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1.
Br J Anaesth ; 122(5): 671-681, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30982593

RESUMO

BACKGROUND: We hypothesised that exposure to multiple, but not single, procedures requiring general anaesthesia before age 3 yr is associated with a specific pattern of deficits in processing speed and fine motor skills. METHODS: A secondary analysis (using factor and cluster analyses) of data from the Mayo Anesthesia Safety in Kids study was conducted, in which unexposed, singly exposed, and multiply exposed children born in Olmsted County, MN, USA from 1994 to 2007 were sampled using a propensity-guided approach and underwent neuropsychological testing at ages 8-12 or 15-20 yr. RESULTS: In the factor analysis, the data were well fit to a five factor model. For subjects multiply (but not singly) exposed to anaesthesia, a factor reflecting motor skills, visual-motor integration, and processing speed was significantly lower [standardised difference of -0.35 (95% confidence interval {CI} -0.57 to -0.13)] compared with unexposed subjects. No other factor was associated with exposure. Three groups were identified in the cluster analysis, with 106 subjects (10.6%) in Cluster A (lowest performance in most tests), 557 (55.9%) in Cluster B, and 334 (33.5%) in Cluster C (highest performance in most tests). The odds of multiply exposed children belonging to Cluster A was 2.83 (95% CI: 1.49-5.35; P=0.001) compared with belonging to Cluster B; there was no other significant association between exposure status and cluster membership. CONCLUSIONS: Multiple, but not single, exposures to procedures requiring general anaesthesia before age 3 yr are associated with a specific pattern of deficits in neuropsychological tests. Factors predicting which children develop the most pronounced deficits remain unknown.


Assuntos
Anestesia Geral/efeitos adversos , Anestésicos Gerais/efeitos adversos , Transtornos do Neurodesenvolvimento/induzido quimicamente , Desempenho Psicomotor/efeitos dos fármacos , Adolescente , Fatores Etários , Anestésicos Gerais/administração & dosagem , Anestésicos Gerais/farmacologia , Criança , Análise por Conglomerados , Análise Fatorial , Feminino , Humanos , Masculino , Destreza Motora/efeitos dos fármacos , Testes Neuropsicológicos , Fatores de Risco , Adulto Jovem
2.
Br J Anaesth ; 122(5): 635-642, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30915994

RESUMO

BACKGROUND: EEG activity in the extended alpha frequency range (7-17 Hz) during maintenance of general anaesthesia is primarily determined by effect-site concentrations of the hypnotic and analgesic drugs used. Intermittent alpha loss during surgery, unexplained by changes in anaesthetic or opioid concentrations, could represent arousal of the cortex as a result of increased surgical stimulation. METHODS: A generalised linear model was fitted to alpha power recorded from patients undergoing general anaesthesia from induction until waking using three explanatory variables: age-adjusted volatile anaesthetic effect-site concentration, and estimated effect-site propofol and opioid concentrations. Model residuals were decomposed into uncorrelated white noise and a fluctuating auto-correlated trend. Deviations of this local trend were classified as 'unexpected alpha dropout events'. To investigate whether these alpha dropouts might be explained by the effect of noxious stimulation, we related their occurrence to whether a patient was undergoing surgery involving the body cavity or not. RESULTS: Alpha power dropouts occurred in 73 of the 237 patients included in the final analysis (31%, median amplitude of -3.5 dB, duration=103 s). They showed a bimodal or broadly skewed distribution, being more probable soon after initial incision (32%), dropping to around 10% at 1 h, and then again increasing to >30% in operations lasting >3 h. Multivariate analysis showed that alpha dropouts were significantly associated with body cavity surgery (P=0.003) and with longer operations (P<0.001). CONCLUSIONS: A loss of alpha power, unexplained by changes in anaesthetic or opioid concentrations, is suggestive of thalamocortical depolarisation induced by body cavity noxious stimuli, and could provide a measure of nociception during surgery.


Assuntos
Anestesia Geral/métodos , Anestésicos Gerais/farmacologia , Eletroencefalografia/efeitos dos fármacos , Monitorização Neurofisiológica Intraoperatória/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/farmacologia , Anestésicos Inalatórios/farmacologia , Anestésicos Intravenosos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Propofol/farmacologia , Processamento de Sinais Assistido por Computador , Adulto Jovem
3.
N Engl J Med ; 380(13): 1214-1225, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30888743

RESUMO

BACKGROUND: Volatile (inhaled) anesthetic agents have cardioprotective effects, which might improve clinical outcomes in patients undergoing coronary-artery bypass grafting (CABG). METHODS: We conducted a pragmatic, multicenter, single-blind, controlled trial at 36 centers in 13 countries. Patients scheduled to undergo elective CABG were randomly assigned to an intraoperative anesthetic regimen that included a volatile anesthetic (desflurane, isoflurane, or sevoflurane) or to total intravenous anesthesia. The primary outcome was death from any cause at 1 year. RESULTS: A total of 5400 patients were randomly assigned: 2709 to the volatile anesthetics group and 2691 to the total intravenous anesthesia group. On-pump CABG was performed in 64% of patients, with a mean duration of cardiopulmonary bypass of 79 minutes. The two groups were similar with respect to demographic and clinical characteristics at baseline, the duration of cardiopulmonary bypass, and the number of grafts. At the time of the second interim analysis, the data and safety monitoring board advised that the trial should be stopped for futility. No significant difference between the groups with respect to deaths from any cause was seen at 1 year (2.8% in the volatile anesthetics group and 3.0% in the total intravenous anesthesia group; relative risk, 0.94; 95% confidence interval [CI], 0.69 to 1.29; P = 0.71), with data available for 5353 patients (99.1%), or at 30 days (1.4% and 1.3%, respectively; relative risk, 1.11; 95% CI, 0.70 to 1.76), with data available for 5398 patients (99.9%). There were no significant differences between the groups in any of the secondary outcomes or in the incidence of prespecified adverse events, including myocardial infarction. CONCLUSIONS: Among patients undergoing elective CABG, anesthesia with a volatile agent did not result in significantly fewer deaths at 1 year than total intravenous anesthesia. (Funded by the Italian Ministry of Health; MYRIAD ClinicalTrials.gov number, NCT02105610.).


Assuntos
Anestesia Intravenosa , Anestésicos Gerais/farmacologia , Ponte de Artéria Coronária , Doença da Artéria Coronariana/cirurgia , Administração por Inalação , Idoso , Anestesia Geral , Anestésicos Intravenosos , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/fisiopatologia , Procedimentos Cirúrgicos Eletivos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mortalidade , Método Simples-Cego , Volume Sistólico
4.
Biochim Biophys Acta Biomembr ; 1861(3): 594-609, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30571949

RESUMO

Computer simulations of four lipid membranes of different compositions, namely neat DPPC and PSM, and equimolar DPPC-cholesterol and PSM-cholesterol mixtures, are performed in the presence and absence of the general anesthetics diethylether and sevoflurane both at 1 and 600 bar. The results are analyzed in order to identify membrane properties that are potentially related to the molecular mechanism of anesthesia, namely that change in the same way in any membrane with any anesthetics, and change oppositely with increasing pressure. We find that the lateral lipid density satisfies both criteria: it is decreased by anesthetics and increased by pressure. This anesthetic-induced swelling is attributed to only those anesthetic molecules that are located close to the boundary of the apolar phase. This lateral expansion is found to lead to increased lateral mobility of the lipids, an effect often thought to be related to general anesthesia; to an increased fraction of the free volume around the outer preferred position of anesthetics; and to the decrease of the lateral pressure in the nearby range of the ester and amide groups, a region into which anesthetic molecules already cannot penetrate. All these changes are reverted by the increase of pressure. Another important finding of this study is that cholesterol has an opposite effect on the membrane properties than anesthetics, and, correspondingly, these changes are less marked in the presence of cholesterol. Therefore, changes in the membrane that can lead to general anesthesia are expected to occur in the membrane domains of low cholesterol content.


Assuntos
Anestésicos Gerais/farmacologia , Bicamadas Lipídicas/química , Lipídeos de Membrana/química , Membranas/efeitos dos fármacos , 1,2-Dipalmitoilfosfatidilcolina/química , 1,2-Dipalmitoilfosfatidilcolina/metabolismo , Colesterol/química , Colesterol/metabolismo , Simulação por Computador , Bicamadas Lipídicas/metabolismo , Lipídeos de Membrana/metabolismo , Membranas/metabolismo , Modelos Moleculares , Simulação de Dinâmica Molecular , Pressão
5.
PLoS Comput Biol ; 14(11): e1006605, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30475796

RESUMO

The direct-site hypothesis assumes general anesthetics bind ion channels to impact protein equilibrium and function, inducing anesthesia. Despite advancements in the field, a first principle all-atom demonstration of this structure-function premise is still missing. We focus on the clinically used sevoflurane interaction to anesthetic-sensitive Kv1.2 mammalian channel to resolve if sevoflurane binds protein's well-characterized open and closed structures in a conformation-dependent manner to shift channel equilibrium. We employ an innovative approach relying on extensive docking calculations and free-energy perturbation of all potential binding sites revealed by the latter, and find sevoflurane binds open and closed structures at multiple sites under complex saturation and concentration effects. Results point to a non-trivial interplay of site and conformation-dependent modes of action involving distinct binding sites that increase channel open-probability at diluted ligand concentrations. Given the challenge in exploring more complex processes potentially impacting channel-anesthetic interaction, the result is revealing as it demonstrates the process of multiple anesthetic binding events alone may account for open-probability shifts recorded in measurements.


Assuntos
Canais Iônicos/metabolismo , Sevoflurano/farmacologia , Algoritmos , Anestésicos Gerais/farmacologia , Anestésicos Inalatórios/farmacologia , Animais , Sítios de Ligação , Biologia Computacional , Ativação do Canal Iônico/efeitos dos fármacos , Canal de Potássio Kv1.2/metabolismo , Ligantes , Conformação Molecular , Simulação de Dinâmica Molecular , Probabilidade , Ligação Proteica , Domínios Proteicos , Software
6.
Br J Anaesth ; 121(3): 605-615, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30115259

RESUMO

BACKGROUND: Current concepts suggest that impaired representation of information in cortical networks contributes to loss of consciousness under anaesthesia. We tested this idea in rat auditory cortex using information theory analysis of multiunit responses recorded under three anaesthetic agents with different molecular targets: isoflurane, propofol, and dexmedetomidine. We reasoned that if changes in the representation of sensory stimuli are causal for loss of consciousness, they should occur regardless of the specific anaesthetic agent. METHODS: Spiking responses were recorded with chronically implanted microwire arrays in response to acoustic stimuli incorporating varied temporal and spectral dynamics. Experiments consisted of four drug conditions: awake (pre-drug), sedation (i.e. intact righting reflex), loss of consciousness (a dose just sufficient to cause loss of righting reflex), and recovery. Measures of firing rate, spike timing, and mutual information were analysed as a function of drug condition. RESULTS: All three drugs decreased spontaneous and evoked spiking activity and modulated spike timing. However, changes in mutual information were inconsistent with altered stimulus representation being causal for loss of consciousness. First, direction of change in mutual information was agent-specific, increasing under dexmedetomidine and decreasing under isoflurane and propofol. Second, mutual information did not decrease at the transition between sedation and LOC for any agent. Changes in mutual information under anaesthesia correlated strongly with changes in precision and reliability of spike timing, consistent with the importance of temporal stimulus features in driving auditory cortical activity. CONCLUSIONS: The primary sensory cortex is not the locus for changes in representation of information causal for loss of consciousness under anaesthesia.


Assuntos
Anestesia Geral/métodos , Anestésicos Gerais/farmacologia , Córtex Auditivo/efeitos dos fármacos , Estado de Consciência/efeitos dos fármacos , Estimulação Acústica/métodos , Anestésicos Inalatórios/farmacologia , Anestésicos Intravenosos/farmacologia , Animais , Córtex Auditivo/fisiologia , Estado de Consciência/fisiologia , Dexmedetomidina/farmacologia , Eletroencefalografia/efeitos dos fármacos , Feminino , Hipnóticos e Sedativos/farmacologia , Isoflurano/farmacologia , Propofol/farmacologia , Ratos Endogâmicos ACI , Tempo de Reação/efeitos dos fármacos , Reflexo de Endireitamento/efeitos dos fármacos , Reflexo de Endireitamento/fisiologia
7.
JACC Clin Electrophysiol ; 4(4): 518-530, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-30067493

RESUMO

OBJECTIVES: This study investigates the electrocardiographic-electrophysiological effects of administration of anesthetic drugs for general anesthesia (GA) in patients with BrS at high risk of sudden cardiac death (SCD). BACKGROUND: The safety of anesthetic agents in Brugada syndrome (BrS) is under debate. METHODS: All consecutive patients with spontaneous type 1 BrS electrocardiographic (ECG) patterns undergoing epicardial ablation of the arrhythmogenic substrate (AS) under GA were enrolled. Anesthesia was induced with single bolus of propofol and maintained with sevofluorane. ECG measurements were collected before, immediately after, and 20 min after induction of GA. Three-dimensional maps during GA and after ajmaline indicated the epicardial AS before ablation. RESULTS: Thirty-six patients with BrS (32 male, 88.9%; mean age 38.8 ± 12.0 years) with a spontaneous type 1 ECG pattern underwent GA. Induction was performed using propofol at mean dose of 1.6 to 2.6 mg/kg (2.1 ± 0.3 mg/kg). Twenty-eight (28 of 36, 77.8%) patients showed a reversion to a nondiagnostic pattern. ST-segment elevation (0.32 ± 0.01 mV vs. 0.19 ± 0.02 mV; p < 0.001) and J-wave amplitude (0.47 ± 0.02 mV vs. 0.31 ± 0.03 mV; p < 0.001) decreased after propofol. The AS area during GA, in the absence of BrS pattern, significantly enlarged after administration of ajmaline (3.6 ± 0.5 cm2 vs. 20.3 ± 0.8 cm2). No patient developed malignant arrhythmias during GA induction and maintenance. CONCLUSIONS: This study shows that GA using single-bolus propofol and volatile anesthetics is safe in high-risk patients with BrS, and it may exert a modulating effect by reducing the manifestation of type 1 BrS pattern and AS in the form of epicardial abnormal ECGs. (Epicardial Ablation in Brugada Syndrome: An Extension Study of 200 BrS Patients; NCT03106701).


Assuntos
Anestesia Geral , Anestésicos Gerais/farmacologia , Síndrome de Brugada/fisiopatologia , Eletrocardiografia/efeitos dos fármacos , Adulto , Anestésicos Gerais/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Propofol/administração & dosagem , Propofol/farmacologia , Estudos Prospectivos , Sevoflurano/administração & dosagem , Sevoflurano/farmacologia
8.
J Neurophysiol ; 120(5): 2232-2245, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30067128

RESUMO

General anesthesia is ubiquitous in research and medicine, yet although the molecular mechanisms of anesthetics are well characterized, their ultimate influence on cortical electrophysiology remains unclear. Moreover, the influence that different anesthetics have on sensory cortexes at neuronal and ensemble scales is mostly unknown and represents an important gap in knowledge that has widespread relevance for neural sciences. To address this knowledge gap, this work explored the effects of isoflurane and ketamine/xylazine, two widely used anesthetic paradigms, on electrophysiological behavior in mouse primary visual cortex. First, multiunit activity and local field potentials were examined to understand how each anesthetic influences spontaneous activity. Then, the interlaminar relationships between populations of neurons at different cortical depths were studied to assess whether anesthetics influenced resting-state functional connectivity. Lastly, the spatiotemporal dynamics of visually evoked multiunit and local field potentials were examined to determine how each anesthetic alters communication of visual information. We found that isoflurane enhanced the rhythmicity of spontaneous ensemble activity at 10-40 Hz, which coincided with large increases in coherence between layer IV with superficial and deep layers. Ketamine preferentially increased local field potential power from 2 to 4 Hz, and the largest increases in coherence were observed between superficial and deep layers. Visually evoked responses across layers were diminished under isoflurane, and enhanced under ketamine anesthesia. These findings demonstrate that isoflurane and ketamine anesthesia differentially impact sensory processing in V1. NEW & NOTEWORTHY We directly compared electrophysiological responses in awake and anesthetized (isoflurane or ketamine) mice. We also proposed a method for quantifying and visualizing highly variable, evoked multiunit activity. Lastly, we observed distinct oscillatory responses to stimulus onset and offset in awake and isoflurane-anesthetized mice.


Assuntos
Anestésicos Gerais/farmacologia , Potenciais Evocados Visuais , Isoflurano/farmacologia , Ketamina/farmacologia , Córtex Visual/efeitos dos fármacos , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Córtex Visual/citologia , Córtex Visual/fisiologia
9.
Physiol Res ; 67(5): 721-728, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30044117

RESUMO

The aim of study was to review the status of arterial pH, pO(2) and pCO(2) under general anesthesias in dependence on the light-dark (LD) cycle in spontaneously breathing rats. The experiments were performed using three- to four-month-old pentobarbital(P)-, ketamine/xylazine(K/X)- and zoletil(Z)-anesthetized female Wistar rats after a four-week adaptation to an LD cycle (12 h light:12 h dark). The animals were divided into three experimental groups according to the anesthetic agent used: P (light n=11; dark n=8); K/X (light n=13; dark n=11); and Z (light n=18; dark n=26). pH and blood gases from arterial blood were analyzed. In P anesthesia, LD differences in pH, pO(2), and pCO(2) were eliminated. In K/X anesthesia, parameters showed significant LD differences. In Z anesthesia, LD differences were detected for pH and pO(2) only. Acidosis, hypoxia, and hypercapnia have been reported for all types of anesthesia during the light period. In the dark period, except for P anesthesia, the environment was more stable and values fluctuated within normal ranges. From a chronobiological perspective, P anesthesia was not the most appropriate type of anesthesia in these rat experiments. It eliminated LD differences, and also produced a more acidic environment and more pronounced hypercapnia than K/X and Z anesthesias.


Assuntos
Anestesia Geral , Anestésicos Gerais/farmacologia , Fenômenos Cronobiológicos/fisiologia , Ketamina/farmacologia , Pentobarbital/farmacologia , Tiletamina/farmacologia , Zolazepam/farmacologia , Anestesia Geral/efeitos adversos , Anestesia Geral/tendências , Anestésicos Gerais/efeitos adversos , Anestésicos Gerais/sangue , Animais , Gasometria/métodos , Fenômenos Cronobiológicos/efeitos dos fármacos , Combinação de Medicamentos , Feminino , Hipercapnia/sangue , Hipercapnia/induzido quimicamente , Hipóxia/sangue , Hipóxia/induzido quimicamente , Ketamina/efeitos adversos , Pentobarbital/efeitos adversos , Ratos , Ratos Wistar , Tiletamina/efeitos adversos , Zolazepam/efeitos adversos
10.
Front Neural Circuits ; 12: 50, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30013465

RESUMO

It has been argued that general anesthetics suppress the level of consciousness, or the contents of consciousness, or both. The distinction between level and content is important because, in addition to clarifying the mechanisms of anesthesia, it may help clarify the neural bases of consciousness. We assess these arguments in the light of evidence that both the level and the content of consciousness depend upon the contribution of apical input to the information processing capabilities of neocortical pyramidal cells which selectively amplify relevant signals. We summarize research suggesting that what neocortical pyramidal cells transmit information about can be distinguished from levels of arousal controlled by sub-cortical nuclei and from levels of prioritization specified by interactions within the thalamocortical system. Put simply, on the basis of the observations reviewed, we hypothesize that when conscious we have particular, directly experienced, percepts, thoughts, feelings and intentions, and that general anesthetics affect consciousness by interfering with the subcellular processes by which particular activities are selectively amplified when relevant to the current context.


Assuntos
Anestésicos Gerais/farmacologia , Nível de Alerta , Estado de Consciência , Neocórtex , Células Piramidais , Transdução de Sinais , Tálamo , Animais , Nível de Alerta/efeitos dos fármacos , Nível de Alerta/fisiologia , Estado de Consciência/efeitos dos fármacos , Estado de Consciência/fisiologia , Humanos , Neocórtex/efeitos dos fármacos , Neocórtex/fisiologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Tálamo/efeitos dos fármacos , Tálamo/fisiologia
11.
J Neurophysiol ; 120(4): 1505-1515, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29947598

RESUMO

Oxygen (O2) is a crucial element for physiological functioning in mammals. In particular, brain function is critically dependent on a minimum amount of circulating blood levels of O2 and both immediate and lasting neural dysfunction can result following anoxic or hypoxic episodes. Although the effects of deficiencies in O2 levels on the brain have been reasonably well studied, less is known about the influence of elevated levels of O2 (hyperoxia) in inspired gas under atmospheric pressure. This is of importance due to its typical use in surgical anesthesia, in the treatment of stroke and traumatic brain injury, and even in its recreational or alternative therapeutic use. Using local field potential (EEG) recordings in spontaneously breathing urethane-anesthetized and naturally sleeping rats, we characterized the influence of different levels of O2 in inspired gases on brain states. While rats were under urethane anesthesia, administration of 100% O2 elicited a significant and reversible increase in time spent in the deactivated (i.e., slow-wave) state, with concomitant decreases in both heartbeat and respiration rates. Increasing the concentration of carbon dioxide (to 5%) in inspired gas produced the opposite result on EEG states, mainly a decrease in the time spent in the deactivated state. Consistent with this, decreasing concentrations of O2 (to 15%) in inspired gases decreased time spent in the deactivated state. Further confirmation of the hyperoxic effect was found in naturally sleeping animals where it similarly increased time spent in slow-wave (nonrapid eye movement) states. Thus alterations of O2 in inspired air appear to directly affect forebrain EEG states, which has implications for brain function, as well as for the regulation of brain states and levels of forebrain arousal during sleep in both normal and pathological conditions. NEW & NOTEWORTHY We show that alterations of oxygen concentration in inspired air biases forebrain EEG state. Hyperoxia increases the prevalence of slow-wave states. Hypoxia and hypercapnia appear to do the opposite. This suggests that oxidative metabolism is an important stimulant for brain state.


Assuntos
Anestésicos Gerais/farmacologia , Excitabilidade Cortical , Hiperóxia/fisiopatologia , Prosencéfalo/fisiopatologia , Sono REM , Inconsciência/fisiopatologia , Uretana/farmacologia , Animais , Masculino , Prosencéfalo/efeitos dos fármacos , Troca Gasosa Pulmonar , Ratos , Ratos Sprague-Dawley , Respiração
12.
Neurosci Bull ; 34(5): 887-900, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29948841

RESUMO

General anesthesia is an unconscious state induced by anesthetics for surgery. The molecular targets and cellular mechanisms of general anesthetics in the mammalian nervous system have been investigated during past decades. In recent years, K+ channels have been identified as important targets of both volatile and intravenous anesthetics. This review covers achievements that have been made both on the regulatory effect of general anesthetics on the activity of K+ channels and their underlying mechanisms. Advances in research on the modulation of K+ channels by general anesthetics are summarized and categorized according to four large K+ channel families based on their amino-acid sequence homology. In addition, research achievements on the roles of K+ channels in general anesthesia in vivo, especially with regard to studies using mice with K+ channel knockout, are particularly emphasized.


Assuntos
Anestésicos Gerais/farmacologia , Canais de Potássio/metabolismo , Anestésicos Gerais/uso terapêutico , Animais , Humanos
13.
Neuroimage ; 179: 414-428, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29920378

RESUMO

The physiological mechanisms by which anaesthetic drugs modulate oscillatory brain activity remain poorly understood. Combining human data, mathematical and computational analysis of both spiking and mean-field models, we investigated the spectral dynamics of encephalographic (EEG) beta-alpha oscillations, observed in human patients undergoing general anaesthesia. The effect of anaesthetics can be modelled as a reduction of neural fluctuation intensity, and/or an increase in inhibitory synaptic gain in the thalamo-cortical circuit. Unlike previous work, which suggested the primary importance of gamma-amino-butryic-acid (GABA) augmentation in causing a shift to low EEG frequencies, our analysis demonstrates that a non-linear transition, triggered by a simple decrease in neural fluctuation intensity, is sufficient to explain the clinically-observed appearance - and subsequent slowing - of the beta-alpha narrowband EEG peak. In our model, increased synaptic inhibition alone, did not correlate with the clinically-observed encephalographic spectral changes, but did cause the anaesthetic-induced decrease in neuronal firing rate. Taken together, our results show that such a non-linear transition results in functional fragmentation of cortical and thalamic populations; highly correlated intra-population dynamics triggered by anaesthesia decouple and isolate neural populations. Our results are able to parsimoniously unify and replicate the observed anaesthetic effects on both the EEG spectra and inter-regional connectivity, and further highlight the importance of neural activity fluctuations in the genesis of altered brain states.


Assuntos
Anestésicos Gerais/farmacologia , Encéfalo/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Modelos Neurológicos , Modelos Teóricos , Adulto , Idoso , Anestesia Geral , Encéfalo/fisiologia , Simulação por Computador , Feminino , Humanos , Neurônios/efeitos dos fármacos
14.
eNeuro ; 5(2)2018.
Artigo em Inglês | MEDLINE | ID: mdl-29766039

RESUMO

The efficacy of benzodiazepines to terminate electrographic status epilepticus (SE) declines the longer a patient is in SE. Therefore, alternative methods for ensuring complete block of SE and refractory SE are necessary. We compared the ability of diazepam and a subanesthetic dose of urethane to terminate prolonged SE and mitigate subsequent pathologies. Adult Sprague Dawley rats were injected with diisopropylfluorophosphate (DFP) to induce SE. Rats were administered diazepam (10 mg/kg, ip) or urethane (0.8 g/kg, s.c.) 1 h after DFP-induced SE and compared to rats that experienced uninterrupted SE. Large-amplitude and high-frequency spikes induced by DFP administration were quenched for at least 46 h in rats administered urethane 1 h after SE onset as demonstrated by cortical electroencephalography (EEG). By contrast, diazepam interrupted SE but seizures with high power in the 20- to 70-Hz band returned 6-10 h later. Urethane was more effective than diazepam at reducing hippocampal neurodegeneration, brain inflammation, gliosis and weight loss as measured on day 4 after SE. Furthermore, rats administered urethane displayed a 73% reduction in the incidence of spontaneous recurrent seizures after four to eight weeks and a 90% reduction in frequency of seizures in epileptic rats. By contrast, behavioral changes in the light/dark box, open field and a novel object recognition task were not improved by urethane. These findings indicate that in typical rodent SE models, it is the return of SE overnight, and not the initially intense 1-2 h of SE experience, that is largely responsible for neurodegeneration, accompanying inflammation, and the subsequent development of epilepsy.


Assuntos
Anestésicos Gerais/farmacologia , Anticonvulsivantes/farmacologia , Diazepam/farmacologia , Gliose/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/fisiopatologia , Uretana/farmacologia , Anestésicos Gerais/administração & dosagem , Animais , Anticonvulsivantes/administração & dosagem , Diazepam/administração & dosagem , Modelos Animais de Doenças , Eletrocorticografia , Inibidores Enzimáticos/toxicidade , Gliose/induzido quimicamente , Inflamação/induzido quimicamente , Isoflurofato/toxicidade , Doenças Neurodegenerativas/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Uretana/administração & dosagem
16.
Methods Enzymol ; 603: 171-180, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29673524

RESUMO

Investigation of how anesthetics produce hypnosis requires knowledge of their effects at the molecular, neuronal, circuit, and whole-brain network level. Anesthetic photolabels have long been used to explore how anesthetics bind and affect known protein targets, but they could potentially assist in investigation of anesthetic effects at higher organizational levels of the central nervous system. Here, we advocate the use and provide detailed methods for the application of anesthetic photolabels in slice electrophysiology and in intact animals as a means of investigating anesthetic effects on distinct circuits and brain centers.


Assuntos
Anestésicos Gerais/farmacologia , Encéfalo/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Neurônios/efeitos dos fármacos , Coloração e Rotulagem/métodos , Anestésicos Gerais/síntese química , Animais , Encéfalo/fisiologia , Eletroencefalografia , Hipnose Anestésica/métodos , Hipnóticos e Sedativos/síntese química , Camundongos , Microtomia , Neurônios/citologia , Neurônios/fisiologia , Técnicas de Patch-Clamp , Processos Fotoquímicos , Reflexo de Endireitamento/efeitos dos fármacos , Reflexo de Endireitamento/fisiologia , Técnicas Estereotáxicas , Técnicas de Cultura de Tecidos
17.
Methods Enzymol ; 603: 181-196, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29673525

RESUMO

Optogenetics and chemogenetics provide the ability to modulate neurons in a type- and region-specific manner. These powerful techniques are useful to test hypotheses regarding the neural circuit mechanisms of general anesthetic end points such as hypnosis and analgesia. With both techniques, a genetic strategy is used to target expression of light-sensitive ion channels (opsins) or designer receptors exclusively activated by designer drugs in specific neurons. Optogenetics provides precise temporal control of neuronal firing with light pulses, whereas chemogenetics provides the ability to modulate neuronal firing for several hours with the single administration of a designer drug. This chapter provides an overview of neuronal targeting and experimental strategies and highlights the important advantages and disadvantages of each technique.


Assuntos
Anestésicos Gerais/farmacologia , Encéfalo/efeitos dos fármacos , Drogas Desenhadas/farmacologia , Hipnóticos e Sedativos/farmacologia , Neurônios/efeitos dos fármacos , Optogenética/métodos , Anestésicos Gerais/síntese química , Animais , Antipsicóticos/farmacologia , Encéfalo/fisiologia , Clozapina/análogos & derivados , Clozapina/farmacologia , Opsinas dos Cones/genética , Opsinas dos Cones/metabolismo , Dependovirus/genética , Dependovirus/metabolismo , Drogas Desenhadas/síntese química , Diterpenos/farmacologia , Diterpenos Clerodânicos , Eletroencefalografia , Expressão Gênica , Humanos , Hipnose Anestésica/métodos , Hipnóticos e Sedativos/síntese química , Camundongos , Neurônios/citologia , Neurônios/fisiologia , Optogenética/instrumentação , Ratos , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Receptores Artificiais/genética , Receptores Artificiais/metabolismo , Receptores Opioides kappa/genética , Receptores Opioides kappa/metabolismo , Reflexo de Endireitamento/efeitos dos fármacos , Reflexo de Endireitamento/fisiologia , Técnicas Estereotáxicas
18.
Methods Enzymol ; 603: 197-220, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29673526

RESUMO

The majority of 20th century investigations into anesthetic effects on the nervous system have used electrophysiology. Yet some fundamental limitations to electrophysiologic recordings, including the invasiveness of the technique, the need to place (potentially several) electrodes in every site of interest, and the difficulty of selectively recording from individual cell types, have driven the development of alternative methods for detecting neuronal activation. Two such alternative methods with cellular scale resolution have matured in the last few decades and will be reviewed here: the transcription of immediate early genes, foremost c-fos, and the influx of calcium into neurons as reported by genetically encoded calcium indicators, foremost GCaMP6. Reporters of c-fos allow detection of transcriptional activation even in deep or distant nuclei, without requiring the accurate targeting of multiple electrodes at long distances. The temporal resolution of c-fos is limited due to its dependence upon the detection of transcriptional activation through immunohistochemical assays, though the development of RT-PCR probes has shifted the temporal resolution of the assay when tissues of interest can be isolated. GCaMP6 has several isoforms that trade-off temporal resolution for signal to noise, but the fastest are capable of resolving individual action potential events, provided the microscope used scans quickly enough. GCaMP6 expression can be selectively targeted to neuronal populations of interest, and potentially thousands of neurons can be captured within a single frame, allowing the neuron-by-neuron reporting of circuit dynamics on a scale that is difficult to capture with electrophysiology, as long as the populations are optically accessible.


Assuntos
Anestésicos Gerais/farmacologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Proteínas de Fluorescência Verde/genética , Hipnóticos e Sedativos/farmacologia , Proteínas Proto-Oncogênicas c-fos/genética , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Anestésicos Gerais/síntese química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Cálcio/metabolismo , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Eletroencefalografia , Genes Precoces , Genes Reporter , Proteínas de Fluorescência Verde/metabolismo , Humanos , Hipnóticos e Sedativos/síntese química , Camundongos , Microscopia de Fluorescência/métodos , Rede Nervosa/citologia , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Transdução de Sinais , Razão Sinal-Ruído , Ativação Transcricional
19.
Anesthesiology ; 129(5): 1029-1044, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29683806

RESUMO

The heterogeneity of molecular mechanisms, target neural circuits, and neurophysiologic effects of general anesthetics makes it difficult to develop a reliable and drug-invariant index of general anesthesia. No single brain region or mechanism has been identified as the neural correlate of consciousness, suggesting that consciousness might emerge through complex interactions of spatially and temporally distributed brain functions. The goal of this review article is to introduce the basic concepts of networks and explain why the application of network science to general anesthesia could be a pathway to discover a fundamental mechanism of anesthetic-induced unconsciousness. This article reviews data suggesting that reduced network efficiency, constrained network repertoires, and changes in cortical dynamics create inhospitable conditions for information processing and transfer, which lead to unconsciousness. This review proposes that network science is not just a useful tool but a necessary theoretical framework and method to uncover common principles of anesthetic-induced unconsciousness.


Assuntos
Anestésicos Gerais/farmacologia , Encéfalo/efeitos dos fármacos , Estado de Consciência/efeitos dos fármacos , Humanos
20.
Methods Enzymol ; 602: 231-246, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29588031

RESUMO

General anesthetics are unique in that they represent a diverse range of chemical structures. Therefore, it is not surprising that the desired and undesired molecular targets, and binding sites therein, are as equally diverse and unique. Photoaffinity labeling has proven to be a valuable strategy for the identification of anesthetic molecular targets, as well as binding sites within those targets. In combination with the advances in mass spectrometry-based proteomics, along with the ability to comprehensively map posttranslational modifications, the method is likely to undergo continued improvement. Here, we provide the fundamentals for the design and development of an anesthetic photolabel. We also outline a protocol for the identification of photolabeled residues by mass spectrometry. The major steps include the photolabeling experiment, sample preparation, high-resolution mass spectrometry, and data analysis. The protocol can be used as a foundation for further optimization for the specific protein of interest and conditions of an experiment. The use of photoaffinity labeling adds an advantageous alternative and/or complementary approach to increase understanding of anesthetic molecular mechanisms.


Assuntos
Anestésicos Gerais/farmacologia , Espectrometria de Massas/métodos , Peptídeos/química , Marcadores de Fotoafinidade/química , Sítios de Ligação , Espectrometria de Massas/instrumentação , Modelos Moleculares , Peptídeos/isolamento & purificação
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