RESUMO
Bronchopulmonary dysplasia (BPD) is a common serious complication of premature babies. No effective means control it. Hyperoxia damage is one of the important mechanisms of BPD. The reaserach confirmed pyroptosis existed in BPD. Dexmedetomidine is a new, high-specific α2 receptor agonist. Previous research foundation found that dexmedetomidine has a protective effect on BPD. To investigate how dexmedetomidine improves hyperoxic lung injury in neonatal mice by regulating pyroptosis. Neonatal rats were randomly divided into four groups: normal control group, hyperoxic injury group, air plus dexmedetomidine group, and hyperoxia plus dexmedetomidine group. After seven days the lungs of rats in each group were extracted, and the wet-to-dry weight ratio of the lung was measured. The lung injury in rats was observed using hematoxylin-eosin staining. Additionally, the expression and localization of nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and gasdermin D (GSDMD) proteins were examined in the lungs of rats using immunofluorescence staining. The mRNA levels of NLRP3, ASC, caspase-1, and interleukin 18 (IL-18) in the lungs of rats were determined using real-time PCR. Moreover, the protein levels of NLRP3, ASC, caspase-1/cleaved caspase-1, interleukin 1beta (IL-1ß), IL-18, and tunor necrosis factor alpha (TNF-α) were detected in lungs of rats using Western blot. The extent of mitochondrial damage in lung tissues of each group was observed by transmission electron microscopy. The lung tissue injury of the neonatal rats was significantly improved in the hyperoxia plus dexmedetomidine group compared to the hyperoxic injury group. Furthermore, the expressions of pyroptosis-related proteins such as NLRP3, ASC, cleaved-caspase-1, and GSDMD were significantly decreased, along with the expressions of inflammatory factors in lung tissues. By inhibiting the NLRP3/caspase-1/GSDMD pyroptosis pathway, dexmedetomidine reduces the activation and release of inflammatory factors and provides a protective effect against hyperoxic lung injury in neonatal mice.
Assuntos
Animais Recém-Nascidos , Dexmedetomidina , Hiperóxia , Lesão Pulmonar , Pulmão , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Ratos Sprague-Dawley , Animais , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Hiperóxia/metabolismo , Hiperóxia/complicações , Hiperóxia/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Piroptose/efeitos dos fármacos , Lesão Pulmonar/metabolismo , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/patologia , Lesão Pulmonar/tratamento farmacológico , Ratos , Proteínas de Ligação a Fosfato/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/metabolismo , Interleucina-18/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Masculino , GasderminasRESUMO
BACKGROUND: Dexmedetomidine (DEX) is a highly selective alpha-2-receptor agonist, and its use has not been well studied in major microvascular reconstructive surgery of the head and neck. PURPOSE: The purpose is to measure the association between DEX and neck hematoma formation in subjects undergoing head and neck microvascular reconstructive surgery. STUDY DESIGN, SETTING, SAMPLE: The investigators implemented a retrospective cohort study on subjects undergoing microvascular head and neck reconstruction for benign and malignant pathology at the University of Alabama at Birmingham from 2014 to 2021. Patients with unresectable tumors were excluded. PREDICTOR VARIABLE: The predictor variable was the intraoperative use of DEX upon emergence from general anesthesia. Subjects received standard anesthetic drugs and DEX, while control subjects received only standard anesthetic drugs. MAIN OUTCOME VARIABLE(S): The primary outcome was postoperative neck hematoma formation necessitating a return to the operating theater. The secondary outcome was the length of stay (LOS). COVARIATES: The covariates were demographic, operative, and oral morphine equivalents of anesthesia drugs. ANALYSES: Bivariate analyses were performed using the Student's t-test and the χ2 test for continuous and categorical variables. Multivariate regression analyses were conducted to assess for associations between DEX and the outcomes adjusted for confounding variables when present. P values of < .05 were regarded as statistically significant. RESULTS: A total of 297 subjects (mean age, 59.6 years, and standard deviation [SD], 14.9) with 61.6% male received DEX, and 304 subjects (mean age, 58.9 years, and SD, 14.6) with 60.2% male served as controls (P > .5). A total of 11 postoperative neck hematoma occurred in the control group when compared to 2 in the DEX (relative risk = 5.4, 95% confidence interval [CI], 1.2 to 24, P = .02). The mean LOS was 7.7 (SD, 4.3) and 9.4 (SD, 8.1) for the DEX and control groups (95% CI, 0.7 to 2.8, P < .01). After adjusting for tobacco history, tracheostomy, and neck dissection, DEX (Beta coefficient (B) = -1.7, 95% CI -2.7 to -0.7, P < .01) and neck dissection (B = 2.2, 95% CI 1.0 to 3.4, P < .01) were statistically associated with LOS. CONCLUSION AND RELEVANCE: The use of intraoperative DEX upon emergence from general anesthesia was associated with lower postoperative neck hematoma formation and a shorter length of stay following microvascular head and neck reconstruction.
Assuntos
Dexmedetomidina , Hematoma , Pescoço , Procedimentos de Cirurgia Plástica , Humanos , Dexmedetomidina/uso terapêutico , Masculino , Hematoma/etiologia , Estudos Retrospectivos , Feminino , Pessoa de Meia-Idade , Procedimentos de Cirurgia Plástica/métodos , Pescoço/cirurgia , Pescoço/irrigação sanguínea , Idoso , Neoplasias de Cabeça e Pescoço/cirurgia , Tempo de Internação , Complicações Pós-Operatórias , Microcirurgia/métodos , Período de Recuperação da Anestesia , Adulto , Anestesia Geral , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêuticoRESUMO
BACKGROUND: Sepsis, characterized by dysregulated host responses to infection, remains a critical global health concern, with high morbidity and mortality rates. The gastrointestinal tract assumes a pivotal role in sepsis due to its dual functionality as a protective barrier against injurious agents and as a regulator of motility. Dexmedetomidine, an α2-adrenergic agonist commonly employed in critical care settings, exhibits promise in influencing the maintenance of intestinal barrier integrity during sepsis. However, its impact on intestinal motility, a crucial component of intestinal function, remains incompletely understood. METHODS: In this study, we investigated dexmedetomidine's multifaceted effects on intestinal barrier function and motility during sepsis using both in vitro and in vivo models. Sepsis was induced in Sprague-Dawley rats via cecal ligation and puncture. Rats were treated with dexmedetomidine post-cecal ligation and puncture, and various parameters were assessed to elucidate dexmedetomidine's impact. RESULTS: Our findings revealed a dichotomous influence of dexmedetomidine on intestinal physiology. In septic rats, dexmedetomidine administration resulted in improved intestinal barrier integrity, as evidenced by reduced mucosal hyper-permeability and morphological alterations. However, a contrasting effect was observed on intestinal motility, as dexmedetomidine treatment inhibited both the frequency and amplitude of contractions in isolated intestinal strips and decreased the distance of ink migration in vivo. Additionally, dexmedetomidine suppressed the secretion of pro-motility hormones while having no influence on hormones that inhibit intestinal peristalsis. CONCLUSION: The study revealed that during sepsis, dexmedetomidine exhibited protective effects on barrier integrity, although concurrently it hindered intestinal motility, partly attributed to its modulation of pro-motility hormone secretion. These findings underscore the necessity of a comprehensive understanding of dexmedetomidine's impact on multiple facets of gastrointestinal physiology in sepsis management, offering potential implications for therapeutic strategies and patient care.
Assuntos
Dexmedetomidina , Motilidade Gastrointestinal , Ratos Sprague-Dawley , Sepse , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Animais , Sepse/tratamento farmacológico , Motilidade Gastrointestinal/efeitos dos fármacos , Ratos , Masculino , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Modelos Animais de Doenças , Permeabilidade/efeitos dos fármacosRESUMO
INTRODUCTION AND OBJECTIVES: To evaluate the impact of dexmedetomidine impact on cardiac surgery-associated acute kidney injury (CSA-AKI), kidney function, and metabolic and oxidative stress in patients undergoing coronary artery bypass grafting with heart-lung machine support. METHODS: A randomized double-masked trial with 238 participants (50-75 years) undergoing coronary artery bypass grafting was conducted from January 2021 to December 2022. The participants were divided into Dex (n=119) and NS (n = 119) groups. Dex was administered at 0.5 mcg/kg over 10minutes, then 0.4 mcg/kg/h until the end of surgery; the NS group received equivalent saline. Blood and urine were sampled at various time points pre- and postsurgery. The primary outcome measure was the incidence of CSA-AKI, defined as the occurrence of AKI within 96hours after surgery. RESULTS: The incidence of CSA-AKI was significantly lower in the Dex group than in the NS group (18.26% vs 32.46%; P=.014). Substantial increases were found in estimated glomerular filtration rate value at T4-T6 (P<.05) and urine volume 24hours after surgery (P<.01). Marked decreases were found in serum creatinine level, blood glucose level at T1-T2 (P<.01), blood urea nitrogen level at T3-T6 (P<.01), free fatty acid level at T2-T3 (P<.01), and lactate level at T3-T4 (P<.01). CONCLUSIONS: Dex reduces CSA-AKI, potentially by regulating metabolic disorders and reducing oxidative stress. Registered with the Chinese Clinical Study Registry (No. ChiCTR2100051804).
Assuntos
Injúria Renal Aguda , Ponte de Artéria Coronária , Dexmedetomidina , Humanos , Dexmedetomidina/uso terapêutico , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/epidemiologia , Ponte de Artéria Coronária/efeitos adversos , Ponte de Artéria Coronária/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Método Duplo-Cego , Idoso , Estudos Prospectivos , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/epidemiologia , Incidência , Taxa de Filtração Glomerular/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Estresse Oxidativo/efeitos dos fármacosRESUMO
Stress-induced hair loss is a prevalent health concern, with mechanisms that remain unclear, and effective treatment options are not yet available. In this study, we investigated whether stress-induced hair loss was related to an imbalanced immune microenvironment. Screening the skin-infiltrated immune cells in a stressed mouse model, we discovered a significant increase in macrophages upon stress induction. Clearance of macrophages rescues mice from stress-induced hair shedding and depletion of hair follicle stem cells (HFSCs) in the skin, demonstrating the role of macrophages in triggering hair loss in response to stress. Further flow cytometry analysis revealed a significant increase in M1 phenotype macrophages in mice under stressed conditions. In searching for humoral factors mediating stress-induced macrophage polarization, we found that the hormone Norepinephrine (NE) was elevated in the blood of stressed mice. In addition, in-vivo and in-vitro studies confirm that NE can induce macrophage polarization toward M1 through the ß-adrenergic receptor, Adrb2. Transcriptome, enzyme-linked immunosorbent assay (ELISA), and western blot analyses reveal that the NLRP3/caspase-1 inflammasome signaling and its downstream effector interleukin 18 (IL-18) and interleukin 1 beta (IL-1ß) were significantly upregulated in the NE-treated macrophages. However, inhibition of the NE receptor Adrb2 with ICI118551 reversed the upregulation of NLRP3/caspase-1, IL-18, and IL-1ß. Indeed, IL-18 and IL-1ß treatments lead to apoptosis of HFSCs. More importantly, blocking IL-18 and IL-1ß signals reversed HFSCs depletion in skin organoid models and attenuated stress-induced hair shedding in mice. Taken together, this study demonstrates the role of the neural (stress)-endocrine (NE)-immune (M1 macrophages) axis in stress-induced hair shedding and suggestes that IL-18 or IL-1ß may be promising therapeutic targets.
Assuntos
Alopecia , Interleucina-18 , Interleucina-1beta , Proteína 3 que Contém Domínio de Pirina da Família NLR , Estresse Psicológico , Animais , Camundongos , Alopecia/imunologia , Caspases , Inflamassomos , Interleucina-18/genética , Interleucina-18/farmacologia , Interleucina-18/uso terapêutico , Interleucina-1beta/genética , Interleucina-1beta/farmacologia , Interleucina-1beta/uso terapêutico , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Estresse Psicológico/complicações , Norepinefrina/uso terapêutico , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Apoptose/efeitos dos fármacosRESUMO
BACKGROUND: Intestinal ischemia/reperfusion injury (IRI) is a multifactorial, complex pathophysiological process in clinical settings. In recent years, intestinal IRI has received increasing attention due to increased morbidity and mortality. To date, there are no effective treatments. Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, has been demonstrated to be effective against intestinal IRI. In this systematic review and meta-analysis, we evaluated the efficacy and potential mechanisms of DEX as a treatment for intestinal IRI in animal models. METHODS: Five databases (PubMed, Embase, Web of Science, Cochrane Library, and Scopus) were searched until March 15, 2023. Using the SYRCLE risk bias tool, we assessed methodological quality. Statistical analysis was conducted using STATA 12 and R 4.2.2. We analyzed the related outcomes (mucosa damage-related indicators; inflammation-relevant markers, oxidative stress markers) relied on the fixed or random-effects models. RESULTS: There were 15 articles including 18 studies included, and 309 animals were involved in the studies. Compared to the model groups, DEX improved intestinal IRI. DEX decreased Chiu's score and serum diamine oxidase (DAO) level. DEX reduced the level of inflammation-relevant markers (interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α). DEX also improved oxidative stress (decreased malondialdehyde (MDA), increased superoxide dismutase (SOD)). CONCLUSIONS: DEX's effectiveness in ameliorating intestinal IRI has been demonstrated in animal models. Antioxidation, anti-inflammation, anti-apoptotic, anti-pyroptosis, anti-ferroptosis, enhancing mitophagy, reshaping the gut microbiota, and gut barrier protection are possible mechanisms. However, in light of the heterogeneity and methodological quality of these studies, further well-designed preclinical studies are warranted before clinical implication.
Assuntos
Dexmedetomidina , Traumatismo por Reperfusão , Ratos , Animais , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Ratos Sprague-Dawley , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Traumatismo por Reperfusão/patologia , Inflamação/tratamento farmacológico , Isquemia/tratamento farmacológicoRESUMO
Immunotherapy based on immunecheckpoint blockade (ICB) using antibodies induces rejection of tumours and brings clinical benefit in patients with various cancer types1. However, tumours often resist immune rejection. Ongoing efforts trying to increase tumour response rates are based on combinations of ICB with compounds that aim to reduce immunosuppression in the tumour microenvironment but usually have little effect when used as monotherapies2,3. Here we show that agonists of α2-adrenergic receptors (α2-AR) have very strong anti-tumour activity when used as monotherapies in multiple immunocompetent tumour models, including ICB-resistant models, but not in immunodeficient models. We also observed marked effects in human tumour xenografts implanted in mice reconstituted with human lymphocytes. The anti-tumour effects of α2-AR agonists were reverted by α2-AR antagonists, and were absent in Adra2a-knockout (encoding α2a-AR) mice, demonstrating on-target action exerted on host cells, not tumour cells. Tumours from treated mice contained increased infiltrating T lymphocytes and reduced myeloid suppressor cells, which were more apoptotic. Single-cell RNA-sequencing analysis revealed upregulation of innate and adaptive immune response pathways in macrophages and T cells. To exert their anti-tumour effects, α2-AR agonists required CD4+ T lymphocytes, CD8+ T lymphocytes and macrophages. Reconstitution studies in Adra2a-knockout mice indicated that the agonists acted directly on macrophages, increasing their ability to stimulate T lymphocytes. Our results indicate that α2-AR agonists, some of which are available clinically, could substantially improve the clinical efficacy of cancer immunotherapy.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Neoplasias , Receptores Adrenérgicos alfa 2 , Animais , Humanos , Camundongos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral , Receptores Adrenérgicos alfa 2/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos Knockout , Análise da Expressão Gênica de Célula ÚnicaRESUMO
BACKGROUND: Although several studies have reported that dexmedetomidine is a highly selective α2-adrenergic receptor agonist that protects liver function in perioperative patients by inhibiting oxidative stress (OS) and inflammatory response, patients with type 2 diabetes mellitus (T2DM) have not been included in the previous studies. The purpose of this study was to investigate the effects of perioperative low-dose dexmedetomidine on perioperative liver function in T2DM patients. METHODS: This was a single-center, placebo-controlled randomized trial. Fifty-four T2DM patients scheduled for debridement of lower extremity ulcers were included in this study and randomly divided into 2 groups (n = 27 per group): the dexmedetomidine group (DEX group) and the control group (CON group). Continuous intravenous infusion of dexmedetomidine (DEX group) or normal saline (CON group) was administered from the completion of monitoring to the end of surgery. All participants received femoral and sciatic nerve block with 0.33% ropivacaine. The main result was the activity of liver enzymes (AST, ALT) reflecting liver function. The secondary results included variables reflecting blood glucose (Glu), blood lipids (TG, HDL, LDL, total cholesterol), biomarkers of OS (MDA, SOD), and systemic inflammatory response (TNF-α, IL-6). RESULTS: Compared with CON group, DEX group exhibited a reduction in hemodynamic parameters, Glu, systemic inflammatory response, and liver injury indicators. OS response MDA activity was lower in DEX group than in CON group, while SOD was higher than that in CON group. The variables reflecting lipid metabolism function showed no differences between the groups. CONCLUSION SUBSECTIONS: Dexmedetomidine administered perioperatively can reduce Glu levels and protect the liver by attenuating OS injury and inflammatory response in T2DM patients without any potential risk.
Assuntos
Dexmedetomidina , Diabetes Mellitus Tipo 2 , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Biomarcadores , Glicemia , Colesterol , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Interleucina-6 , Fígado/cirurgia , Ropivacaina , Solução Salina , Superóxido Dismutase , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Fator de Necrose Tumoral alfaRESUMO
Dexmedetomidine, a highly selective α2-adrenoceptor agonist, has been recently reported to alleviate systemic inflammatory response induced by lipopolysaccharide (LPS), in addition to its sedative, analgesic, bradycardic and hypotensive properties. This study aimed to illustrate the molecular mechanisms underlying dexmedetomidine-induced anti-inflammation. In the LPS-pretreated mice, subcutaneous injection of dexmedetomidine reduced the spleen weight as well as serum and spleen expression of proinflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1ß, and increased serum and spleen expression of IL-10, a known anti-inflammatory cytokine. In addition, dexmedetomidine-attenuated proinflammatory cytokine reduction was entirely inhibited by selective α7 nicotinic acetylcholine receptor (nAChR) antagonist methyllycaconitine but not α2-adrenoceptor antagonist yohimbine. Dexmedetomidine also increased macrophageal IL-10 expression in the presence and absence of LPS, which was also attenuated by methyllycaconitine but not yohimbine. Furthermore, the stimulatory effect of dexmedetomidine on the expression of IL-10 was also reduced by the α7 nAChR gene silencer siRNA/α7 nAChR. Lastly, pretreatment with the IL-10 neutralizing antibody reversed dexmedetomidine-supressed expression of proinflammatory cytokines. Our findings illustrate that dexmedetomidine-induced anti-inflammation is through macrophageal expression of IL-10 following activation of α7 nAchRs but not α2-adrenoceptors.
Assuntos
Dexmedetomidina , Lipopolissacarídeos , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Citocinas/metabolismo , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Receptores Adrenérgicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismoRESUMO
INTRODUCTION: Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status. METHODS AND ANALYSIS: This five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 µg/kg/hour. The infusion rate will be decreased to 0.2 µg/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first.Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery. ETHICS AND DISSEMINATION: This trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: NCT05029050.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Disfunção Cognitiva , Delírio , Dexmedetomidina , Fragilidade , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Clonidina/uso terapêutico , Disfunção Cognitiva/etiologia , Delírio/diagnóstico , Delírio/etiologia , Delírio/prevenção & controle , Dexmedetomidina/uso terapêutico , Método Duplo-Cego , Fragilidade/complicações , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: One-lung ventilation (OLV) is widely used in thoracic surgery. However, OLV may also increase CERO2 and aggravate delayed cognitive recovery. Here, we aimed to investigate the effect of dexmedetomidine (DEX) on cognitive function in rats undergoing OLV. METHODS: Sprague-Dawley rats were randomly divided into two-lung ventilation (TLV) group, OLV group and OLV treated with DEX group. Group DEX received 25 µg/kg DEX i.p. 30 min before induction. After mechanical ventilation (MV), Morris water maze (MWM) test was carried out to examine spatial memory function. Western blotting was used to detect pERK1/2, pCREB, Bcl-2 and BAX in hippocampal tissues. Transmission electron microscopy (TEM) was used to observe the hippocampal CA1 region. RESULTS: Post-MV, compared with group OLV, group DEX showed increases in percentage of target quadrant time (P < 0.05), platform crossings (P < 0.05), a reduction in CERO2 (P < 0.05), and pERK1/2, pCREB, and Bcl-2 significantly increased (P < 0.01 or P < 0.05), while BAX significantly decreased (P < 0.01), besides, a less damaged synaptic structure was observed in group DEX. CONCLUSIONS: DEX improved post-MV cognitive function in rats undergoing OLV, reduced cerebral oxygen consumption, protected synaptic structure and upregulated ERK1/2-CREB anti-apoptotic signaling pathway in hippocampal CA1 region.
Assuntos
Disfunção Cognitiva , Dexmedetomidina , Ventilação Monopulmonar , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Ventilação Monopulmonar/efeitos adversos , Ratos , Ratos Sprague-Dawley , Proteína X Associada a bcl-2RESUMO
The purpose of this study was to investigate the mechanism of antiallodynic effect of tizanidine in neuropathic rats. Spinal nerve ligation reduced withdrawal threshold which was interpreted as tactile allodynia. Increasing doses of tizanidine induced a dose-dependent antiallodynic effect in nerve injured rats. Tizanidine was more effective in female than male neuropathic rats. This drug induced a lower antiallodynic effect in ovariectomized, compared with non-ovariectomized, neuropathic rats, while systemic reconstitution of estradiol (E2) levels in ovariectomized neuropathic females fully restored the antiallodynic effect of tizanidine. Naloxone reduced the antiallodynic effect of tizanidine in male but not in female neuropathic rats. Ovariectomy restored the antagonizing effect of naloxone in the antiallodynic effect of tizanidine, whereas treatment with E2 abolished the effect of naloxone on tizanidine activity. Rauwolscine (α2 antagonist) and imiloxan (α2B antagonist) completely abated tizanidine-induced antiallodynic effect in female neuropathic rats. In contrast, BRL-44408 (α2A antagonist) partially decreased the effect of tizanidine while JP-1302 (α2C antagonist) was ineffective. Rauwolscine, imiloxan and BRL-44408 decreased withdrawal threshold in naïve female rats. Rauwolscine did not modify withdrawal threshold in naïve male rats. AGN192403 (I1 antagonist), BU224 (I2 antagonist), prazosin (α1 antagonist) and methiothepin (5-HT antagonist) did not modify tizanidine-induced antiallodynia in neuropathic females and males. These data indicate that tizanidine exhibits a sex-dependent antiallodynic effect in neuropathy. Data also suggest that activation of adrenergic α2B and α2A and opioid receptors participate in the antiallodynic effect of tizanidine in female and male, respectively, neuropathic rats.
Assuntos
Neuralgia , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Clonidina/análogos & derivados , Clonidina/farmacologia , Clonidina/uso terapêutico , Feminino , Hiperalgesia/tratamento farmacológico , Masculino , Neuralgia/tratamento farmacológico , RatosRESUMO
WHAT IS KNOWN AND OBJECTIVE: Acute kidney injury (AKI) is a complication following surgery and has been associated with worsened patient outcomes. Providers have used agents that may confer a degree of renal protection in the perioperative stage. Such is the case of dexmedetomidine, a selective alpha-2 adrenergic agonist used in the intensive care unit (ICU) as a sedative agent. The primary objective of this meta-analysis was to characterize the use of dexmedetomidine and to evaluate its impact on renal markers and outcomes in patients after surgery. METHODS: A systematic review of manuscripts was performed to identify patients who received dexmedetomidine after surgery by searching the PubMed, Embase, and Cochrane databases. The following parameters were captured: blood urea nitrogen (BUN), serum creatinine, creatinine clearance, neutrophil gelatinase-associated lipoprotein (NGAL), cystatin C, urine output, duration of mechanical ventilation, ICU length of stay, AKI, need for dialysis, and mortality. RESULTS AND DISCUSSION: Nineteen studies with 3,395 patients were included in the analyses. The mean bolus and infusion dose of dexmedetomidine were 0.82 µg/kg and 0.54 mcg/kg/hr, respectively. There was a significant difference in creatinine clearance and NGAL in favour of the dexmedetomidine group. In addition, the dexmedetomidine group had a shorter ICU length of stay, and a lower risk of acute kidney injury and mortality compared to the control. There was no difference in the rest of the parameters. WHAT IS NEW AND CONCLUSION: Dexmedetomidine appears to have postoperative renal protective effects. This is evidenced by lower NGAL levels and increased creatinine clearance in those who received dexmedetomidine. These effects are associated with decreases in ICU length of stay and risk of AKI and mortality.
Assuntos
Injúria Renal Aguda , Dexmedetomidina , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Dexmedetomidina/farmacologia , Humanos , Hipnóticos e Sedativos/efeitos adversos , Rim/fisiologiaRESUMO
OBJECTIVE: The purpose of this study was to evaluate the effect of dexmedetomidine administration on myocardial ischemia/reperfusion (I/R) injury in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). MATERIALS AND METHODS: Online databases including PubMed, the Cochrane Library, Web of Science, Medline, and EMBASE were searched for clinical trials that investigated the application of dexmedetomidine in CPB patients prior to May 2021. A total of 17 studies involving 866 patients were included in this study. RESULTS: The result of the meta-analysis showed that there was a significant difference in serum creatinine-kinase-MB (CK-MB) between the dexmedetomidine group and the control group at the end of the operation and 24 h after the operation. Compared to the control group, cardiac troponin I (cTn-I) concentration in the dexmedetomidine group was significantly decreased at the end of the operation, 24 h after the operation, and 48 h after the operation. There was also a significant difference between the dexmedetomidine group and the control group in the length of a patient's ICU stay. CONCLUSIONS: Dexmedetomidine can reduce CK-MB and cTn-I concentrations and shorten the length of ICU stays for patients undergoing cardiac surgery with CPB. It can also provide myocardial protection from I/R injury.
Assuntos
Ponte Cardiopulmonar/métodos , Dexmedetomidina/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Procedimentos Cirúrgicos Cardíacos/métodos , Creatina Quinase Forma MB/sangue , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Tempo de Internação , Traumatismo por Reperfusão Miocárdica/fisiopatologiaRESUMO
BACKGROUND AND OBJECTIVES: AKI is a common complication after pediatric cardiac surgery and has been associated with higher morbidity and mortality. We aimed to compare the efficacy of available pharmacologic and nonpharmacologic strategies to prevent AKI after pediatric cardiac surgery. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: PubMed/MEDLINE, Embase, Cochrane Controlled Trials Register, and reference lists of relevant articles were searched for randomized controlled trials from inception until August 2020. Random effects traditional pairwise, Bayesian network meta-analyses, and trial sequential analyses were performed. RESULTS: Twenty randomized controlled trials including 2339 patients and 11 preventive strategies met the eligibility criteria. No overall significant differences were observed compared with control for corticosteroids, fenoldopam, hydroxyethyl starch, or remote ischemic preconditioning in traditional pairwise meta-analysis. In contrast, trial sequential analysis suggested a 80% relative risk reduction with dexmedetomidine and evidence of <57% relative risk reduction with remote ischemic preconditioning. Nonetheless, the network meta-analysis was unable to demonstrate any significant differences among the examined treatments, including also acetaminophen, aminophylline, levosimendan, milrinone, and normothermic cardiopulmonary bypass. Surface under the cumulative ranking curve probabilities showed that milrinone (76%) was most likely to result in the lowest risk of AKI, followed by dexmedetomidine (70%), levosimendan (70%), aminophylline (59%), normothermic cardiopulmonary bypass (57%), and remote ischemic preconditioning (55%), although all showing important overlap. CONCLUSIONS: Current evidence from randomized controlled trials does not support the efficacy of most strategies to prevent AKI in the pediatric population, apart from limited evidence for dexmedetomidine and remote ischemic preconditioning.
Assuntos
Injúria Renal Aguda/prevenção & controle , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Dexmedetomidina/uso terapêutico , Precondicionamento Isquêmico , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Fatores Etários , Teorema de Bayes , Ponte Cardiopulmonar/efeitos adversos , Pré-Escolar , Dexmedetomidina/efeitos adversos , Feminino , Humanos , Lactente , Recém-Nascido , Precondicionamento Isquêmico/efeitos adversos , Masculino , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Dexmedetomidine (Dexm), a selective alpha-2 adrenoceptor agonist, and dexamethasone (Dexa), a very potent and highly selective glucocorticoid, have both been proven effectively to prolong the duration of local anesthetics (LA) in regional anesthesia. However, data comparing the efficacy of Dexm and Dexa as perineural adjuvants are inconsistent. Therefore, this systematic review and meta-analysis of randomized and quasi-randomized controlled trials (RCTs) was conducted to compare the effects of Dexm and Dexa when used as LA adjuvants on peripheral nerve block (PNB). METHODS: We systematically searched PubMed, Cochrane Library, EMBASE, Web of Science, and ScienceDirect databases up to October, 2020. The primary outcome was the duration of analgesia. Secondary outcomes included incidence of rescue analgesia, cumulative opioid consumption, time required for onset of sensory and motor blockades, duration of sensory and motor blockades, incidence of postoperative nausea and vomiting (PONV), and side effect-associated outcomes (e.g., bradycardia, sedation, hypotension, rates of infection, and neurological complications). The study was registered on PROSPERO, number CRD42020188796. RESULTS: After screening of full-text relevant articles, 13 RCTs that met the inclusion criteria were retrieved for this systematic review. It was revealed that perineural Dexm provided equivalent analgesic duration to perineural Dexa. Besides, the intake of Dexm increased the incidence of rescue analgesia in limbs surgery, as well as the cumulative opioid consumption, and decreased the time required for onset of sensory and motor blockades for long-acting LA (all Pâ<â.05). Other analysis revealed insignificant difference between the 2 groups in terms of the incidence of PONV (Pâ>â.05). Additionally, 2 studies demonstrated that Dexm possesses more sedative properties than Dexa (Pâ<â.05). CONCLUSIONS: This meta-analysis indicated that the analgesic duration of Dexm and Dexa as LA adjuvants in PNB is the same. Meanwhile, the effects of perineural Dexm and Dexa on some secondary outcomes, including the incidence of rescue analgesia, cumulative opioid consumption, and time required for onset of sensory and motor blockades, are associated with the surgical site and type of LA.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Anestesia Local/métodos , Dexametasona/uso terapêutico , Dexmedetomidina/uso terapêutico , Glucocorticoides/uso terapêutico , Bloqueio Nervoso/métodos , Adjuvantes Anestésicos , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Dexametasona/administração & dosagem , Dexmedetomidina/administração & dosagem , Glucocorticoides/administração & dosagem , Humanos , Nervos Periféricos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Dexmedetomidine has been increasingly introduced into the perioperative care of surgical patients. Because a subset of anesthetics/sedatives are immunomodulatory, it is critical to understand the role of dexmedetomidine in our host immune functions. Here we reviewed the role of dexmedetomidine in different immune cells. We also reviewed published clinical articles that described the role of dexmedetomidine in organ injury, cancer surgery, and infection. In animal studies, dexmedetomidine attenuated organ injury. In clinical studies, dexmedetomidine was associated with an improvement in outcomes in cardiac surgery and transplant surgery. However, there is a paucity in research examining how dexmedetomidine is associated with these outcomes. Further studies are needed to understand its clinical application from immunological standpoints.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Dexmedetomidina/farmacologia , Fatores Imunológicos/farmacologia , Leucócitos/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Dexmedetomidina/uso terapêutico , Modelos Animais de Doenças , Humanos , Fatores Imunológicos/uso terapêutico , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Período Perioperatório , Receptores Adrenérgicos alfa 2/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/imunologia , Procedimentos Cirúrgicos Operatórios/efeitos adversosRESUMO
BACKGROUND: Neovascular age-related macular degeneration (AMD) with choroidal neovascularization (CNV) is a leading cause of blindness in elderly people. Anti-vascular endothelial growth factor (anti-VEGF)-drugs are used to treat AMD patients; however, some patients are resistant to these therapies. OBJECTIVE: The purpose of this study was to investigate the anti-angiogenic effects of α2-adrenergic agonists, including guanabenz and clonidine. METHODS: We evaluated the anti-angiogenic effects of α2-adrenergic agonists in human retinal microvascular endothelial cells (HRMECs). A proliferation assay was conducted, and the migration ratio was evaluated. In a laser-induced CNV model, guanabenz and clonidine were delivered via intraperitoneal injection or implantation of an osmotic pump device. Fourteen days following CNV induction, CNV lesion size and fundus fluorescein angiography (FFA) were evaluated. RESULTS: Guanabenz and clonidine inhibited VEGF-induced retinal endothelial cell growth and migration. In the CNV model mice, CNV lesion sizes were reduced by intraperitoneal administration of guanabenz or clonidine. Data, including body weight, systolic blood pressure, and heart rate showed that guanabenz (0.5 and 2.0 mg/kg/day) had little effect on these parameters; conversely, a high dose of clonidine (1.0 mg/kg/day) did affect these parameters. Additionally, clonidine did not affect CNV size, but continuous administration of guanabenz attenuated both CNV size and leakage from neovessels. CONCLUSION: Our study suggests a key role for α2-adrenergic receptors during CNV formation. Therefore, we suggest that α2-adrenergic receptor agonists may represent novel therapeutic drugs for patients with neovascular AMD.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Neovascularização de Coroide/tratamento farmacológico , Clonidina/uso terapêutico , Guanabenzo/uso terapêutico , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Animais , Movimento Celular/efeitos dos fármacos , Neovascularização de Coroide/patologia , Clonidina/administração & dosagem , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Guanabenzo/administração & dosagem , Humanos , Masculino , Camundongos , Retina/efeitos dos fármacos , Retina/patologia , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
Approximately 7 million people are reported to be undergoing radiotherapy (RT) at any one time in the world. However, it is still not possible to prevent damage to secondary organs that are off-target. This study, therefore, investigated the potential adverse effects of RT on the brain, using cognitive, histopathological, and biochemical methods, and the counteractive effect of the α2-adrenergic receptor agonist dexmedetomidine. Thirty-two male Sprague Dawley rats aged 5-6 months were randomly allocated into four groups: untreated control, and RT, RT + dexmedetomidine-100, and RT + dexmedetomidine-200-treated groups. The passive avoidance test was applied to all groups. The RT groups received total body X-ray irradiation as a single dose of 8 Gy. The rats were sacrificed 24 h after X-ray irradiation, and following the application of the passive avoidance test. The brain tissues were subjected to histological and biochemical evaluation. No statistically significant difference was found between the control and RT groups in terms of passive avoidance outcomes and 8-hydroxy-2'- deoxyguanosine (8-OHdG) positivity. In contrast, a significant increase in tissue MDA and GSH levels and positivity for TUNEL, TNF-α, and nNOS was observed between the control and the irradiation groups (p < 0.05). A significant decrease in these values was observed in the groups receiving dexmedetomidine. Compared with the control group, gradual elevation was determined in GSH levels in the RT group, followed by the RT + dexmedetomidine-100 and RT + dexmedetomidine-200 groups. Dexmedetomidine may be beneficial in countering the adverse effects of RT in the cerebral and hippocampal regions.