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Although anesthesia provides favorable conditions for surgical procedures, recent studies have revealed that the brain remains active in processing noxious signals even during anesthesia. However, whether and how these responses affect the anesthesia effect remains unclear. The ventrolateral periaqueductal gray (vlPAG), a crucial hub for pain regulation, also plays an essential role in controlling general anesthesia. Hence, it was hypothesized that the vlPAG may be involved in the regulation of general anesthesia by noxious stimuli. Here, we found that acute noxious stimuli, including capsaicin-induced inflammatory pain, acetic acid-induced visceral pain, and incision-induced surgical pain, significantly delayed recovery from sevoflurane anesthesia in male mice, whereas this effect was absent in the spared nerve injury-induced chronic pain. Pretreatment with peripheral analgesics could prevent the delayed recovery induced by acute nociception. Furthermore, we found that acute noxious stimuli, induced by the injection of capsaicin under sevoflurane anesthesia, increased c-Fos expression and activity in the GABAergic neurons of the ventrolateral periaqueductal gray. Specific reactivation of capsaicin-activated vlPAGGABA neurons mimicked the effect of capsaicin and its chemogenetic inhibition prevented the delayed recovery from anesthesia induced by capsaicin. Finally, we revealed that the vlPAGGABA neurons regulated the recovery from anesthesia through the inhibition of ventral tegmental area dopaminergic neuronal activity, thus decreasing dopamine (DA) release and activation of DA D1-like receptors in the brain. These findings reveal a novel, cell- and circuit-based mechanism for regulating anesthesia recovery by nociception, and it is important to provide new insights for guiding the management of the anesthesia recovery period.
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Anestésicos Inalatórios , Camundongos Endogâmicos C57BL , Nociceptividade , Substância Cinzenta Periaquedutal , Sevoflurano , Sevoflurano/farmacologia , Animais , Masculino , Camundongos , Anestésicos Inalatórios/farmacologia , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Mesencéfalo/efeitos dos fármacos , Estado de Consciência/efeitos dos fármacos , Estado de Consciência/fisiologia , Período de Recuperação da Anestesia , Capsaicina/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/fisiologiaRESUMO
Importance: Posttraumatic stress disorder (PTSD) is common in people who have experienced trauma, especially those hospitalized for surgery. Dexmedetomidine may reduce or reverse the early consolidation and formation of conditioned fear memory and prevent the occurrence of postoperative PTSD. Objective: To evaluate the effects of intraoperative and postoperative low-dose intravenous pumping dexmedetomidine on PTSD among patients with trauma undergoing emergency surgery. Design, Setting, and Participants: This double-blind, randomized clinical trial was conducted from January 22 to October 20, 2022, with follow-up 1 month postoperatively, in patients with trauma undergoing emergency surgery at 4 hospital centers in Jiangsu Province, China. A total of 477 participants were screened. The observers were blinded to patient groupings, particularly for subjective measurements. Interventions: Dexmedetomidine or placebo (normal saline) was administered at a maintenance dose of 0.1 µg/kg hourly from the start of anesthesia until the end of surgery and at the same rate after surgery from 9 pm to 7 am on days 1 to 3. Main Outcomes and Measures: The primary outcome was the difference in the incidence of PTSD 1 month after surgery in the 2 groups. This outcome was assessed with the Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (CAPS-5). The secondary outcomes were the pain score within 48 hours and 1 month postoperatively; incidence of postoperative delirium, nausea, and pruritus; subjective sleep quality; anxiety; and occurrence of adverse events. Results: A total of 310 patients (154 in the normal saline group and 156 in the dexmedetomidine group) were included in the modified intention-to-treat analysis (mean [SD] age, 40.2 [10.3] years; 179 men [57.7%]). The incidence of PTSD was significantly lower in the dexmedetomidine group than in the control group 1 month postoperatively (14.1% vs 24.0%; P = .03). The participants in the dexmedetomidine group had a significantly lower CAPS-5 score than those in the control group (17.3 [5.3] vs 18.9 [6.6]; mean difference, 1.65; 95% CI, 0.31-2.99; P = .02). After adjusting for potential confounders, the patients in the dexmedetomidine group were less likely to develop PTSD than those in the control group 1 month postoperatively (adjusted odds ratio, 0.51; 95% CI, 0.27-0.94; P = .03). Conclusions and Relevance: In this randomized clinical trial, the administration of intraoperative and postoperative dexmedetomidine reduced the incidence of PTSD among patients with trauma. The findings of this trial support the use of dexmedetomidine in emergency trauma surgery. Trial Registration: Chinese Clinical Trial Register Identifier: ChiCTR2200056162.
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Dexmedetomidina , Delírio do Despertar , Transtornos de Estresse Pós-Traumáticos , Masculino , Humanos , Adulto , Dexmedetomidina/uso terapêutico , Dexmedetomidina/efeitos adversos , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/prevenção & controle , Solução Salina , Delírio do Despertar/induzido quimicamente , Administração IntravenosaRESUMO
Background: Obesity is a risk factor for sedation-related respiratory depression during colonoscopy. In a colonoscopy, propofol is frequently used because of its strong sedative and hypnotic properties. However, propofol is associated with marked respiratory depression. The objective of this trial was to investigate the effectiveness and safety of dexmedetomidine plus oxycodone for conscious sedation during colonoscopy in obese patients. Methods: A total of 120 patients had colonoscopies, and they were divided into two groups at random: Dexmedetomidine and oxycodone were used to sedate group Dex + oxy; while group Pro + oxy received anesthesia with propofol plus oxycodone. Parameters including blood pressure, heart rate, respiration, blood oxygen saturation, injection pain, and recovery time were recorded for both groups. Results: The incidence of hypoxemia was significantly reduced in group Dex + oxy compared with group Pro + oxy (4.9% vs 20.3%, P = 0.011). Blood pressure was lower, and heart rate was higher in group Pro + oxy compared with group Dex + oxy (P < 0.05). In addition, group Dex + oxy showed a significantly shorter caecal insertion time, recovery time to orientation, and recovery time to walking than group Pro + oxy (P < 0.05). Endoscopist satisfaction scores were significantly higher in group Dex + oxy compared with group Pro + oxy (P = 0.042). Conclusion: For obese patients, dexmedetomidine plus oxycodone effectively sedate them with few adverse effects, while also reducing colonoscopy operation difficulty by allowing obese patients to reposition. Thus, dexmedetomidine plus oxycodone could be used safely as a conscious sedation method for colonoscopy in obese patients. Trial registration: The protocol was registered at www.chictr.org.cn (ChiCTR1800017283, July 21, 2018).
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PURPOSE: The aim of the study was to evaluate the value of lung ultrasound (LUS) in patients with cardiogenic shock treated by venoarterial extracorporeal membrane oxygenation (VA-ECMO). METHODS: A retrospective study was conducted in Xuzhou Central Hospital from September 2015 to April 2022. Patients with cardiogenic shock who received VA-ECMO treatment were enrolled in this study. The LUS score was obtained at the different time points of ECMO. RESULTS: Twenty-two patients were divided into a survival group (n = 16) and a nonsurvival group (n = 6). The intensive care unit (ICU) mortality was 27.3% (6/22). The LUS scores in the nonsurvival group were significantly higher than those in the survival group after 72 h (P < 0.05). There was a significant negative correlation between LUS scores and PaO2/FiO2 and LUS scores and pulmonary dynamic compliance(Cdyn) after 72 h of ECMO treatment (P < 0.001). ROC curve analysis showed that the area under the ROC curve (AUC) of T72-LUS was 0.964 (95% CI 0.887 ~ 1.000, P < 0.01). CONCLUSION: LUS is a promising tool for evaluating pulmonary changes in patients with cardiogenic shock undergoing VA-ECMO. TRIAL REGISTRATION: The study had been registered in the Chinese Clinical Trial Registry(NO.ChiCTR2200062130 and 24/07/2022).
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Oxigenação por Membrana Extracorpórea , Choque Cardiogênico , Humanos , Mortalidade Hospitalar , Pulmão/diagnóstico por imagem , Estudos Retrospectivos , Choque Cardiogênico/diagnóstico por imagem , Choque Cardiogênico/terapiaRESUMO
OBJECTIVE: To investigate postoperative functional connectivity (FC) alterations across impaired cognitive domains and their causal relationships with systemic inflammation. BACKGROUND: Postoperative cognitive dysfunction commonly occurs after cardiac surgery, and both systemic and neuroinflammation may trigger its development. Whether FC alterations underlying deficits in specific cognitive domains after cardiac surgery are affected by inflammation remains unclear. METHODS: Seventeen patients, who underwent cardiac valve replacement, completed a neuropsychological test battery and brain MRI scan before surgery and on days 7 and 30 after surgery compared to age-matched healthy controls. Blood samples were taken for tumor necrosis factor-a and interleukin-6 measurements. Seed-to-voxel FC of the left dorsolateral prefrontal cortex (DLPFC) was examined. Bivariate correlation and linear regression models were used to determine the relationships among cognitive function, FC alterations, and cytokines. RESULTS: Executive function was significantly impaired after cardiac surgery. At day 7 follow-up, the surgical patients, compared to the controls, demonstrated significantly decreased DLPFC FC with the superior parietal lobe and attenuated negative connectivity in the default mode network, including the angular gyrus and posterior cingulate cortex. The left DLPFC enhanced the connectivity in the right DLPFC and posterior cingulate cortex, all of which were related to the increased tumor necrosis factor-a and decreased executive function up to day 7 after cardiac surgery. CONCLUSIONS: The decreased FC of executive control network and its anticorrelation with the default mode network may contribute to executive function deficits after cardiac surgery. Systemic inflammation may trigger these transient FC changes and executive function impairments.
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Procedimentos Cirúrgicos Cardíacos , Função Executiva , Humanos , Encéfalo , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Inflamação/etiologia , Fatores de Necrose Tumoral , Imageamento por Ressonância MagnéticaRESUMO
Objective: Posttraumatic stress disorder (PTSD) is a frequent and disabling consequence of traumatic events. A previous study found that early use of propofol was a potential risk factor for PTSD. This prospective study aimed to investigate the effect of propofol and sevoflurane on PTSD after emergency surgery in trauma patients. Methods: A total of 300 trauma patients undergoing emergency surgery were randomly divided into two groups and anesthetized with propofol and/or sevoflurane. Perioperative clinical data were collected. The incidence of PTSD was evaluated with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) in the two groups 1 month after the operation. The relevance of the injury time and CAPS-5 scores was assessed by Spearman correlation analysis. Logistic regression analysis was used to analyze the risk factors for PTSD. Results: The incidence of PTSD in the propofol group was higher than that in the sevoflurane group 1 month postoperatively (23.2 vs. 12.2%, P = 0.014). The injury time was negatively correlated with the CAPS-5 score in the propofol group (r = -0.226, P < 0.001). In the logistic regression analysis, the utilization of propofol was an independent risk factor for PTSD (P = 0.017). Conclusion: Early use of propofol general anesthesia in emergency surgery for trauma patients may increase the risk of PTSD. Clinical Trial Registration: www.chictr.org.cn, identifier: ChiCTR2100050202.
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Evidence from both basic and clinical science suggests that neuropathic pain can induce cognitive dysfunction. However, these results are mainly based on a series of behavioral tests, there is a lack of quantitative variables to indicate cognitive impairment. Neuronal activity-regulated pentraxin (NPTX2) is a ubiquitously expressed, secreted protein in the nervous system. NPTX2 has been implicated to be involved in a variety of neuropathic diseases including Parkinson's disease, ischemia, and Alzheimer's disease. In a mouse model of chronic pain, NPTX2 is involved in the regulation of inflammatory responses. Here, we employ a variety of behavioral approaches to demonstrate that mice with chronic neuropathic pain have cognitive impairment and exhibit an increased anxiety response. The expression of NPTX2, but not NPTX1, was down-regulated in the hippocampus and cortex after chronic neuropathic pain exposure. The modulation effect of NPTX2 on cognitive function was also verified by behavioral tests using Nptx2 knock-out mice. Above all, we conclude that downregulation of NPTX2 induced by neuropathic pain may serve as an indicator of a progressive cognitive dysfunction during the induction and maintenance of spared nerve injury.
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Proteína C-Reativa/genética , Córtex Cerebral/metabolismo , Disfunção Cognitiva/metabolismo , Hipocampo/metabolismo , Proteínas do Tecido Nervoso/genética , Neuralgia/metabolismo , Animais , Comportamento Animal , Proteína C-Reativa/metabolismo , Disfunção Cognitiva/etiologia , Regulação para Baixo , Teste de Labirinto em Cruz Elevado , Locomoção , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Neuralgia/complicações , Teste de Campo Aberto , Limiar da Dor , Nervo Isquiático/cirurgiaRESUMO
BACKGROUND The association of preexisting neurocognitive impairments with perioperative neurocognitive disorders is not well-established. The objective of this study was to record incidences of perioperative neurocognitive disorders, to record changes in perioperative neurocognition, and to analyze factors of perioperative neurocognitive changes after hip joint replacement surgeries. MATERIAL AND METHODS Patients scheduled for hip joint replacement surgery were included in the test group (n=499) and patients with osteoarthritis but who were not planned for any type of surgeries were included in the control group (n=499). The cognitive tests were evaluated at the time of enrollment and at 1 week, 3 months, 1 year, and 4 years after baseline. Neurocognitive disorders for the individual parameter was defined as more than 2 SD of mean below norms for that parameter. Neurocognitive disorders were defined as a significant worst condition in at least 2 parameters out of all parameters. RESULTS Compared to baseline, after 3 months the numbers of patients with perioperative neurocognitive disorders were increased (55 vs. 81, p=0.021). After 4 years, there was a significant decline in numbers of patients with perioperative neurocognitive disorders in the test group (55 vs. 3, p<0.0001). At the end of the 3-month follow-up period, elderly patients (p=0.002) and patients with preexisting neurocognitive impairments (p=0.005) had a higher incidence of perioperative neurocognitive disorders. CONCLUSIONS Age and preexisting neurocognitive impairments are markers predicting the risk of perioperative neurocognitive disorders.
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Artroplastia de Quadril/efeitos adversos , Transtornos Cognitivos/etiologia , Transtornos Neurocognitivos/etiologia , Idoso , Idoso de 80 Anos ou mais , Artroplastia de Quadril/métodos , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Neurocognitivos/metabolismo , Complicações Pós-Operatórias/epidemiologia , Estudos ProspectivosRESUMO
Background: Recent studies have shown that early diagnosis and intervention promote the patient's good prognosis. For patients who underwent cardiac surgery and require extracorporeal circulation support, the incidence of postoperative cognitive dysfunction (POCD) is higher than in other types of surgery due to greater changes in brain perfusion compared with normal physiological conditions. Recent studies have confirmed that the use of ulinastatin or dexmedetomidine in the perioperative period effectively reduces the incidence of POCD. In this study, ulinastatin was combined with dexmedetomidine to assess whether the combination of the two drugs could reduce the incidence of POCD. Methods: One hundred and eighty patients with heart valve replacement surgery undergoing cardiopulmonary bypass from August 2017 to December 2018 were enrolled, with age 60-80 years, American Society of Anesthesiologists (ASA) grades I-III, education level above elementary school, and either gender. According to the random number table method, patients were grouped into ulinastatin + dexmedetomidine (U+D) group, ulinastatin (U) group, dexmedetomidine (D) group, and normal saline (N) control group. Group U was pumped 20,000 UI/kg immediately after induction and the first day after surgery, group D continued to pump 0.4 µg/kg/h from induction to 2 h before extubation, group U+D dexmedetomidine 0.4 µg/kg/h + ulinastatin 20,000 UI/kg, and group N equal volume of physiological saline. The patients were enrolled with Mini-Mental State Examination (MMSE) before surgery. The cognitive function was assessed by Montreal Cognitive Assessment (MoCA) on the first day before surgery and on the seventh day after surgery. Inflammatory factors, such as S100ß protein, interleukin (IL)-6, matrix metalloproteinase (MMP)-9, and tumor necrosis factor (TNF)-α, were detected in peripheral blood before anesthesia (T0), immediately after surgery (T1), and immediately after extubation (T2). Results: One hundred and fifty-four patients enrolled in this study. Compared with group N, the incidence of POCD in group U+D was the lowest (P < 0.05), followed by group U and group D. Group U+D had the lowest concentration of inflammatory factors at the T1 and T2 time points, followed by group U and group D. Conclusions: Both ulinastatin and dexmedetomidine can reduce the perioperative inflammatory response and the incidence of POCD in patients with heart valve surgery, and their combination can better reduce the incidence of POCD.
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Objective: Inflammation plays a key role in the etiology and pathology of postoperative cognitive dysfunction (POCD). Cyclooxygenase (COX)-2 inhibitor celecoxib is used for the treatment of acute pain due to its potent anti-inflammatory and analgesic effects. Herein, we evaluated the effects of celecoxib on POCD in geriatric patients. Methods: A total of 178 geriatric patients undergoing total knee arthroplasty were randomly divided into two groups and treated with celecoxib (group C) or placebo (group P). The levels of perioperative plasma COX-2, IL-1ß, IL-6, TNF-α, neuron-specific enolase, and S100ß were detected in all patients. The pain intensity was measured by numerical rating scale (NRS). A battery of 9 neuropsychological tests was performed pre-operatively and 1 week, and 3 months postoperatively. Patients, whose postoperative performance declined by â§1 standard deviation as compared to each preoperative test score on â§2 tests, were classified as POCD. Results: A significant decrease in POCD incidence was found in group C as compared to group P on postoperative day 7 (12.3% vs. 34.1%; p < 0.05). POCD incidence did not differ between the two groups at the 3-month follow-up (8.8 vs. 9.7%). NRS scores at days 3 and 4 post-surgery were significantly lower in group C (p < 0.05). Patients in group C showed lower level of plasma COX-2, IL-1ß, IL-6, TNF-α, and S100ß as compared to group P postoperatively (p < 0.05). Conclusion: These results demonstrated that celecoxib can decrease early POCD incidence after total knee arthroplasty in geriatric patients, which might be mediated by suppressing inflammation and acute postoperative pain caused by surgical trauma. Registration: Chinese Clinical Trial Register, ChiCTR-IOR-16008168.
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Spinal cord injury (SCI) is currently incurable since treatments applied to clinic are limited to minimizing secondary complications and the mechanisms of injury-induced spinal cord damage are poorly understood. Zbtb38, also called CIBZ, is highly expressed in spinal cord and it functions as a negative regulator in SCI-induced apoptosis. We show here that Zbtb38 is downregulated under endoplasmic reticulum (ER) stress, which promotes ER stress-associated apoptosis in human bone marrow neuroblastoma cells. In the traumatic SCI mice, ER stress presented in injured spinal cord induced repression of Zbtb38 expression and triggered Zbtb38-mediated apoptosis. ChIP-QPCR analysis revealed that ATF4, an ER-stress inducible transcription factor, directly activated Zbtb38 transcription by binding to the Zbtb38 promoter. However, this binding was significantly reduced following SCI, leading to a sharp decrease in Zbtb38 expression. Restoring Zbtb38 function in injured spinal cord by injection of lentivirus containing Zbtb38 into SCI mice, significantly alleviated secondary damage of spinal cord with decreased ER stress-associated apoptosis and partially recovered spinal cord functions. These findings demonstrate that restoration of Zbtb38 expression can reduce secondary tissue damage after SCI, and suggest that a therapeutic strategy for targeting Zbtb38 may promote functional recovery of spinal cord for patients with SCI.
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Proteínas Repressoras/metabolismo , Traumatismos da Medula Espinal/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Animais , Apoptose/genética , Células da Medula Óssea , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/genética , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Modelos Biológicos , Regiões Promotoras Genéticas , Ligação Proteica , Recuperação de Função Fisiológica , Proteínas Repressoras/genética , Traumatismos da Medula Espinal/etiologia , Traumatismos da Medula Espinal/patologiaRESUMO
RATIONALE: Stellate ganglion blocks have been shown to provide effective pain relief in a number of different conditions, but no one had reported stellate ganglion blocks for the treatment of epileptic pain. We describe a case report of the successful use of stellate ganglion block in the treatment of epileptic pain in the patient. PATIENT CONCERNS: A 8-year-old girl who had experienced severe paroxysmal pain in her right upper limb. DIAGNOSES: She was diagnosed as drug-resistant partial epilepsy. INTERVENTIONS: The patient received stellate ganglion blocks with lidocaine for 2 courses with 2 weeks in a course of treatment and oral carbamazepine once a day. OUTCOMES: Carbamazepine dosage gradually tapered until stop and epileptic pain attacks become less and less, eventually disappear. LESSONS: Stellate ganglion block may be an effective treatment of intractable partial epilepsy. However, more research is now needed to verify the validity.
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Anestésicos Locais/uso terapêutico , Bloqueio Nervoso Autônomo/métodos , Epilepsia/tratamento farmacológico , Lidocaína/uso terapêutico , Manejo da Dor/métodos , Gânglio Estrelado , Anestésicos Locais/administração & dosagem , Criança , Feminino , Humanos , Lidocaína/administração & dosagemRESUMO
BACKGROUND: Mounting evidence indicates that children who experience abuse and neglect are prone to chronic diseases and premature mortality later in life. One mechanistic hypothesis for this phenomenon is that early life adversity alters the expression or functioning of the glucocorticoid receptor (GR) throughout the course of life and thereby increases sensitivity to inflammatory stimulation. An exaggerated pro-inflammatory response is generally considered to be a key cause of postoperative cognitive dysfunction (POCD). The aim of this study was to examine the effects of early life adversity on cognitive function and neuroinflammation after sevoflurane anesthesia in adult rats and to determine whether such effects are associated with the epigenetic regulation of GR. METHODS: Wistar rat pups were repeatedly subjected to infant maternal separation (early life stress) from postnatal days 2-21. In adulthood, their behavior and the signaling of hippocampal pro-inflammatory factors and nuclear factor-kappa B (NF-κB) after sevoflurane anesthesia were evaluated. We also examined the effects of maternal separation (MS) on the expression of GR and the DNA methylation status of the promoter region of exon 17 of GR and whether behavioral changes and neuroinflammation after anesthesia were reversible when the expression of GR was increased by altering DNA methylation. RESULTS: MS induced cognitive decline after sevoflurane inhalation in the Morris water maze and context fear conditioning tests and enhanced the release of cytokines and the activation of astrocyte intracellular NF-κB signaling induced by sevoflurane in the hippocampus of adult rats. Blocking NF-κB signaling by pyrrolidine dithiocarbamate (PDTC) inhibited the release of cytokines. MS also reduced the expression of GR and upregulated the methylation levels of the promoter region of GR exon 17, and such effects were reversed by treatment with the histone deacetylase inhibitor trichostatin A (TSA) in adult rats. Moreover, TSA treatment in adult MS rats inhibited the overactivation of astrocyte intracellular NF-κB signaling and the release of cytokines and alleviated cognitive dysfunction after sevoflurane anesthesia. CONCLUSIONS: Early life stress induces cognitive dysfunction after sevoflurane anesthesia, perhaps due to the aberrant methylation of the GR gene promoter, which reduces the expression of the GR gene and facilitates exaggerated inflammatory responses.
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Anestésicos Inalatórios/toxicidade , Transtornos Cognitivos , Metilação de DNA/efeitos dos fármacos , Encefalite/etiologia , Privação Materna , Éteres Metílicos/toxicidade , Receptores de Glucocorticoides/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/psicologia , Condicionamento Psicológico/efeitos dos fármacos , Citocinas/metabolismo , Encefalite/patologia , Inibidores Enzimáticos/farmacologia , Medo/efeitos dos fármacos , Medo/psicologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Receptores de Glucocorticoides/genética , Sevoflurano , Transdução de Sinais/efeitos dos fármacosRESUMO
Urotensin II (U-II), a cyclic peptide originally isolated from the caudal neurosecretory system of fishes, can produce proinflammatory effects through its specific G protein-coupled receptor, GPR14. Neuropathic pain, a devastating disease, is related to excessive inflammation in the spinal dorsal horn. However, the relationship between U-II and neuropathic pain has not been reported. This study was designed to investigate the effect of U-II antagonist on neuropathic pain and to understand the associated mechanisms. We reported that U-II and its receptor GPR14 were persistently upregulated and activated in the dorsal horn of L4-6 spinal cord segments after chronic constriction injury (CCI) in rats. Intrathecal injection of SB657510, a specific antagonist against U-II, reversed CCI-induced thermal hyperalgesia and mechanical allodynia. Furthermore, we found that SB657510 reduced the expression of phosphorylated c-Jun N-terminal kinase (p-JNK) and nuclear factor-κB (NF-κB) p65 as well as subsequent secretion of interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α). It was also showed that both the JNK inhibitor SP600125 and the NF-κB inhibitor PDTC significantly attenuated thermal hyperalgesia and mechanical allodynia in CCI rats. Our present research showed that U-II receptor antagonist alleviated neuropathic pain possibly through the suppression of the JNK/NF-κB pathway in CCI rats, which will contribute to the better understanding of function of U-II and pathogenesis of neuropathic pain.
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Hiperalgesia/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Neuralgia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Urotensinas/antagonistas & inibidores , Animais , Citocinas/metabolismo , Hiperalgesia/metabolismo , Masculino , Neuralgia/metabolismo , Estimulação Física , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologiaRESUMO
BACKGROUND: Trial design neuroinflammation and postoperative pain after surgery are increasingly reported in association with postoperative cognitive dysfunction (POCD). Parecoxib, a selective cyclooxygenase (COX)-2 inhibitor, is used for postoperative analgesia for its potent anti-inflammatory and analgesic effects. This study aimed to evaluate parecoxib's effects on POCD in elderly patients undergoing total knee arthroplasty. METHODS: Around 134 elderly patients undergoing total knee arthroplasty were randomly divided into parecoxib (group P) and control (groupâC) groups, and treated with parecoxib sodium and saline, respectively, shortly after induction of general anesthesia and 12-h postsurgery, respectively. Perioperative plasma IL-1ß, IL-6, TNF-α, and C-reactive protein (CRP) 1evels were measured. Postoperative pain was assessed following surgery. Neuropsychological tests were performed before surgery, and 1 week and 3 months postoperation. RESULTS: POCD incidence in group P was significantly lower compared with that of group C at 1 week after surgery (16.7% vs 33.9%; Pâ<â0.05); no significant difference was found between groups C and P at 3-month follow-up (9.7% vs 6.7%). Compared with group C values, visual analog pain scale (VAS) scores at 3, 6, and 12âhours after surgery were significantly lower in group P(Pâ<â0.05). Plasma IL-1ß, IL-6, and TNF-α levels were lower in group P than in group C after the operation (Pâ<â0.05). No significant difference in the plasma CRP level was found between groups P and C. CONCLUSIONS: Parecoxib sodium decreases POCD incidence after total knee arthroplasty in elderly patients and may explain how this drug suppresses inflammation and acute postoperative pain caused by surgical trauma.
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Artroplastia do Joelho , Disfunção Cognitiva/prevenção & controle , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Isoxazóis/uso terapêutico , Dor Pós-Operatória/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Humanos , Masculino , Testes NeuropsicológicosRESUMO
BACKGROUND: In this study, we investigated the effect of propofol, a commonly used IV anesthetic, on lipopolysaccharide (LPS)-induced inflammatory responses in astrocytes and explored the molecular mechanisms by which it occurs. METHODS: Astrocytes were stimulated with LPS (1.0 µg/mL) in the absence and presence of different concentrations of propofol. The expression of astrocyte marker glial fibrillary acidic protein (GFAP) in astrocytes was detected using immunofluorescence staining and Western blot analysis. The levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α were measured using an enzyme-linked immunosorbent assay. The mRNA level of Toll-like receptor 4 (TLR4) was determined by semiquantitative reverse transcriptase-polymerase chain reaction. The protein expressions of TLR4, myeloid differentiation factor 88 (MyD88), p- extracellular signal-regulated protein kinases (ERK)1/2, p-c-Jun N-terminal kinase, p-p38 mitogen-activated protein kinase (MAPK), p-I-κBα, I-κBα, and p-nuclear factor-κB (NF-κB)p65 were detected by Western blot. RESULTS: Our results show that after stimulation with LPS, the levels of IL-1ß, IL-6, and tumor necrosis factor-α and the expression of GFAP in astrocytes were up-regulated significantly. In addition, the expression of TLR4, MyD88, p-ERK1/2, p-c-Jun N-terminal kinase, p-p38 MAPK, and p-NF-κBp65 increased, whereas the expression of total I-κBα decreased upon stimulation with LPS. Propofol (10 µM) reduced the secretion of proinflammatory cytokines, inhibited the expressions of GFAP, TLR4, MyD88, p-ERK1/2, p-p38 MAPK, and p-NF-κBp65 in astrocytes challenged with LPS. CONCLUSIONS: In the present study, propofol 10 µM but not lower clinically relevant or higher supra-clinical concentrations attenuated LPS-induced astrocyte activation and subsequent inflammatory responses by inhibiting the TLR4/MyD88-dependent NF-κB, ERK1/2, and p38 MAPK pathways.
Assuntos
Anti-Inflamatórios/farmacologia , Astrócitos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Fármacos Neuroprotetores/farmacologia , Propofol/farmacologia , Receptor 4 Toll-Like/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Animais Recém-Nascidos , Astrócitos/enzimologia , Astrócitos/imunologia , Células Cultivadas , Citocinas/metabolismo , Citoproteção , Relação Dose-Resposta a Droga , Proteína Glial Fibrilar Ácida/metabolismo , Mediadores da Inflamação/metabolismo , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismoRESUMO
BACKGROUND: Previous studies have shown ketamine can alter the proliferation and differentiation of neural stem cells (NSCs) in vitro. However, these effects have not been entirely clarified in vivo in the subventricular zone (SVZ) of neonatal rats. The present study was designed to investigate the effects of ketamine on the proliferation and differentiation of NSCs in the SVZ of neonatal rats in vivo. METHODS: Postnatal day 7 (PND-7) male Sprague-Dawley rats were administered four injections of 40 mg/kg ketamine at 1-h intervals, and then 5-bromodeoxyuridine (BrdU) was injected intraperitoneally at PND-7, 9 and 13. NSC proliferation was assessed with Nestin/BrdU double-labeling immunostaining. Neuronal and astrocytic differentiation was evaluated with ß-tubulin III/BrdU and GFAP/BrdU double-labeling immunostaining, respectively. The expressions of nestin, ß-tubulin III and GFAP were measured using Western blot analysis. The apoptosis of NSCs and astrocytes in the SVZ of neonatal rats was evaluated using nestin/caspase-3 and GFAP/caspase-3 double-labeling immunostaining. RESULTS: Neonatal ketamine exposure significantly reduced the number of nestin/BrdU and GFAP/BrdU double-positive cells in the SVZ. Meanwhile, the expressions of nestin and GFAP in the SVZ from the ketamine group were significantly decreased compared those in the control group. Still, no double-positive cells for nestin/caspase-3 and GFAP/caspase-3 were found after ketamine exposure. In addition, the neuronal differentiation of NSCs in the SVZ was markedly promoted by ketamine with an increased number of ß-tubulin III/BrdU double-positive cells and enhanced expression of ß-tubulin III. These effects of ketamine on the NSCs in the SVZ often lasted at least 1 week after ketamine anesthesia. CONCLUSION: In the present study, it was demonstrated that ketamine could alter neurogenesis by inhibiting the proliferation of NSCs, suppressing their differentiation into astrocytes and promoting the neuronal differentiation of the NSCs in the SVZ of neonatal rats during a critical period of their neurodevelopment.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ketamina/farmacologia , Ventrículos Laterais/metabolismo , Animais , Animais Recém-Nascidos , Anticorpos/imunologia , Apoptose/efeitos dos fármacos , Astrócitos/citologia , Caspase 3/imunologia , Caspase 3/metabolismo , Ventrículos Laterais/citologia , Masculino , Nestina/imunologia , Nestina/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Tubulina (Proteína)/imunologia , Tubulina (Proteína)/metabolismoRESUMO
BACKGROUND/AIMS: Ketamine is a widely used anesthetic in obstetric and pediatric anesthesia. In the developing brain, the widespread neuron apoptosis triggered by ketamine has been demonstrated. However, little is known about its effect on neural stem cells (NSCs) function. This study aimed to investigate the effect of ketamine on proliferation of NSCs from neonatal rat hippocampus. METHODS: Neural stem cells were isolated from the hippocampus of Sprague-Dawley rats on postnatal day 3. In dose-response experiments, cultured neural stem cells (NSCs) were exposed to different concentrations of ketamine (0-1000 µM) for 24 hrs. The proliferative activity of NSCs was evaluated by 5-Bromo-2'-deoxyuridine (BrdU) incorporation assay. Apoptosis of neural stem cells were assessed using caspase-3 by western blot. The intracellular Ca(2+) concentration ([Ca(2+)]i) in NSCs was analyzed by flow cytometry. The activation of protein kinase C-α (PKCα) and the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) were measured by western blot analysis. RESULTS: Clinical relevant concentration of ketamine (10, 20 and 50 µM) did not markedly alter the proliferation of NSCs from neonatal rat hippocampus in vitro. However, ketamine (200, 500, 800 and 1000µM) significantly inhibited the proliferation of NSCs and did not affect the expression of caspase-3. Meanwhile, ketamine (200, 500, 800 and 1000µM) also markedly decreased [Ca(2+)]i as well as suppressed PKCα activation and ERK1/2 phosphorylation in NSCs. A combination of subthreshold concentrations of ketamine (100 µM) and Ca(2+) channel blocker verapamil (2.5 µM), PKCα inhibitor chelerythrine (2.5 µM) or ERK1/2 kinase inhibitor PD98059 (5 µM) significantly produced suprathreshold effects on PKCα activation, ERK1/2 phosphorylation and NSC proliferation. CONCLUSION: Ketamine inhibited proliferation of NSCs from neonatal rat hippocampus in vitro. Suppressing Ca(2+)-PKCα-ERK1/2 signaling pathway may be involved in this inhibitory effect of ketamine on NSCs proliferation.
Assuntos
Proliferação de Células/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Ketamina/farmacologia , Células-Tronco Neurais/efeitos dos fármacos , Animais , Animais Recém-Nascidos/metabolismo , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Caspase 3/metabolismo , Células Cultivadas , Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Fosforilação/efeitos dos fármacos , Proteína Quinase C-alfa/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: Recently, salusin-ß has been reported to have pro-atherosclerotic effects, but salusin-α has anti-atherosclerotic effects. Our previous study has shown that salusin-ß but not salusin-α promotes vascular inflammation in apoE-deficient mice. However, the underlying mechanism remains unknown. In this study, we observed the effect of salusins on inflammatory responses and the MAPK-NF-κB signaling pathway in human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS: HUVECs were incubated with different concentrations of salusin-α and salusin-ß. The levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were determined using enzyme-linked immunosorbent assay (ELISA). The mRNA expressions of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) were quantified using quantitative real-time polymerase chain reaction (PCR). The protein expressions of VCAM-1, MCP-1, I-κBα, NF-κB, p-JNK and p-p38 MAPK were measured using western blotting analysis. Our results showed that in HUVECs, salusin-ß could up-regulate the levels of IL-6, TNF-α, VCAM-1 and MCP-1, promote I-κBα degradation and NF-κB activation, and increase the phosphorylation of JNK and p38 MAPK. These effects could be inhibited by p38 MAPK inhibitor SB203580 and/or JNK inhibitor SP600125. In contrast, salusin-α could selectively decrease VCAM-1 protein, but did not show any effect on the expressions of VCAM-1 mRNA, TNF-α, IL-6, MCP-1, I-κBα, NF-κB, p-JNK or p-p38 MAPK. CONCLUSION: Salusin-ß was able to promote inflammatory responses in HUVECs via the p38 MAPK-NF-κB and JNK-NF-κB pathways. In contrast, salusin-α failed to show any significant effects on the inflammatory responses in HUVECs. These results provide further insight into the mechanisms behind salusins in vascular inflammation and offer a potential target for the prevention and treatment of atherosclerosis.
Assuntos
Células Endoteliais da Veia Umbilical Humana/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Sistema de Sinalização das MAP Quinases , Células Cultivadas , Quimiocina CCL2/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Vasculite/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Cysteinyl leukotrienes and their receptors have been shown to be involved in the generation of neuropathic pain. We performed this study to determine the antagonistic effect of montelukast, a cysteinyl leukotrienes receptor antagonist, on neuropathic pain and its underlying mechanism. METHODS: Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in rats. After CCI, rats were repeatedly administered montelukast (0.5, 1.0, and 2.0 mg/kg intraperitoneal, once daily) for a period of 14 days. Mechanical withdrawal threshold and thermal withdrawal latency were assessed before surgery and on days 1, 3, 5, 7, and 14 after CCI. The levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α in the spinal cord were determined by enzyme-linked immunosorbent assay. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) and activation of nuclear factor-kappaB (NF-κB) were assessed by Western blot. The expression of astrocyte marker glial fibrillary acidic protein and microglia marker Iba-1 and the coexpression of p-p38MAPK and Iba-1 or NF-κB and Iba-1 were observed by immunofluorescent staining. RESULTS: The CCI group displayed significantly decreased mechanical withdrawal threshold and thermal withdrawal latency on days 1, 3, 5, 7 and 14 compared with sham groups (P <0.05, P < 0.0001), which were markedly increased by montelukast (P < 0.05, P < 0.01, P <0.0001). After administration with montelukast for 14 days, as biological markers of inflammation, the levels of IL-1ß (P < 0.0001), IL-6 (P = 0.001 for low dosage, P < 0.0001 for middle and high dosages), and TNF-α (P =0.002, 0.001, < 0.0001 for low, middle, and high dosage, respectively) in the spinal cord were lower than those in the CCI group. Western blot analysis demonstrated that montelukast reduced the elevated expression of p-p38 MAPK (P =0.006, 0.015, < 0.0001 for low, middle, and high dosage, respectively) and NF-κB (P < 0.0001) in the spinal cord induced by CCI. Immunofluorescent staining showed that montelukast could inhibit CCI-induced activation of microglia but not astrocytes in the spinal cord. In addition, montelukast (2.0 mg/kg) significantly decreased the number of p38MAPK and Iba-1 or NF-κBp65 and Iba-1 double-positive cells. CONCLUSIONS: These results suggest that montelukast could effectively attenuate neuropathic pain in CCI rats by inhibiting the activation of p38MAPK and NF-κB signaling pathways in spinal microglia.