RESUMO
Anesthetic-induced developmental neurotoxicity (AIDN) can arise due to various factors, among which aberrant nerve cell death is a prominent risk factor. Animal studies have reported that repeated or prolonged anesthetic exposure can cause significant neuroapoptosis in the developing brain. Lately, non-apoptotic programmed cell deaths (PCDs), characterized by inflammation and oxidative stress, have gained increasing attention. Substantial evidence suggests that non-apoptotic PCDs are essential for neuronal cell death in AIDN compared to apoptosis. This article examines relevant publications in the PubMed database until April 2024. Only original articles in English that investigated the potential manifestations of non-apoptotic PCD in AIDN were analysed. Specifically, it investigates necroptosis, pyroptosis, ferroptosis, and parthanatos, elucidating the signaling mechanisms associated with each form. Furthermore, this study explores the potential relevance of these non-apoptotic PCDs pathways to the pathological mechanisms underlying AIDN, drawing upon their distinctive characteristics. Despite the considerable challenges involved in translating fundamental scientific knowledge into clinical therapeutic interventions, this comprehensive review offers a theoretical foundation for developing innovative preventive and treatment strategies targeting non-apoptotic PCDs in the context of AIDN.
Assuntos
Anestésicos , Apoptose , Síndromes Neurotóxicas , Humanos , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/etiologia , Animais , Anestésicos/efeitos adversos , Anestésicos/toxicidade , Anestésicos/farmacologia , Apoptose/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Piroptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/crescimento & desenvolvimento , Ferroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
The effect of anesthesia/euthanasia with ethyl 3-aminobenzoate methanesulfonate (MS-222) on the oxidative status of Hyla arborea tadpoles was examined to determine whether the use of the anesthetic can confound the experimental results of the oxidative stress-based investigation. The experiment was conducted on two groups of tadpoles reared at different temperatures to produce differences in antioxidant capacity between the groups. After development at different temperatures (20 °C and 25 °C), the animals were exposed to different concentrations of MS-222 (0, 0.1, 1, and 5 g/L) for 15 min. The higher temperature decreased catalase activity, glutathione and protein carbonyl levels and increased glutathione reductase activity. The glutathione level and glutathione/thiol-related parameters were significantly changed after MS-222 exposure. However, individuals from the different temperature groups responded differently to the tested anesthetic, pointing to the possible influence of the initial levels of antioxidant capacity. The analysis of the interaction between the factors (temperature and MS-222) confirmed that the anesthetic can confound the results regarding the effects of temperature on the oxidative status parameters. The concentration of 0.1 g/L MS-222 had the lowest influence on the alterations in oxidative status and the results of the effect of temperature. A brief review of the current literature on the use of MS-222 in tadpoles made clear the absence of precise information on anesthetic concentration and exposure time. Similar studies should be repeated and extended to other amphibian species and other factors of interest to provide better guidance on tadpole anesthesia/euthanasia for future experiments that consider oxidative status parameters.
Assuntos
Aminobenzoatos , Anestésicos , Antioxidantes , Humanos , Animais , Anestésicos/toxicidade , Ésteres , Glutationa , Mesilatos , Estresse OxidativoRESUMO
Nile tilapia, Oreochromis niloticus, is the most cultivated fish species in the world, due to its low cost, high growth rate, environmental adaptability, and resistance to disease and stress. Anesthetics for fish become necessary in management because they minimize mortality during transport and maintenance of ponds, one of the most used anesthetics is clove oil, which has eugenol as the major substance, representing 90-95 % of clove oil. The present study evaluates the effect of eugenol on cardiac activity in Oreochromis niloticus specimens and relates it to behavioral data to determine a concentration window for safe anesthesia. For the comportamental analysis, was used five treatments (50, 75, 100, 125, and 150 µL·L-1) were evaluated and for the eletrocardiographic test was used seven groups (Control, Vehicle, 50, 75, 100, 125, and 150 µL·L-1), n = 9/treatment, totaling 108 animals. Behavioral and electrocardiographic tests were performed on all treatments during induction and recovery. The results of the behavioral tests demonstrated the reversibility of the effects with recovery of the posture reflex, varying according to the concentration. The ECG results showed a slow recovery because, at concentrations above 100 µL·L-1, there was no full reversibility of the cardiac effects in the observed experiment time, which could cause greater changes in the tilapia hemodynamics, which led us to identify a window for safe anesthesia. Eugenol is an effective anesthetic in Nile tilapia juveniles when used in concentrations ranging from 50 to 100 µL·L-1, if there is a need for anesthetic deepening, doses above 100 µL·L-1, however, the animals must be monitored due to hemodynamic changes.
Assuntos
Anestesia , Anestésicos , Ciclídeos , Animais , Eugenol/toxicidade , Óleo de Cravo , Banhos , Imersão , Anestésicos/toxicidade , Anestesia/veterináriaRESUMO
Zebrafish (Danio rerio) are widely employed as an experimental model in various scientific fields. The investigation of glucose metabolism dysfunctions has gained recent significant prominence. Considering that certain anesthetics may impact glycemic levels, it is imperative to carefully select an anesthetic that does not induce such side effects, thereby mitigating potential adverse influences on research outcomes. In this sense, this study aimed to evaluate potential glucose alterations and induction and recovery times resulting from the use of eugenol, menthol and lidocaine as anesthetics in zebrafish. A total of 150 adult male and female zebrafish were divided into ten groups, comprising a control group euthanized by rapid chilling, and three groups anesthetized with low (40 mg/L eugenol, 60 mg/L menthol, 100 mg/L lidocaine), intermediate (60 mg/L eugenol, 90 mg/L menthol, 225 mg/L lidocaine), and high (80 mg/L eugenol, 120 mg/L menthol, 350 mg/L lidocaine) anesthetic concentrations. Glucose levels and induction and recovery times were assessed. The findings reveal that eugenol and menthol did not cause glucose level alterations at any of the investigated concentrations, while lidocaine caused a non-concentration-dependent hyperglycemia. Eugenol and menthol also exhibited similar recovery times at different concentrations, while lidocaine recovery times were concentration-dependent. This study, therefore, concludes that eugenol and menthol are safe and satisfactory anesthetics for use in zebrafish research involving glucose analyses, while lidocaine use can cause biases due to altered glucose levels and safety concerns. Researchers should, therefore, carefully consider anesthetic selection to ensure reliable results in zebrafish assessments.
Assuntos
Anestésicos , Perciformes , Animais , Feminino , Masculino , Eugenol/toxicidade , Peixe-Zebra , Mentol/toxicidade , Lidocaína/toxicidade , Anestésicos/toxicidade , GlucoseRESUMO
Electrocardiographic evaluation is performed in rhesus monkeys to establish the cardiovascular safety of candidate molecules before progressing to clinical trials. These animals are usually immobilized chemically by ketamine (KTM) and tiletamine-zolazepam (TZ) to obtain a steady-state heart rate and to ensure adequate human safety. The present study aimed to evaluate the effect of these anesthetic regimens on different electrocardiographic parameters. Statistically significant lower HR and higher P-wave duration, RR, QRS, and QT intervals were observed in the KTM-anesthetized group in comparison to TZ-anesthetized animals. No significant changes were noticed in the PR interval and p-wave amplitude. Sex-based significance amongst these parameters was observed in male and female animals of TZ- and KTM-anesthetized groups. Regression analysis of four QTc formulas in TZ-anesthetized rhesus monkeys revealed that QTcNAK (Nakayama) better corrected the QT interval than QTcHAS (Hassimoto), QTcBZT (Bazett), and QTcFRD (Fridericia) formulas. QTcNAK exhibited the least correlation with the RR interval (slope closest to zero and r = .01) and displayed no statistical significance between male and female animals. These data will prove useful in the selection of anesthetic regimens for chemical restraint of rhesus monkeys in nonclinical safety evaluation studies.
Assuntos
Anestésicos , Ketamina , Animais , Humanos , Masculino , Feminino , Ketamina/toxicidade , Tiletamina/toxicidade , Macaca mulatta , Zolazepam/toxicidade , Estudos Retrospectivos , Anestésicos/toxicidade , Frequência CardíacaRESUMO
Concerns about the potential neurotoxic effects of anesthetics on developing brain exist. When making clinical decisions, the timing and dosage of anesthetic exposure are critical factors to consider due to their associated risks. In our study, we investigated the impact of repeated anesthetic exposures on the brain development trajectory of a cohort of rhesus monkeys (n = 26) over their first 2 yr of life, utilizing longitudinal magnetic resonance imaging data. We hypothesized that early or high-dose anesthesia exposure could negatively influence structural brain development. By employing the generalized additive mixed model, we traced the longitudinal trajectories of brain volume, cortical thickness, and white matter integrity. The interaction analysis revealed that age and cumulative anesthetic dose were variably linked to white matter integrity but not to morphometric measures. Early high-dose exposure was associated with increased mean, axial, and radial diffusivities across all white matter regions, compared to late-low-dose exposure. Our findings indicate that early or high-dose anesthesia exposure during infancy disrupts structural brain development in rhesus monkeys. Consequently, the timing of elective surgeries and procedures that require anesthesia for children and pregnant women should be strategically planned to account for the cumulative dose of volatile anesthetics, aiming to minimize the potential risks to brain development.
Assuntos
Anestésicos , Substância Branca , Humanos , Animais , Criança , Feminino , Gravidez , Macaca mulatta , Imagem de Tensor de Difusão/métodos , Encéfalo , Imageamento por Ressonância Magnética , Substância Branca/patologia , Anestésicos/toxicidadeRESUMO
Advances in the field of pediatric anesthesiology have enabled the performance of complex and life-saving procedures with minimal patient discomfort. However, preclinical studies over the past two decades have been reporting substantial neurotoxic potential of general anesthetics in young brain, thus challenging the safety of these agents in pediatric anesthesiology practice. Notwithstanding the overwhelming preclinical evidence, the translatability of these findings has proven inconsistent in human observational studies. The significant degree of anxiety and apprehension surrounding the uncertainty of long-term developmental outcomes following early exposure to anesthesia has prompted numerous studies around the world to investigate the putative mechanisms and translatability of preclinical findings regarding anesthesia-induced developmental neurotoxicity. Guided by the vast preclinical evidence, we aim to highlight relevant human findings presented in the currently available clinical literature.
Assuntos
Anestesia , Anestesiologia , Anestésicos , Síndromes Neurotóxicas , Criança , Humanos , Anestésicos/toxicidade , Anestesia/efeitos adversos , Encéfalo , Síndromes Neurotóxicas/etiologiaRESUMO
Pre-clinical experimental evidence, along with a plausible biological rational suggests that exposure of neonates and young children to anesthesia may harm brain development. However, the translational relevance of these observations remains unsolved. While a variety of lasting morpho-functional effects can be attributed to early life exposure to anesthetics in laboratory animals, we do not have a convincing human phenotype that reflects any causal effects of general anesthetic exposure on brain development and functional outcome. This review is aimed to provide a comprehensive description of the current state of clinical research alongside exploring future challenges in this field by focusing on the critical appraisal of methodological approaches applied in clinical research into developmental anesthesia neurotoxicity.
Assuntos
Anestésicos , Síndromes Neurotóxicas , Criança , Recém-Nascido , Animais , Humanos , Pré-Escolar , Encéfalo , Anestésicos/toxicidade , Anestesia Geral/efeitos adversos , Síndromes Neurotóxicas/etiologiaRESUMO
Over the past 20 years, hundreds of preclinical studies of the developing central nervous system have been published concluding that the common γ-aminobutryic acid and N-methyl-d-aspartate binding anesthetic agents cause neuroapoptosis and other forms of neurodegeneration. Some clinical studies, including controlled trials, both prospective and ambidirectional in design, indicate an association between any exposure (single or multiple) to anesthesia and surgery at a young age, generally less than 3-4 years, and later behavioral and neurodevelopmental problems. A consideration of neuroprotective strategies is important, as scientists and clinicians alike ponder methods to potentially improve the neurodevelopmental outcomes of the millions of infants and children who undergo surgery and anesthesia annually around the world. This review will address plausible neuroprotective strategies and include alternative anesthetics, neuroprotective nonanesthetic drugs, and physiologic neuroprotection.
Assuntos
Anestesia , Anestésicos , Fármacos Neuroprotetores , Síndromes Neurotóxicas , Criança , Pré-Escolar , Humanos , Anestesia/efeitos adversos , Anestésicos/toxicidade , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Estudos Prospectivos , LactenteRESUMO
Since its invention, general anesthesia has been an indispensable component of modern surgery. While traditionally considered safe and beneficial in many pathological settings, hundreds of preclinical studies in various animal species have raised concerns about the detrimental and long-lasting consequences that general anesthetics may cause to the developing brain. Clinical evidence of anesthetic neurotoxicity in humans continues to mount as we continue to contemplate how to move forward. Notwithstanding the alarming evidence, millions of children are being anesthetized each year, setting the stage for substantial healthcare burdens in the future. Hence, furthering our knowledge of the molecular underpinnings of anesthesia-induced developmental neurotoxicity is crucially important and should enable us to develop protective strategies so that currently available general anesthetics could be safely used during critical stages of brain development. In this mini-review, we provide a summary of select strategies with primary focus on the mechanisms of neuroprotection and potential for clinical applicability. First, we summarize a diverse group of chemicals with the emphasis on intracellular targets and signal-transduction pathways. We then discuss epigenetic and transgenerational effects of general anesthetics and potential remedies, and also anesthesia-sparing or anesthesia-delaying approaches. Finally, we present evidence of a novel class of anesthetics with a distinct mechanism of action and a promising safety profile.
Assuntos
Anestésicos/toxicidade , Desenvolvimento Infantil/efeitos dos fármacos , Síndromes Neurotóxicas/prevenção & controle , Animais , Criança , Epigênese Genética , Humanos , Mitocôndrias/metabolismo , Síndromes Neurotóxicas/metabolismoRESUMO
Numerous animal models have been used to study developmental neurotoxicity associated with short-term or prolonged exposure of common general anesthetics at clinically relevant concentrations. Pediatric anesthesia models using the nonhuman primate (NHP) may more accurately reflect the human condition because of their phylogenetic similarity to humans with regard to reproduction, development, neuroanatomy, and cognition. Although they are not as widely used as other animal models, the contribution of NHP models in the study of anesthetic-induced developmental neurotoxicity has been essential. In this review, we discuss how neonatal NHP animals have been used for modeling pediatric anesthetic exposure; how NHPs have addressed key data gaps and application of the NHP model for the studies of general anesthetic-induced developmental neurotoxicity. The appropriate application and evaluation of the NHP model in the study of general anesthetic-induced developmental neurotoxicity have played a key role in enhancing the understanding and awareness of the potential neurotoxicity associated with pediatric general anesthetics.
Assuntos
Anestesia , Anestésicos Gerais , Anestésicos , Síndromes Neurotóxicas , Anestesia/efeitos adversos , Anestésicos/toxicidade , Anestésicos Gerais/toxicidade , Animais , Animais Recém-Nascidos , Criança , Humanos , Síndromes Neurotóxicas/etiologia , Filogenia , PrimatasRESUMO
Recent animal studies have drawn concerns regarding most commonly used anesthetics and their long-term cytotoxic effects, specifically on the nervous tissue. It is therefore imperative that the search continues for agents that are non-toxic at both the cellular and behavioural level. One such agent appears to be dexmedetomidine (DEX) which has not only been found to be less neurotoxic but has also been shown to protect neurons from cytotoxicity induced by other anesthetic agents. However, DEX's effects on the growth and synaptic connectivity at the individual neuronal level, and the underlying mechanisms have not yet been fully resolved. Here, we tested DEX for its impact on neuronal growth, synapse formation (in vitro) and learning and memory in a rodent model. Rat cortical neurons were exposed to a range of clinically relevant DEX concentrations (0.05-10 µM) and cellular viability, neurite outgrowth, synaptic assembly and mitochondrial morphology were assessed. We discovered that DEX did not affect neuronal viability when used below 10 µM, whereas significant cell death was noted at higher concentrations. Interestingly, in the presence of DEX, neurons exhibited more neurite branching, albeit with no differences in corresponding synaptic puncta formation. When rat pups were injected subcutaneously with DEX 25 µg/kg on postnatal day 7 and again on postnatal day 8, we discovered that this agent did not affect hippocampal-dependent memory in freely behaving animals. Our data demonstrates, for the first time, the non-neurotoxic nature of DEX both in vitro and in vivo in an animal model providing support for its utility as a safer anesthetic agent. Moreover, this study provides the first direct evidence that although DEX is growth permissive, causes mitochondrial fusion and reduces oxygen reactive species production, it does not affect the total number of synaptic connections between the cortical neurons in vitro.
Assuntos
Dexmedetomidina/farmacologia , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Anestésicos/farmacologia , Anestésicos/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dexmedetomidina/toxicidade , Feminino , Lobo Frontal/citologia , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Dinâmica Mitocondrial/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurônios/citologia , Fármacos Neuroprotetores/farmacologia , Gravidez , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/fisiologiaRESUMO
Gamma hydroxybutyric acid (GHB) has been approved clinically to treat excessive daytime sleepiness and cataplexy in patients with narcolepsy, alcohol and opioid withdrawal, and as an anesthetic. The use of GHB clinically is limited due to its high abuse potential. The absorption, clearance and tissue uptake of GHB is mediated by proton-dependent and sodium-coupled monocarboxylate transporters (MCTs and SMCTs) and inhibition of these transporters may result in a change in GHB pharmacokinetics and pharmacodynamics. Previous studies have reported that non-steroidal anti-inflammatory drugs (NSAIDs) may inhibit these monocarboxylate transporters. Therefore, the purpose of this work was to analyze the interaction between GHB (at a dose of 600 mg/kg i. v.) and the NSAID, diclofenac, by examining the effects of this drug on the in vivo pharmacokinetics and pharmacodynamics in rat studies. The pharmacodynamic effect evaluated was respiratory depression, a measure of toxicity observed by GHB at this dose. There was an improvement in the respiratory rate with diclofenac administration suggesting an effect of diclofenac on GHB toxicity. In vitro studies with rat blood brain endothelial cells (RBE4) that express MCT1 indicated that diclofenac can inhibit GHB transport with an IC50 of 10.6 µM at pH 7.4. In vivo studies found a decrease in brain GHB concentrations and a decrease in the brain-to-plasma concentration ratio following diclofenac treatment. With this study we can conclude that diclofenac and potentially other NSAIDs can inhibit the transport of GHB into the brain, therefore decreasing GHB's pharmacodynamic effects and toxicity.
Assuntos
Encéfalo , Diclofenaco/farmacocinética , Interações Medicamentosas , Hidroxibutiratos/farmacocinética , Transportadores de Ácidos Monocarboxílicos , Insuficiência Respiratória , Simportadores , Anestésicos/farmacocinética , Anestésicos/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Transporte Biológico Ativo/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Hidroxibutiratos/toxicidade , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Transportadores de Ácidos Monocarboxílicos/metabolismo , Ratos , Ratos Sprague-Dawley , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/tratamento farmacológico , Oxibato de Sódio/farmacocinética , Simportadores/antagonistas & inibidores , Simportadores/metabolismoRESUMO
Tricaine methanesulfonate (MS-222) is a commonly used anaesthetic agent for immobilization of aquatic species. However, delayed development and malformations have been observed in 24 hpf (hours post-fertilization) zebrafish embryos after long-term immobilization. Still, no comprehensive study has been described regarding zebrafish exposure to MS-222 during the first hours of development, which are one of the most sensitive life stages to toxicants. Therefore, this research aimed to assess the toxicity of a 24 h exposure to MS-222 on zebrafish embryonic development. Based on the MS-222 LC50, early blastula stage embryos (~2 hpf) were exposed to 0, 12.5, 25 and 50 mg L-1 for 24 h and then allowed to develop up to 144 hpf. The chromatographic analysis showed that this anaesthetic agent bioaccumulates in 26 hpf zebrafish larvae in a concentration-dependent manner. In addition, increased mortalities and skeletal abnormalities were observed at 144 hpf, namely in the highest tested concentration. Yet, no craniofacial anomalies were observed either by alcian blue or calcein staining methods. Independently of the tested concentration, decreased speed and distance travelled were perceived in 144 hpf larvae. At the biochemical level, decreased in vivo reactive oxygen species (ROS) generation and apoptosis was observed. Additionally, catalase activity was increased at 26 hpf while results of mRNA expression showed a decreased gclc transcript content at the same time-point. Overall, data obtained highlight the toxicological risk of MS-222 and support ROS-mediated cell death signalling changes through the elevation of catalase activity as an adaptative or protective response.
Assuntos
Aminobenzoatos/toxicidade , Anestésicos/toxicidade , Catalase/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Aminobenzoatos/metabolismo , Anestésicos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Catalase/genética , Relação Dose-Resposta a Droga , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Regulação da Expressão Gênica no Desenvolvimento , Locomoção/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo , Regulação para Cima , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
This study was aimed at examining propofol- (a known anesthetic) induced emotion-related behavioral disorders in mice, and exploring the possible molecular mechanisms. A total of 60 mice were divided into two groups: control and propofol group. Mice were injected with propofol (150 mg/kg, ip) at 8:00 a.m. (once a day, lasting for 30 days). During the 30 days, loss of righting reflex (LORR) and return of righting reflex (RORR) of mice were recorded every day. At the 1st (T1) and 30th (T2) day of drug discontinuance (T2), 15 mice of each group were selected to perform the open field test; then the mice underwent perfusion fixation, and the midbrain and corpus striatum were separated for immunofluorescence assay with anti-tyrosine hydroxylase (Th) and anti- dopamine transporter (DAT) antibodies. Results showed that after propofol injection, LORR and RORR increased and decreased, respectively. Long-term use of propofol resulted in decreased activities of mice (activity trajectory, line crossing, rearing time, scratching times and defecating frequency). Immunofluorescence assay showed long-term use of propofol induced decrease of Th and DAT. Collectively, our present work suggested long-term abuse of propofol induces neuropsychiatric function impairments, and the possible mechanisms are related to dopamine dyssynthesis via down-regulating tyrosine hydroxylase and dopamine transporter.
Assuntos
Anestésicos/toxicidade , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/patologia , Transtornos Mentais/induzido quimicamente , Propofol/toxicidade , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/patologia , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/patologia , Anestésicos/efeitos adversos , Animais , Neurônios Dopaminérgicos/metabolismo , Emoções/efeitos dos fármacos , Masculino , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Camundongos Endogâmicos C57BL , Propofol/efeitos adversos , Reflexo de Endireitamento/efeitos dos fármacosRESUMO
MS-222, the most widely used anaesthetic in fish, has been shown to induce embryotoxic effects in zebrafish. However, the underlying molecular effects are still elusive. This study aimed to investigate the effects of MS-222 exposure during early developmental stages by evaluating biochemical and molecular changes. Embryos were exposed to 50, 100 or 150â¯mgâ¯L-1 MS-222 for 20â¯min at one of three developmental stages (256-cell, 50% epiboly, or 1-4 somite stage) and oxidative-stress, cell proliferation and apoptosis-related parameters were determined at two time-points (8 and 26 hpf). Following exposure during the 256-cell stage, the biochemical redox balance was not affected. The genes associated with glutathione homeostasis (gstpi and gclc) were affected at 8 hpf, while genes associated with apoptosis (casp3a and casp6) and cellular proliferation (pcna) were found affected at 26 hpf. An inverted U-shaped response was observed at 8 hpf for catalase activity. After exposure at the 50% epiboly stage, the gclc gene associated with oxidative stress was found upregulated at 8 hpf, while gstpi was downregulated and casp6 was upregulated later on, coinciding with a decrease in glutathione peroxidase (GPx) activity and a non-monotonic elevation of protein carbonyls and casp3a. Additionally, MS-222 treated embryos showed a decrease in DCF-staining at 26 hpf. When exposure was performed at the 1-4 somite stage, a similar DCF-staining pattern was observed. The activity of GPx was also affected whereas RT-qPCR showed that caspase transcripts were dose-dependently increased (casp3a, casp6 and casp9). The pcna mRNA levels were also found to be upregulated while gclc was changed by MS-222. These results highlight the impact of MS-222 on zebrafish embryo development and its interference with the antioxidant, cell proliferation and cellular death systems by mechanisms still to be explained; however, the outcomes point to the Erk/Nrf2 signalling pathway as a target candidate.
Assuntos
Aminobenzoatos/toxicidade , Anestésicos/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Embrião não Mamífero , Perfilação da Expressão Gênica , Espécies Reativas de Oxigênio/metabolismo , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Up to date, there is no information on the influence of 2,2,2-tribromoethanol (TBE; Avertin), a commonly used anaesthetic, on mice with impaired antioxidant capacity. We aimed to analyse the effect of a single dose of Avertin on anaesthesia duration time, inflammatory response, oxidative stress and collagen deposition in the large intestine of Nrf2 transcriptional knockout mice (tNrf2-/-). The studies were performed on six-month-old female mice Nrf2+/+ and tNrf2-/- randomly assigned to Avertin (250 mg/kg b.w. single i.p. injection) or vehicle group. We observed a 2-fold increase in anaesthesia time and longer recovery time (p = 0.015) in tNrf2-/- in comparison to Nrf2+/+. However, no hepato- or nephrotoxicity was detected. Interestingly, we found severe changes in colon morphology of untreated tNrf2-/- mice associated with colon shortening (p = 0.02) and thickening (p = 0.015). Avertin treatment caused colon damage manifested with epithelial layer damage and goblet depletion in Nrf2+/+ mice but not in tNrf2-/- individuals. Additionally, Avertin did not induce oxidative stress in colon tissue, but it increased leukocyte infiltration in Nrf2+/+ mice (p = 0.02). Immunofluorescent staining also revealed enhanced deposition of collagen I and collagen III in the colon of untreated tNrf2-/- mice. Avertin contributed to increased deposition of collagen I in Nrf2+/+ mice but reduced deposition of collagen I and III in tNrf2-/- individuals. In conclusion, tNrf2-/- respond to Avertin with prolonged anaesthesia that is not associated with acute toxicity, inflammatory reaction or enhanced oxidative stress. Avertin does not impair intestine morphology in tNrf2-/- mice but can normalise the enhanced fibrosis.
Assuntos
Anestésicos/farmacologia , Colo/efeitos dos fármacos , Estado de Consciência/efeitos dos fármacos , Etanol/análogos & derivados , Fator 2 Relacionado a NF-E2/metabolismo , Período de Recuperação da Anestesia , Anestésicos/toxicidade , Animais , Colágeno/metabolismo , Colo/metabolismo , Colo/patologia , Etanol/farmacologia , Etanol/toxicidade , Feminino , Fibrose , Mediadores da Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Fatores de TempoRESUMO
This study evaluated both telomere length (TL) and micronucleus (MN) as indicators of genome instability in 40 anesthesiologists occupationally exposed to anesthetics and in 40 physicians without occupational exposure to anesthetics who were matched by age, sex, and lifestyle. Blood and buccal samples were collected from both groups at the same period. Anesthetic exposure assessment was performed. The studied groups were assessed regarding relative TL by quantitative polymerase chain reaction and MN by buccal MN assay. Mean trace concentrations of anesthetics were below two parts per million. No significant differences between groups were found for both biomarkers. However, MN frequency was slightly increased (1.9-fold; p = .094) in the exposed group compared to the control group and in the exposed males (2.4-fold; p = .090) compared to unexposed males. TL and age showed a significant negative correlation. Anesthetic occupational exposure below recommended levels is not associated with changes in TL and MN in anesthesiologists.
Assuntos
Anestésicos/toxicidade , Instabilidade Genômica , Testes para Micronúcleos , Exposição Ocupacional , Médicos , Telômero , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Injectable solutions containing epinephrine (EPI) and norepinephrine (NE) are not stable, and their degradation is favored mainly by the oxidation of catechol moiety. As studies of these drugs under forced degradation conditions are scarce, herein, we report the identification of their degradation products (DP) in anesthetic formulations by the development of stability-indicating HPLC method. Finally, the risk assessment of the major degradation products was evaluated using in silico toxicity approach. HPLC method was developed to obtain a higher selectivity allowing adequate elution for both drugs and their DPs. The optimized conditions were developed using a C18 HPLC column, sodium 1-octanesulfonate, and methanol (80:20, v/v) as mobile phase, with a flow rate of 1.5 mL/min, UV detection at 199 nm. The analysis of standard solutions with these modifications resulted in greater retention time for EPI and NE, which allow the separation of these drugs from their respective DPs. Then, five DPs were identified and analyzed by in silico studies. Most of the DPs showed important alerts as hepatotoxicity and mutagenicity. To the best of our acknowledgment, this is the first report of a stability-indicating HPLC method that can be used with formulations containing catecholamines.
Assuntos
Anestésicos , Cromatografia Líquida de Alta Pressão/métodos , Epinefrina , Norepinefrina , Anestesia Dentária , Anestésicos/análise , Anestésicos/química , Anestésicos/toxicidade , Animais , Simulação por Computador , Estabilidade de Medicamentos , Epinefrina/análise , Epinefrina/química , Epinefrina/toxicidade , Limite de Detecção , Modelos Lineares , Camundongos , Norepinefrina/análise , Norepinefrina/química , Norepinefrina/toxicidade , Ratos , Reprodutibilidade dos TestesRESUMO
Exposure to anesthetic agents in early childhood or late intrauterine life might be associated with neurotoxicity and long-term neurocognitive decline in adulthood. This could be attributed to induction of neuroapoptosis and inhibition of neurogenesis by several mechanisms, with a pivotal role of microRNAs in this milieu. MicroRNAs are critical regulators of gene expression that are differentially expressed in response to internal and external environmental stimuli, including general anesthetics. Through this systematic review, we aimed at summarizing the current knowledge apropos of the roles and implications of deregulated microRNAs pertaining to anesthesia-induced neurotoxicity in animal models and derived neuronal cultures. OVID/Medline and PubMed databases were lastly searched on April 1st, 2019, using the Medical Subject Heading (MeSH) or Title/Abstract words ("microRNA" and "anesthesia"), to identify all published research studies on microRNAs and anesthesia. During the review process, data abstraction and methodological assessment was done by independent groups of reviewers. In total, 29 studies were recognized to be eligible and were thus involved in this systematic review. Anesthetic agents studied included sevoflurane, isoflurane, propofol, bupivacaine, and ketamine. More than 40 microRNAs were identified to have regulatory roles in anesthesia-induced neurotoxicity. This field of study still comprises several gaps that should be filled by conducting basic, clinical, and translational research in the future to decipher the exact role of microRNAs and their functions in the context of anesthesia-induced neurotoxicity.