in a mouse model of lipopolysaccharide-induced neuroinflammation.

Activated microglia and subsequent release of pro-inflammatory cytokines result in neuroinflammatory status which further damage neurological function including cognitive impairments in various neurological conditions. However, the underlying molecular mechanisms during these pathological processing remain unknown. In the current study, mice received intraperitoneal administrations of LPS (0.5 mg/kg, daily, Escherichia coli O55:B5) for seven consecutive days and their different cohorts were used for behavioral assessment with open field, Y maze, and novel object recognition test or for electrophysiology recordings of mEPSC, LFP or LTP in in vivo or ex vivo preparation. The hippocampus from some cohorts were harvested for immunostaining or Western blotting of c1q, Iba-1, CD68, PSD95 and dendritic spine density or for transcriptome and proteomics analysis. Repeated LPS injections induced an up-regulation of complement system protein c1q and distinct microglial phenotype with an enrichment of the complement-phagosome pathway. Microglial synaptic engulfment and profound synaptic loss were found. These pathological changes were accompanied with the significantly decreased excitatory synaptic transmission, disturbed theta oscillations, impaired hippocampal long-term potentiation, and cognitive impairments. Notably, neutralization of c1q signaling robustly prevented these changes. Collectively, our data provide evidence that activated microglia and complement cascade c1q signaling in the hippocampus may account for synaptic loss and cognitive impairments in a mouse model of neuroinflammation induced by repeated LPS injections. Our work implicates that complement system may be a therapeutic target for developing therapies to prevent or treat cognitive disorders related to neuroinflammation or other disease conditions including neurodegenerative disease per se.

Biochar-Dual Oxidant Composite Particles Alleviate the Oxidative Stress of Phenolic Acid on Tomato Seed Germination.

Phenolic acid is a well-known allelochemical, but also a pollutant in soil and water impeding crop production. Biochar is a multifunctional material widely used to mitigate the phenolic acids allelopathic effect. However, phenolic acid absorbed by biochar can still be released. In order to improve the removal efficiency of phenolic acids by biochar, the biochar-dual oxidant (BDO) composite particles were synthesized in this study, and the underlying mechanism of the BDO particles in ameliorating p-coumaric acid (p-CA) oxidative damage to tomato seed germination was revealed. Upon p-CA treatment, the BDO composite particles application increased the radical length, radical surface area, and germination index by 95.0%, 52.8%, and 114.6%, respectively. Compared to using biochar or oxidants alone, the BDO particles addition resulted in a higher removal rate of p-CA and produced more O2•-, HO•, SO4•- and 1O2 radicals via autocatalytic action, suggesting that BDO particles removed phenolic acid by both adsorption and free radical oxidation. The addition of BDO particles maintained the levels of the antioxidant enzyme activity close to the control, and reduced the malondialdehyde and H2O2 by 49.7% and 49.5%, compared to the p-CA treatment. Integrative metabolomic and transcriptomic analyses revealed that 14 key metabolites and 62 genes were involved in phenylalanine and linoleic acid metabolism, which increased dramatically under p-CA stress but down-regulated with the addition of BDO particles. This study proved that the use of BDO composite particles could alleviate the oxidative stress of phenolic acid on tomato seeds. The findings will provide unprecedented insights into the application and mechanism of such composite particles as continuous cropping soil conditioners.

HMGB1 mediates synaptic loss and cognitive impairment in an animal model of sepsis-associated encephalopathy.

BACKGROUND: Microglial activation-mediated neuroinflammation is one of the essential pathogenic mechanisms of sepsis-associated encephalopathy (SAE). Mounting evidence suggests that high mobility group box-1 protein (HMGB1) plays a pivotal role in neuroinflammation and SAE, yet the mechanism by which HMGB1 induces cognitive impairment in SAE remains unclear. Therefore, this study aimed to investigate the mechanism of HMGB1 underlying cognitive impairment in SAE. METHODS: An SAE model was established by cecal ligation and puncture (CLP); animals in the sham group underwent cecum exposure alone without ligation and perforation. Mice in the inflachromene (ICM) group were continuously injected with ICM intraperitoneally at a daily dose of 10 mg/kg for 9 days starting 1 h before the CLP operation. The open field, novel object recognition, and Y maze tests were performed on days 14-18 after surgery to assess locomotor activity and cognitive function. HMGB1 secretion, the state of microglia, and neuronal activity were measured by immunofluorescence. Golgi staining was performed to detect changes in neuronal morphology and dendritic spine density. In vitro electrophysiology was performed to detect changes in long-term potentiation (LTP) in the CA1 of the hippocampus. In vivo electrophysiology was performed to detect the changes in neural oscillation of the hippocampus. RESULTS: CLP-induced cognitive impairment was accompanied by increased HMGB1 secretion and microglial activation. The phagocytic capacity of microglia was enhanced, resulting in aberrant pruning of excitatory synapses in the hippocampus. The loss of excitatory synapses reduced neuronal activity, impaired LTP, and decreased theta oscillation in the hippocampus. Inhibiting HMGB1 secretion by ICM treatment reversed these changes. CONCLUSIONS: HMGB1 induces microglial activation, aberrant synaptic pruning, and neuron dysfunction in an animal model of SAE, leading to cognitive impairment. These results suggest that HMGB1 might be a target for SAE treatment.

A role of GABAA receptor α1 subunit in the hippocampus for rapid-acting antidepressant-like effects of ketamine.

Ketamine can produce rapid-acting antidepressant effects in treatment-resistant patients with depression. Although alterations in glutamatergic and GABAergic neurotransmission in the brain play a role in depression, the precise molecular mechanisms in these neurotransmission underlying ketamine's antidepressant actions remain largely unknown. Mice exposed to FSS (forced swimming stress) showed depression-like behavior and decreased levels of GABA (γ-aminobutyric acid), but not glutamate, in the hippocampus. Ketamine increased GABA levels and decreased glutamate levels in the hippocampus of mice exposed to FSS. There was a correlation between GABA levels and depression-like behavior. Furthermore, ketamine increased the levels of enzymes and transporters on the GABAergic neurons (SAT1, GAD67, GAD65, VGAT and GAT1) and astrocytes (EAAT2 and GAT3), without affecting the levels of enzymes and transporters (SAT2, VGluT1 and GABAAR γ2) on glutamatergic neurons. Moreover, ketamine caused a decreased expression of GABAAR α1 subunit, which was specifically expressed on GABAergic neurons and astrocytes, an increased GABA synthesis and metabolism in GABAergic neurons, a plasticity change in astrocytes, and an increase in ATP (adenosine triphosphate) contents. Finally, GABAAR antagonist bicuculline or ATP exerted a rapid antidepressant-like effect whereas pretreatment with GABAAR agonist muscimol blocked the antidepressant-like effects of ketamine. In addition, pharmacological activation and inhibition of GABAAR modulated the synthesis and metabolism of GABA, and the plasticity of astrocytes in the hippocampus. The present data suggest that ketamine could increase GABA synthesis and astrocyte plasticity through downregulation of GABAAR α1, increases in GABA, and conversion of GABA into ATP, resulting in a rapid-acting antidepressant-like action. This article is part of the Special Issue on 'Ketamine and its Metabolites'.

Reduced inhibition underlies early life LPS exposure induced-cognitive impairment: Prevention by environmental enrichment.

Early life immune activation has negative effects on the development of central nervous system and cognitive function, yet the underlying mechanism remains unclear. Increasing evidence has demonstrated that inflammation induces changes in microglia morphology, which lead to excessive synaptic pruning and improper function of neural circuits. Therefore, we hypothesized that early immune activation induced microglia activation, contributing to synaptic and cognitive impairments in adolescent mice. To establish the animal model of early immune activation, pups received a single intraperitoneal injection of 100 µg/kg lipopolysaccharide (LPS) on postnatal 10 (P10). Environmental enrichment (EE) was conducted four hours per day during P10-P38. Behavioral tests were performed by open field (P39), elevated plus-maze (P40) and Y maze tests (P41). The protein levels of glutamic acid decarboxylas67 (GAD67), parvalbumin (PV), vesicular gaba amino acid transporter (vGAT) and vesicular glutamate transporters (vGLUT1) were determined in the hippocampi and medial prefrontal cortex (mPFC). The protein levels of nuclear factor κB (NF-κB)/p65, NF-κB/p50, interleukin-1ß (IL-1ß), tumor necrosis factor - ɑ (TNF-ɑ) were determined in the hippocampi. The dendritic spine density was evaluated in the CA1 of the hippocampus. In our study, we showed that early life LPS exposure induced microglia activation and excessive inhibitory synapse engulfment, decreased number of perisomatic puncta on both inhibitory PV interneurons and excitatory neurons, which might contribute to excitation/inhibition imbalance, dendritic spine loss, and cognitive impairment in adolescent mice. Notably, EE rescued most of these abnormalities and improved cognitive impairment. In conclusion, our study demonstrated that reduced inhibition might contribute to early life LPS exposure induced-cognitive impairment. We also provided the possibility of the protective role of EE in rescuing these long-term adverse effects.

Aging-Related Neural Disruption Might Predispose to Postoperative Cognitive Impairment Following Surgical Trauma.

BACKGROUND: Accumulating evidence has demonstrated that aging is associated with an exaggerated response to surgical trauma together with cognitive impairments. This has significant implications for the development of clinical phenotype such as perioperative neurocognitive disorders (PND), which is a common complication following surgery, especially for the elderly. However, the mechanism by which aging brain is vulnerable to surgical trauma remains to be elucidated. OBJECTIVE: To test whether age-related alterations in hippocampal network activities contribute to increased risk of PND following surgery. METHODS: Thirty-two adult and seventy-two aged male C57BL/6 mice undergone sevoflurane anesthesia and exploratory laparotomy were used to mimic human abdominal surgery. For the interventional study, mice were treated with minocycline. Behavioral tests were performed post-surgery with open field, novel object recognition and fear conditioning tests, respectively. The brain tissues were then harvested and subjected to biochemistry studies. Local field potential (LFP) recording was performed in another separate experiment. RESULTS: Aged mice displayed signs of neuroinflammation, as reflected by significantly increased proinflammatory mediators in the hippocampus. Also, aged mice displayed persistently decreased oscillation activities under different conditions, both before and after surgery. Further correlation analysis suggested that theta power was positively associated with time with novel object, while γ oscillation activity was positively associated with freezing time to context. Of note, downregulation of neuroinflammation by microglia inhibitor minocycline reversed some of these abnormities. CONCLUSION: Our study highlights that age-related hippocampal oscillation dysregulation increases the risk of PND incidence, which might provide diagnostic/prognostic biomarkers for PND and possible other neurodegenerative diseases.

Frailty is an independent risk factor of one-year mortality after elective orthopedic surgery: a prospective cohort study.

Frailty is associated with perioperative adverse outcomes, especially for the elderly. This study aimed to assess whether frailty was an independent risk factor of one-year mortality in frail patients after elective orthopedic surgery. In this prospective study, three hundred and thirteen patients aged ≥ 65 years, undergoing elective orthopedic surgery were finally included. Frailty assessed by the Clinical Frailty Score (CFS) before the surgery was present in 29.7% (93/313). Among them, 7.7% of patients (24/313) died at one year after surgery. In multivariate logistic analysis, higher CFS (OR = 2.271, 95% CI= 1.472-3.504) was found to be an independent risk factor of one-year mortality after surgery in elderly orthopedic patients. The area under the receiver operating characteristic curve of the model was 0.897 (95% CI 0.834-0.959). In addition, we found higher Charlson comorbidity index (OR= 1.498, 95% CI = 1.082-2.073) was also a significant risk factor. In conclusion, frailty is associated with increased one-year mortality in elderly patients after elective orthopedic surgery, which should be considered as a routine assessment tool in preoperative practice.

Parvalbumin interneuron-mediated neural disruption in an animal model of postintensive care syndrome: prevention by fluoxetine.

Postintensive care syndrome (PICS) is defined as a new or worsening impairment in cognition, mental health, and physical function after critical illness and persisting beyond hospitalization, which is associated with reduced quality of life and increased mortality. Recently, we have developed a clinically relevant animal model of PICS based on two-hit hypothesis. However, the underlying mechanism remains unclear. Accumulating evidence has demonstrated that hippocampal GABAergic interneuron dysfunction is implicated in various mood disorders induced by stress. Thus, this study investigated the role of hippocampal GABAergic interneurons and relevant neural activities in an animal model of PICS. In addition, we tested whether fluoxetine treatment early following combined stress can prevent these anatomical and behavioral pathologies. In the present study, we confirmed our previous study that this PICS model displayed reproducible anxiety- and depression like behavior and cognitive impairments, which resembles clinical features of human PICS. This behavioral state is accompanied by hippocampal neuroinflammation, reduced parvalbumin (PV) expression, and decreased theta and gamma power. Importantly, chronic fluoxetine treatment reversed most of these abnormities. In summary, our study provides additional evidence that PV interneuron-mediated hippocampal network activity disruption might play a key role in the pathology of PICS, while fluoxetine offers protection via modulation of the hippocampal PV interneuron and relevant network activities.

Contribution of DNA methyltransferases to spared nerve injury induced depression partially through epigenetically repressing Bdnf in hippocampus: Reversal by ketamine.

Long-lasting pain can induce depression, which seriously affects life quality of the patients, but little is known about the underlying mechanism. Chronic neuropathic pain can modulate DNA methylation in target genes related to neuroplasticity and mood regulation, which was induced by DNA methyltransferases (DNMTs). Methylation changes of brain-derived neurotrophic factor (Bdnf) in the hippocampus are critical for neuropathic pain and depression. Thus, we hypothesized that DNMTs are required for depression genesis, probably by repressing hippocampus Bdnf gene expression in rats with neuropathic pain, which can be rescued by ketamine. In the present study, rats were randomly subjected to spared nerve injury (SNI) or sham surgery. SNI upregulated DNMTs and downregulated Bdnf and exon I in the hippocampus and induced depression behaviors, whereas blocking the upregulation of DNMTs with RG108 alleviated SNI-induced depression by up-regulation of the expression of Bdnf and exon I. In addition, we showed that a single dose of ketamine could ameliorate SNI-induced depression-like behaviors, which was related to normalization of DNMTs and Bdnf. In conclusion, our study suggested that DNMTs-induced decreased expression of Bdnf may induce the comorbid of pain and depression, which can be prevented by ketamine.

A randomized double-blind study comparing prophylactic norepinephrine and ephedrine infusion for preventing maternal spinal hypotension during elective cesarean section under spinal anesthesia: A CONSORT-compliant article.

BACKGROUND: Studies have shown the efficacy of norepinephrine in the treatment of maternal hypotension during cesarean section by comparing it to treatment with phenylephrine. However, few studies have compared the efficacy of norepinephrine to ephedrine. METHODS: Ninety-seven women undergoing elective cesarean section were administered norepinephrine at 4 µg/minute (group N; n = 48) or ephedrine at 4 mg/minute (group E; n = 49) immediately postspinal anesthesia, with an on-off titration to maintain systolic blood pressure (SBP) at 80% to 120% of baseline. A rescue bolus of 8 µg norepinephrine was given whenever SBP reached the predefined lower limit. Our primary outcome was the incidence of tachycardia. Secondary outcomes included the incidence of bradycardia, hypertension, hypotension, severe hypotension, hypotensive episodes, number of rescue top-ups, hemodynamic performance error including median performance error (MDPE), and median absolute performance error (MDAPE). Neonatal Apgar scores and umbilical arterial (UA) blood gas data were also collected. RESULTS: Women in group N experienced fewer cases of tachycardia (4.2% vs 30.6%, P = .002, odds ratio: 0.11 [95% confidence interval, CI: 0.02-0.47]), a lower standardized heart rate (HR) (70.3 ±â€Š11 vs 75 ±â€Š11, P = .04, difference: 4.7 ±â€Š2.2 [95% CI: 0.24-9.1]), and a lower MDPE for HR (1.3 ±â€Š9.6 vs 8.4 ±â€Š13.5 bpm, P = .003, difference: 3.1 ±â€Š1.8 [95% CI: -0.6-6.7]). In addition, the lowest or the highest HR was lower in group N compared to group E (both P < .05). Meanwhile, the standardized SBP in group N was lower than that in group E (P = .04). For neonates, the UA blood gas showed a higher base excess (BE) and a lower lactate level in group N compared to E (both P < .001). Other hemodynamic variables, maternal, and neonatal outcomes were similar. CONCLUSION: Infusion of 4 µg/minute norepinephrine presented fewer cases of tachycardia, less fluctuation and a lower HR compared to baseline values, as well as a less stressed fetal status compared to ephedrine infusion at 4 mg/minute. In addition, norepinephrine infusion presented a lower standardized SBP compared to ephedrine.

Environmental enrichment improves pain sensitivity, depression-like phenotype, and memory deficit in mice with neuropathic pain: role of NPAS4.

Patients suffering from neuropathic pain have a higher incidence of depression and cognitive decline. Although environment enrichment (EE) may be effective in the treatment of neuropathic pain, the precise mechanisms underlying its actions remain determined. The aim of the study was to examine the molecular mechanisms underlying the EE's beneficial effects in mice with neuropathic pain. EE attenuated the pain threshold reduction, depression-like phenotype, and memory deficit in mice after chronic constriction injury (CCI). Furthermore, EE attenuated decreased neurogenesis and increased inflammation in the hippocampus of mice with neuropathic pain after CCI. Moreover, the suppression of adult hippocampal neurogenesis by temozolomide antagonized the beneficial effects of EE on depression-like phenotype and cognitive deficit in the mice with neuropathic pain. In addition, lipopolysaccharide-induced increase in tumor necrosis factor-α (TNF-α) in the hippocampus antagonized the beneficial effects of EE for these behavioral abnormalities in mice with neuropathic pain. Knock-down of NPAS4 (neuronal PAS domain protein 4) in the hippocampus by lentivirus targeting NPAS4 blocked these beneficial effects of EE in the mice with neuropathic pain. These all findings suggest that hippocampal NPAS4 plays a key role in the beneficial effects of EE on the pain sensitivity, depression-like phenotype, and memory deficit in mice with neuropathic pain. Therefore, it is likely that NPAS4 would be a new therapeutic target for perceptional, affective, and cognitive dimensions in patients with chronic pain.

Environmental enrichment improves long-term memory impairment and aberrant synaptic plasticity by BDNF/TrkB signaling in nerve-injured mice.

Nerve injury can induce memory impairment in mice. The aim of this research is to study the effect of environmental enrichment (EE) on long-term memory impairment in nerve-injured mice and the underlying mechanisms. Adult male C57BL/6 mice were received sham or chronic constriction injury (CCI) operation and reared in a standard environment (SE) or EE for 4 weeks after the operation. The pain threshold, long-term memory, expression of brain-derived neurotrophic factor (BDNF) and synaptic plasticity in hippocampus were determined. The results showed that CCI can induce the reduction in the mechanical and thermal pain thresholds, which were accompanied by long-term memory deficits in mice. CCI also induced the reduction of BDNF expression and synaptic plasticity impairments in the hippocampus, as represented by the dendritic spine density and postsynaptic density protein (PSD)-95 reduction, and long-term potential (LTP) dysfunction. Notably, EE can ameliorate the pain threshold and BDNF reduction, long-term memory deficits, and synaptic plasticity impairments in nerve-injured mice. However, the tropomyosin receptor kinase (Trk) B antagonist, ANA-12, blocked the EE-induced improvement in the long-term memory and synaptic plasticity impairment in nerve-injured mice. In conclusion, EE improved the pain threshold reduction, long-term memory and synaptic plasticity deficits in nerve-injured mice; BDNF / Trk B signaling may contribute to the relief of long-term memory and synaptic plasticity deficits induced by EE in nerve-injured mice.

Neopterin and mini-mental state examination scores, two independent risk factors for postoperative delirium in elderly patients with open abdominal surgery.

BACKGROUND: Postoperative delirium is described as one of the most common complications for elderly patients with unknown pathophysiological pathways. In this present study, we analyzed the clinical and biochemical parameters in elderly patients with or without a delirium after open abdominal surgery to investigate the possible predicative factors for a delirium. MATERIALS AND METHODS: Patients aged ≥60 years scheduled to undergo elective gastrointestinal tumor resection via laparotomy from July 2012 to June 2015 were enrolled in this study. Demographic and clinical data, characteristics of the surgical and anesthetic procedure, biochemical parameters were compared between patients with or without a delirium. Multivariate logistic regression testing was used for the evaluation of independent risk factors for postoperative delirium. RESULTS: Overall, 112 participants were enrolled in this study, 49 of which were diagnosed with postoperative delirium. Patients with a delirium had an older age (P = 0.013) and a lower Mini-Mental State Examination (MMSE) score (P < 0.01) compared with those patients who had no delirium. The duration of surgery and anesthesia, the levels of neopterin, C-reactive protein, interleukin-6, insulin-like growth factor-1 in patients with a delirium were significantly higher than those without a delirium (P < 0.05). Independent risk factors in the logistic regression for postoperative delirium were the levels of neopterin and MMSE scores. CONCLUSIONS: Our present study suggested the potential roles of neopterin and MMSE scores in the pathophysiology and prediction of delirium in elderly patients after open abdominal surgery.

Neuroinflammation-Induced Downregulation of Hippocampacal Neuregulin 1-ErbB4 Signaling in the Parvalbumin Interneurons Might Contribute to Cognitive Impairment in a Mouse Model of Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy (SAE) is a common complication associated with poor prognosis in septic patients, but the underlying mechanism remains unclear. We hypothesized that disturbed neuregulin 1 (NRG1)-ErbB4 signaling in the parvalbumin interneurons was involved in sepsis-induced cognitive impairment in a mouse model of SAE. The SAE model was induced by cecal ligation/perforation (CLP). Animals were randomly divided into the following six groups: sham + vehicle group, sham + NRG1 group, CLP + vehicle group, CLP + NRG1 group, CLP + NRG1 + AG1478 (ErbB4 inhibitor) group, and CLP + minocycline group. Behavioral tests and in vivo electrophysiology were performed at the indicated time points. The brain tissues were harvested to determine the levels of hippocampcal cytokines, IBA1-positive cells, NRG1, ErbB4, and parvalbumin. In the present study, sepsis induced the anxiety-like behavior and hippocampal-dependent cognitive impairment, as reflected by significantly increased distance spent in the open field test and decreased freezing time to context in the fear conditioning test. The abnormal behavioral changes co-occurred with significant increases in hippocampal IBA1-positive cells, IL-1ß and IL-6 levels, and decreased NRG1, ErbB4, parvalbumin expressions, and evoked gamma activity. NRG1 treatment attenuated the sepsis-induced cognitive impairment and the associated biochemical markers, which were abolished by AG1478 administration. Notably, minocycline treatment attenuated neuroinflammation and mimicked the beneficial effects of NRG1 treatment. In summary, we provided additional evidence that the disruption of NRG1-ErbB4 signaling in the parvalbumin interneurons mediated by neuroinflammation might lead to abnormal gamma oscillations and thus contribute to cognitive impairment in a mouse model of SAE.

Sepsis-induced selective parvalbumin interneuron phenotype loss and cognitive impairments may be mediated by NADPH oxidase 2 activation in mice.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by many pathological events, including neuroinflammation and oxidative stress damage. Increasing evidence suggests that parvalbumin (PV) interneurons play a key role in the cognitive process, whereas the dysfunction of these interneurons has been implicated in a number of major psychiatric disorders. Here, we aimed to investigate whether enhanced inflammation and oxidative stress-mediated PV interneuron phenotype loss plays a role in sepsis-induced cognitive impairments. METHODS: Male C57BL/6 mice were subjected to cecal ligation and puncture or sham operation. For the interventional study, the animals were chronically treated with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin, at 5 mg/kg. The mice were euthanized at the indicated time points, and the brain tissues were harvested for determination of the PV, membrane subunit of NADPH oxidase gp91(phox), and markers of oxidative stress (4-hydroxynonenal and malondialdehyde) and inflammation (tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß, IL-6, and IL-10). A separate cohort of animals was used to evaluate the behavioral alterations by the open field and fear conditioning tests. Primary hippocampal neuronal cultures were used to investigate the mechanisms underlying the dysfunction of PV interneurons. RESULTS: Sepsis resulted in cognitive impairments, which was accompanied by selective phenotype loss of PV interneurons and increased gp91(phox), 4-hydroxynonenal, malondialdehyde, IL-1ß, and IL-6 expressions. Notably, these abnormalities could be rescued by apocynin treatment. CONCLUSION: Selective phenotype loss of PV interneurons, as a result of NADPH oxidase 2 (Nox2) activation, might partly contribute to cognitive impairments in a mouse model of SAE.

Flurbiprofen improves dysfunction of T-lymphocyte subsets and natural killer cells in cancer patients receiving post-operative morphine analgesia.

OBJECTIVE: Acute pain can lead to immune dysfunction, which can be partly ameliorated by successful pain management. Opioids, which are widely used for analgesia, can result in the deterioration of immune function. This study aimed to investigate the influence of morphine with or without flurbiprofen as post-operative analgesics on the immune systems of patients undergoing gastric cancer surgery. METHODS: 60 patients undergoing gastric cancer surgery were equally randomized into two groups. They received post-operative patient-controlled intravenous (IV) analgesia using morphine either with or without flurbiprofen. Visual analogue scale (VAS) scores, Bruggemann comfort scale (BCS) scores, morphine consumption, time of first flatus, incidence of nausea/vomiting, and T-lymphocyte subsets (CD3⁺, CD4⁺, and CD8⁺) and natural killer cells (CD3⁻CD16⁺CD56⁺) were evaluated. RESULTS: No significant difference was observed in the VAS scores, BCS scores, and nausea/vomiting incidence between groups. Less morphine was consumed and the time of first flatus was earlier in patients receiving morphine with flurbiprofen than morphine alone. The expression of CD3⁺, CD4⁺, CD4⁺/CD8⁺, and CD3⁻CD16⁺CD56⁺ decreased at 2 hours after incision and, except for CD3⁻CD16⁺CD56⁺, returned to baseline at 120 hours after surgery. Moreover, the expression of CD3⁻CD16⁺CD56⁺ at 2 hours after incision and the expression of CD3⁺, CD4⁺, CD4⁺/CD8⁺, and CD3⁻CD16⁺CD56⁺ at 24 hours after surgery were higher in patients receiving morphine with flurbiprofen than morphine alone. CONCLUSION: The combination of morphine and flurbiprofen ameliorates the immune depression in Tlymphocyte subsets and natural killer cells and provides a similar analgesic efficacy to morphine alone in patients undergoing gastric cancer surgery.