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.

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.

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.

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.

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.

Comparison of restrictive and liberal transfusion strategy on postoperative delirium in aged patients following total hip replacement: a preliminary study.

Few studies have examined the association between perioperative blood transfusion and postoperative delirium (POD) in aged patients undergoing total hip replacement surgery. In this prospective study, 186 patients older than 65 years undergoing elective unilateral total hip replacement surgery were enrolled. Of those, 94 patients were randomly assigned to the restrictive strategy transfusion strategy group, in which red blood cells were transfused in order to maintain 10.0 g/dL>hemoglobin≧8.0 g/dL. Ninety-two patients were randomly assigned to the liberal transfusion strategy group, in which red blood cells were transfused in order to maintain hemoglobin≧10.0 g/dL. POD was diagnosed by confusion assessment method. The baseline characteristics of patients, the length of hospital stay, the incidence of POD, myocardial infarction, stroke, wound infection, pulmonary embolism, and the transfusion volume were recorded. No difference was observed in the baseline characteristics, the length of hospital stay, and the incidence of POD, myocardial infarction, stroke, wound infection, and pulmonary embolism between the two groups (P>0.05). The proportion of patients transfused with red blood cell and frozen plasma was decreased in the restrictive transfusion group compared with the liberal transfusion group (P<0.05). In conclusion, restrictive transfusion does not influence the incidence of POD but reduces blood transfusion. Thus, restrictive transfusion may serve as an effective and safe strategy for aged patients following total hip replacement.

Early postoperative cognitive dysfunction is associated with higher cortisol levels in aged patients following hip fracture surgery.

This study aimed to evaluate the relationship between plasma cortisol levels and the occurrence of postoperative cognitive dysfunction (POCD) in aged patients following hip fracture surgery. A total of 175 patients, aged 65 years or older, who were scheduled for hip fracture surgery with spinal anesthesia were enrolled. Perioperative plasma levels of cortisol and neurocognitive tests were determined at 1 day preoperatively and 7 days postoperatively. Seventy-seven patients completed both blood sample collections and neurocognitive tests. POCD occurred in 29.9 % of patients at 7 days postoperatively. POCD patients presented significantly higher cortisol levels compared with non-POCD patients (P < 0.05). Furthermore, plasma cortisol levels were negatively correlated with mini-mental state examination (MMSE) scores at 7 days postoperatively (P < 0.0001). A specificity of 93 % and a sensitivity of 35 % were identified for the plasma cortisol measurement to discriminate POCD patients from non-POCD patients. The results suggest higher plasma cortisol levels are associated with POCD in aged patients following hip fracture surgery with spinal anesthesia.

Spinal neuroimmune activation inhibited by repeated administration of pioglitazone in rats after L5 spinal nerve transection.

Neuroimmune activation contributes to the generation and maintenance of neuropathic pain after peripheral nerve injury. Peroxisome proliferator activated receptor gamma (PPAR-γ) agonists have potential neuroprotection. The current study aimed to determine the effects of a PPAR-γ agonist pioglitazone on mechanical hyperalgesia and neuroimmune activation in a rat model of neuropathic pain induced by L5 spinal nerve transection (SNT). Thirty-two rats were equally randomized into 4 groups: sham operation with vehicle; L5 SNT with vehicle or pioglitazone; or L5 SNT with pioglitazone and a PPAR-γ antagonist GW9662. Pioglitazone or vehicle was administered 1h before operation and continued daily to day 14 after operation. The paw pressure threshold (PPT) was measured before operation and on days 3, 7, 14 after operation. Glial fibrillary acidic protein (GFAP) expression, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 levels, and nuclear factor-kappa B (NF-κB) activity in the lumbar spinal cord were determined on day 14 after operation. The results displayed pioglitazone improved the mechanical hyperalgesia, and attenuated the astrocyte and NF-κB activation and the inflammatory cytokine upregulation in nerve-injured rats, which might be reversed by GW9662. In conclusion, pioglitazone ameliorates the mechanical hyperalgesia induced by L5 SNT via inhibiting the spinal neuroimmune activation in rats, suggesting spinal PPAR-γ signaling pathway may be involved in the pathogenesis of mechanical hyperalgesia.

Effect of equivalent doses of fentanyl, sufentanil, and remifentanil on the incidence and severity of cough in patients undergoing abdominal surgery: A prospective, randomized, double-blind study.

BACKGROUND: Fentanyl congeners have been found to induce cough during induction of general anesthesia. Studies of fentanyl and sufentanil have found incidence rates of 28% to 65% and 15%, respectively. However, no study has assessed the occurrence of cough induced by remifentanil. OBJECTIVE: The aim of this study was to assess the effect of equivalent doses of fentanyl, sufentanil, and remifentanil on cough. METHODS: Patients rated American Society of Anesthesiologists class I or II of either sex, aged 18 to 60 years, who were scheduled for elective abdominal surgery with general anesthesia were randomly and equally assigned to 3 groups using a computer-generated table of random numbers. The patients received equivalent doses of fentanyl 2 µg/kg, sufentanil 0.2 µg/kg, or remifentanil 2 µg/kg via IV push. Vital signs (systolic blood pressure [SBP], heart rate [HR], and oxygen saturation via pulse oximetry [SpO2]) and the occurrence and severity of cough were recorded for 2 minutes after drug administration by an anesthesiologist who was blinded to the drug treatment. The severity of cough was graded as none (0), mild (1-2), moderate (3-5), or severe (>5). RESULTS: A total of 315 Chinese patients (197 women, 118 men; mean [SD] age, 37.9 [10.4] years) were approached for enrollment and assigned to 3 groups of 105 patients each; all patients completed the study protocol. The 3 treatment groups were similar in terms of demographic characteristics and type of abdominal surgery. The incidence of cough was significantly greater in the remifentanil group (57 [54.3%] patients) than in the fentanyl group (35 [33.3%]; P < 0.01) or the sufentanil group (32 [30.5%]; P < 0.01). The severity of cough was significantly greater in the remifentanil group (severe, moderate, mild, none: 24, 7, 26, 48) than in the fentanyl (7, 9, 19, 70; P < 0.01) or sufentanil group (4, 2, 26, 73; P < 0.01). In all 3 groups, when the patients coughed, significant increases were observed in their SBP (128 [12]-139 [16] mm Hg; P < 0.01) and HR (74 [10]-87 [16] beats/min; P < 0.01). Within 2 minutes after drug administration, 62 patients (59%) in the remifentanil group experienced hypoxemia (SpO2 <90%) necessitating manually assisted mask ventilation, while no patients experienced hypoxemia in the fentanyl or sufentanil group. Three patients (2.9%) in the remifentanil group experienced muscle rigidity and deterioration of SBP, HR, and SpO2. No other adverse events were recorded. Cunclusion: Remifentanil was associated with a significantly greater incidence and severity of cough than equivalent doses of fentanyl or sufentanil. Fentanyl and sufentanil appeared comparable in these Chinese patients undergoing abdominal surgery.

Hemodynamic changes due to infiltration of the scalp with epinephrine-containing lidocaine solution: a hypotensive episode before craniotomy.

Epinephrine-containing lidocaine solution is commonly infiltrated on the scalp before craniotomy. But the hemodynamic changes caused by epinephrine-containing lidocaine solution have been less intensely studied. A prospective randomized double blind control study was designed to observe hemodynamic changes caused by epinephrine-containing lidocaine solution in neurosurgical operations under general anesthesia. One hundred twenty patients undergoing scheduled craniotomy were allocated randomly to 4 groups. All the patients received 1% lidocaine 16 mL with different dose (concentration) epinephrine: group 1 with 40 microg (2.5 microg/mL); group 2 with 80 microg (5 microg/mL); group 3 with 160 microg (10 microg/mL); and group 4 (control group) without epinephrine. mean arterial pressure (MAP) and heart rate were recorded at 30-second interval in 5 minutes after the beginning of local infiltration. In group 1, group 2, and group 3, the lowest MAP and the highest MAP during this period also were recorded. Bleeding was assessed after raising the craniotomy flap. Compared with the baseline, significant hemodynamic changes, particularly decrease in MAP with increase in heart rate at 1.5 minutes after the beginning of local infiltration, were observed in group 1, group 2, and group 3 (P<0.001), but not in group 4. The highest MAP increased significantly compared with the baseline in group 3 (P<0.05), but not in group 1 or group 2. Epinephrine-containing lidocaine solution reduced bleeding significantly (P<0.01). Infiltration with epinephrine-containing lidocaine solution elicits temporary but significant hemodynamic changes including hypotension before craniotomy. Commonly clinically used concentrations of epinephrine (2.5 to 10 microg/mL) can reduce the bleeding on the scalp.