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1.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(1): 18-24, 2021 Jan 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33678632

RESUMO

OBJECTIVES: To investigate the effects of propofol on the proliferation and invasion of glioma U87 cells and to explore the possible anti-tumor mechanisms. METHODS: The glioma U87 cells was divided into a blank group, a positive control group, and the propofol groups (1.00, 2.00 or 5.00 mmol/L). Cell counting kit-8 (CCK-8) was used to detect cell proliferation; Transwell method was used to detect the effect of propofol on invasion and migration of U87 cells; real-time PCR was used to detect the expression of microRNA-134 (miR-134); Western blotting was used to detect the expression levels of reproduction-related protein Ki-67, invasion-related protein metalloproteinase-2 (MMP-2), metalloproteinase-9 (MMP-9) and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway-related protein. RESULTS: Compared with the blank group, the proliferation, invasion and migration capacity of U87 cells were reduced in the positive control group and the propofol groups after 48 hours (all P<0.05), along with the decreased expression of Ki-67, MMP-2 and MMP-9 and the ratio of p-PI3K/PI3K and p-Akt/Akt (all P<0.05), while the level of miR-134 was increased significantly (P<0.05). Compared with the positive control group and the 1.00 mmol/L propofol-treated group, the proliferation, invasion and migration capacity of U87 cells, the expression of Ki-67, MMP-2 and MMP-9, and the ratio of p-PI3K/PI3K and p-Akt/Akt was decreased significantly after 48 hours (all P<0.05), while the level of miR-134 was increased significantly in the 2.00 and 5.00 mmol/L propofol-treated groups (both P<0.05). Compared with the 2.00 mmol/L propofol-treated group, the proliferation, invasion and migration capacity of U87 cells, the expression of Ki-67, MMP-2 and MMP-9, and the ratio of p-PI3K/PI3K and p-Akt/Akt was decreased significantly after 48 hours in the 5.00 mmol/L propofol-treated group (all P<0.05), while the level of miR-134 was increased significantly (P<0.05). CONCLUSIONS: Propofol can decrease the proliferation rate, and the invasion and migration abilities of U87 cells, which may be achieved by up-regulation of miR-134 and suppression of PI3K/Akt signaling pathway.


Assuntos
Glioma , MicroRNAs , Propofol , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Glioma/genética , Humanos , Metaloproteinase 2 da Matriz/genética , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/genética , Propofol/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética
3.
Epilepsia ; 62(1): 238-249, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33417274

RESUMO

OBJECTIVE: LMR-101 is a bisphenol derivative of propofol, a short-acting general anesthetic, which is also used to manage status epilepticus (SE). We evaluated the sedative and anticonvulsant effects of LMR-101 to discover its potential to manage epilepsy and SE in the clinic. METHODS: Comparative studies between LMR-101 and propofol were performed in mice to elucidate an appropriate dose range for LMR-101 that produced anticonvulsant effects without significant sedation. Then, the anticonvulsive efficacy for LMR-101 was evaluated using seizure models induced by pentylenetetrazol and (+)-bicuculline. The ability of LMR-101 to inhibit SE was assessed using a rat model of SE induced by pilocarpine. Radioligand binding assay profiles for LMR-101 were performed to evaluate the potential mechanisms of action underlying its anticonvulsant properties. RESULTS: In the mouse study, LMR-101 exhibited greater anticonvulsant and lesser sedative effect compared with propofol. LMR-101 completely inhibited pentylenetetrazol-induced seizures at a dose of 50 mg/kg and exhibited heavy sedation at 300 mg/kg. Propofol anesthetized all mice and only decreased the seizure rate at 25 mg/kg. LMR-101 also suppressed seizure behaviors evoked by (+)-bicuculline in mice in a dose-dependent manner. In the pilocarpine-induced SE model, LMR-101 significantly decreased the maximum seizure score and seizure duration in a dose-dependent manner. The median effective dose for LMR-101 was 14.30 mg/kg and 121.87 mg/kg to prevent and inhibit sustained SE, respectively. In binding assays, LMR-101 primarily inhibited tert-[35 S] butylbicyclophosphorothionate binding to γ-aminobutyric acid type A (GABAA ) receptors (half-maximal inhibitory concentration = 2.06 µmol·L-1 ), but it did not affect [3 H] flunitrazepam or [3 H] muscimol binding. SIGNIFICANCE: It is anticipated that LMR-101 might play an essential role in the clinical management of epilepsy and SE. LMR-101 also might bind to a novel target site on the GABAA receptor that is different from existing antiepileptic drugs. Further study of the mechanisms of action of LMR-101 would be of considerable value in the search for new active drug sites on GABAA receptors.


Assuntos
Anticonvulsivantes/farmacologia , Propofol/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Convulsões/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Bicuculina/toxicidade , Eletroencefalografia , Antagonistas de Receptores de GABA-A/toxicidade , Hipnóticos e Sedativos/farmacologia , Camundongos , Agonistas Muscarínicos/toxicidade , Pentilenotetrazol/toxicidade , Fenóis/farmacologia , Pilocarpina/toxicidade , Propofol/análogos & derivados , Ratos , Receptores de GABA-A/metabolismo , Convulsões/induzido quimicamente , Estado Epiléptico/induzido quimicamente
4.
Mol Med Rep ; 23(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33398367

RESUMO

Endotoxin lipopolysaccharide (LPS) is one of the primary causes of myocardial injury. Propofol confers protective effects against LPS­induced myocardial damage; however, the biological functions and mechanisms underlying propofol are not completely understood. The present study aimed to investigate the effects of propofol on LPS­induced myocardial injury. Primary neonatal rat cardiomyocytes were treated with LPS to establish a myocardial injury model. LDH release in the culture media was measured using a LDH assay kit. The interactions between NLR family pyrin domain containing 3 (NLRP3), apoptosis­associated speck­like protein containing A CARD (ASC) and pro­caspase­1 were determined using a co­immunoprecipitation assay. Cell viability was measured using an MTT assay, and the levels of cell apoptosis were determined using flow cytometry, JC­1 staining (mitochondrial membrane potential) and caspase­3 activity assays. The mRNA expression levels of TNF­α, IL­6, IL­1ß and IL­18, and the protein expression levels of NLRP3, ASC, pro­caspase­1, caspase­1 p10, pro­IL­1ß, IL­1ß, pro­IL­18, IL­18, high mobility group box­1 (HMGB1) and peroxisome proliferator­activated receptor Î³ (PPARγ) were analyzed using reverse transcription­quantitative PCR and western blotting analyses, respectively. ELISAs were performed to measure the production of inflammatory mediators, including TNF­α, IL­6, IL­1ß and IL­18. The present results demonstrated that pretreatment with propofol significantly attenuated LPS­induced neonatal rat cardiomyocyte injury in a concentration­ and time­dependent manner. Propofol pretreatment also significantly inhibited LPS­induced cardiomyocyte inflammation and apoptosis. The results suggested that propofol pretreatment inactivated HMGB1­dependent NLRP3 inflammasome signaling, which involved PPARγ activation. Therefore, the results indicated that propofol reduced endotoxin­induced cardiomyocyte injury by inhibiting inflammation and apoptosis via the PPARγ/HMGB1/NLRP3 axis, suggesting that propofol may serve as a potential therapeutic agent for septic myocardial damage.


Assuntos
Apoptose/efeitos dos fármacos , Proteína HMGB1/metabolismo , Lipopolissacarídeos/toxicidade , Miocárdio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , PPAR gama/metabolismo , Propofol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley
5.
Br J Anaesth ; 126(4): 835-844, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33386125

RESUMO

BACKGROUND: Propofol, a commonly used intravenous anaesthetic, binds to type A gamma aminobutyric acid (GABA) receptors in mammalian brain. Previous work on its anaesthetic action has characterised either the biochemistry underlying propofol binding or the associated changes in brain network dynamics during sedation. Despite these advances, no study has focused on understanding how propofol action at the cellular level results in changes in brain network connectivity. METHODS: We used human whole-brain microarray data to generate distribution maps for genes that mark the primary GABAergic cortical interneurone subtypes (somatostatin, parvalbumin [PV], and 5-hydroxytryptamine 3A. Next, 25 healthy participants underwent propofol-induced sedation during resting state functional MRI scanning. We used partial least squares analysis to identify the brain regions in which connectivity patterns were most impacted by propofol sedation. We then correlated these multimodal cortical patterns to determine if a specific interneurone subtype was disproportionately expressed in brain regions in which connectivity patterns were altered during sedation. RESULTS: Brain networks that were significantly altered by propofol sedation had a high density of PV-expressing GABAergic interneurones. Brain networks that anticorrelated during normal wakefulness, namely the default mode network and attentional and frontoparietal control networks, increased in correlation during sedation. CONCLUSIONS: PV-expressing interneurones are highly expressed in brain regions with altered connectivity profiles during propofol-induced sedation. This study also demonstrates the utility of leveraging multiple datasets to address multiscale neurobiological problems.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Interneurônios/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Parvalbuminas , Propofol/farmacologia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Feminino , Neurônios GABAérgicos/metabolismo , Humanos , Interneurônios/metabolismo , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Parvalbuminas/metabolismo , Análise Serial de Proteínas/métodos
6.
Neuroimage ; 227: 117633, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33316393

RESUMO

We present a detailed analysis of the Hindriks and van Putten thalamocortical mean-field model for propofol anesthesia [NeuroImage 60(23), 2012]. The Hindriks and van Putten (HvP) model predicts increases in delta and alpha power for moderate (up to 130%) prolongation of GABAA inhibitory response, corresponding to light anesthetic sedation. Our analysis reveals that, for deeper anesthetic effect, the model exhibits an unexpected abrupt jump in cortical activity from a low-firing state to an extremely high-firing stable state (∼250 spikes/s), and remains locked there even at GABAA prolongations as high as 300% which would be expected to induce full comatose suppression of all firing activity. We demonstrate that this unphysiological behavior can be completely suppressed with appropriate tuning of the parameters controlling the sigmoidal functions that map soma voltage to firing rate for the excitatory and inhibitory neural populations, coupled with elimination of the putative population-dependent anesthetic efficacies introduced in the HvP model. The modifications reported here constrain the anesthetized brain activity into a biologically plausible range in which the cortex now has access to a moderate-firing state ("awake") and a low-firing ("anesthetized") state such that the brain can transition from "awake" to "anesthetized" states at a critical level of drug concentration. The modified HvP model predicts a drug-effect hysteresis in which the drug concentration required for induction is larger than that at emergence. In addition, the revised model shows a decrease in the intensity and frequency of alpha-band fluctuations, transitioning to delta-band dominance, with deepening anesthesia. These predicted drug concentration-dependent changes in EEG dynamics are consistent with clinical reports.


Assuntos
Anestésicos Intravenosos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Modelos Neurológicos , Rede Nervosa/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Propofol/farmacologia , Córtex Cerebral/fisiologia , Humanos , Rede Nervosa/fisiologia , Inibição Neural/fisiologia , Neurônios/fisiologia
7.
Anesthesiology ; 134(2): 219-233, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33332534

RESUMO

BACKGROUND: The general anesthetic propofol induces frontal alpha rhythm in the cerebral cortex at a dose sufficient to induce loss of consciousness. The authors hypothesized that propofol-induced facilitation of unitary inhibitory postsynaptic currents would result in firing synchrony among postsynaptic pyramidal neurons that receive inhibition from the same presynaptic inhibitory fast-spiking neurons. METHODS: Multiple whole cell patch clamp recordings were performed from one fast-spiking neuron and two or three pyramidal neurons with at least two inhibitory connections in rat insular cortical slices. The authors examined how inhibitory inputs from a presynaptic fast-spiking neuron modulate the timing of spontaneous repetitive spike firing among pyramidal neurons before and during 10 µM propofol application. RESULTS: Responding to activation of a fast-spiking neuron with 150-ms intervals, pyramidal cell pairs that received common inhibitory inputs from the presynaptic fast-spiking neuron showed propofol-dependent decreases in average distance from the line of identity, which evaluates the coefficient of variation in spike timing among pyramidal neurons: average distance from the line of identity just after the first activation of fast-spiking neuron was 29.2 ± 24.1 (mean ± SD, absolute value) in control and 19.7 ± 19.2 during propofol application (P < 0.001). Propofol did not change average distance from the line of identity without activating fast-spiking neurons and in pyramidal neuron pairs without common inhibitory inputs from presynaptic fast-spiking neurons. The synchronization index, which reflects the degree of spike synchronization among pyramidal neurons, was increased by propofol from 1.4 ± 0.5 to 2.3 ± 1.5 (absolute value, P = 0.004) and from 1.5 ± 0.5 to 2.2 ± 1.0 (P = 0.030) when a presynaptic fast-spiking neuron was activated at 6.7 and 10 Hz, respectively, but not at 1, 4, and 13.3 Hz. CONCLUSIONS: These results suggest that propofol facilitates pyramidal neuron firing synchrony by enhancing inhibitory inputs from fast-spiking neurons. This synchrony of pyramidal neurons may contribute to the alpha rhythm associated with propofol-induced loss of consciousness.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Interneurônios/efeitos dos fármacos , Propofol/farmacologia , Células Piramidais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Feminino , Masculino , Modelos Animais , Ratos , Ratos Transgênicos , Sinapses/efeitos dos fármacos
8.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333797

RESUMO

Background: Mice carrying the GABAA receptor ß3(N265M) point mutation, which renders receptors incorporating ß3-subunits insensitive to many general anesthetics, have been used experimentally to link modulation of different receptor subtypes to distinct behavioral endpoints. Remarkably, however, the effect of the mutation on the susceptibility to modulation by isoflurane (a standard reference agent for inhalational vapors) has never been tested directly. Therefore, we compared the modulation by isoflurane of expressed α5ß3(N265M)γ2L receptors with their wild type counterparts. Methods: Using whole-cell electrophysiological recording and rapid solution exchange techniques, we tested the effects of isoflurane at concentrations ranging from 80 µM to 320 µM on currents activated by 1 µM GABA. We measured drug modulation of wild-type α5ß3γ2L GABAA receptors and their counterparts harboring the ß3(N265M) mutation. Results: Currents elicited by GABA were enhanced two- to four-fold by isoflurane, in a concentration-dependent manner. Under the same conditions, receptors incorporating the ß3(N265M) mutation were enhanced by approximately 1.5- to two-fold; i.e., modulation by isoflurane was attenuated by approximately one-half. Direct activation by isoflurane was also present in mutant receptors but also attenuated. Conclusions: In contrast to the complete insensitivity of ß3(N265M) mutant receptors to etomidate and propofol, the mutation has only a partial effect on receptor modulation by isoflurane. Therefore, the persistence of isoflurane effects in mutant mice does not exclude a possible contribution of ß3-GABAA receptors.


Assuntos
Anestésicos Inalatórios/farmacologia , Isoflurano/farmacologia , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/farmacologia , Animais , Etomidato/farmacologia , Células HEK293 , Humanos , Camundongos Transgênicos , Técnicas de Patch-Clamp , Mutação Puntual , Propofol/farmacologia , Receptores de GABA-A/fisiologia , Proteínas Recombinantes
9.
PLoS Comput Biol ; 16(12): e1008418, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33347455

RESUMO

Whether the brain operates at a critical "tipping" point is a long standing scientific question, with evidence from both cellular and systems-scale studies suggesting that the brain does sit in, or near, a critical regime. Neuroimaging studies of humans in altered states of consciousness have prompted the suggestion that maintenance of critical dynamics is necessary for the emergence of consciousness and complex cognition, and that reduced or disorganized consciousness may be associated with deviations from criticality. Unfortunately, many of the cellular-level studies reporting signs of criticality were performed in non-conscious systems (in vitro neuronal cultures) or unconscious animals (e.g. anaesthetized rats). Here we attempted to address this knowledge gap by exploring critical brain dynamics in invasive ECoG recordings from multiple sessions with a single macaque as the animal transitioned from consciousness to unconsciousness under different anaesthetics (ketamine and propofol). We use a previously-validated test of criticality: avalanche dynamics to assess the differences in brain dynamics between normal consciousness and both drug-states. Propofol and ketamine were selected due to their differential effects on consciousness (ketamine, but not propofol, is known to induce an unusual state known as "dissociative anaesthesia"). Our analyses indicate that propofol dramatically restricted the size and duration of avalanches, while ketamine allowed for more awake-like dynamics to persist. In addition, propofol, but not ketamine, triggered a large reduction in the complexity of brain dynamics. All states, however, showed some signs of persistent criticality when testing for exponent relations and universal shape-collapse. Further, maintenance of critical brain dynamics may be important for regulation and control of conscious awareness.


Assuntos
Anestésicos Dissociativos/farmacologia , Encéfalo/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Ketamina/farmacologia , Propofol/farmacologia , Animais , Encéfalo/fisiologia , Estado de Consciência/efeitos dos fármacos , Estado de Consciência/fisiologia , Eletroencefalografia/métodos , Haplorrinos , Vigília/fisiologia
10.
Anesth Analg ; 131(5): 1529-1539, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33079876

RESUMO

BACKGROUND: A number of recent studies have reported an association between intraoperative burst suppression and postoperative delirium. These studies suggest that anesthesia-induced burst suppression may be an indicator of underlying brain vulnerability. A prominent feature of electroencephalogram (EEG) under propofol and sevoflurane anesthesia is the frontal alpha oscillation. This frontal alpha oscillation is known to decline significantly during aging and is generated by prefrontal brain regions that are particularly prone to age-related neurodegeneration. Given that burst suppression and frontal alpha oscillations are both associated with brain vulnerability, we hypothesized that anesthesia-induced frontal alpha power could also be associated with burst suppression. METHODS: We analyzed EEG data from a previously reported cohort in which 155 patients received propofol (n = 60) or sevoflurane (n = 95) as the primary anesthetic. We computed the EEG spectrum during stable anesthetic maintenance and identified whether or not burst suppression occurred during the anesthetic. We characterized the relationship between burst suppression and alpha power using logistic regression. We proposed 5 different models consisting of different combinations of potential contributing factors associated with burst suppression: (1) a Base Model consisting of alpha power; (2) an Extended Mechanistic Model consisting of alpha power, age, and drug dosing information; (3) a Clinical Confounding Factors Model consisting of alpha power, hypotension, and other confounds; (4) a Simplified Model consisting only of alpha power and propofol bolus administration; and (5) a Full Model consisting of all of these variables to control for as much confounding as possible. RESULTS: All models show a consistent significant association between alpha power and burst suppression while adjusting for different sets of covariates, all with consistent effect size estimates. Using the Simplified Model, we found that for each decibel decrease in alpha power, the odds of experiencing burst suppression increased by 1.33-fold. CONCLUSIONS: In this study, we show how a decrease in anesthesia-induced frontal alpha power is associated with an increased propensity for burst suppression, in a manner that captures individualized information above and beyond a patient's chronological age. Lower frontal alpha band power is strongly associated with higher propensity for burst suppression and, therefore, potentially higher risk of postoperative neurocognitive disorders. We hypothesize that low frontal alpha power and increased propensity for burst suppression together characterize a "vulnerable brain" phenotype under anesthesia that could be mechanistically linked to brain metabolism, cognition, and brain aging.


Assuntos
Ritmo alfa/efeitos dos fármacos , Anestesia/efeitos adversos , Encéfalo/efeitos dos fármacos , Eletroencefalografia/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/farmacologia , Química Encefálica/efeitos dos fármacos , Cognição , Estudos de Coortes , Relação Dose-Resposta a Droga , Delírio do Despertar/diagnóstico , Delírio do Despertar/fisiopatologia , Feminino , Humanos , Monitorização Neurofisiológica Intraoperatória , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Propofol/administração & dosagem , Propofol/farmacologia , Adulto Jovem
11.
Anesth Analg ; 131(5): 1616-1625, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33079886

RESUMO

BACKGROUND: Anesthesia in pregnant rodents causes neurotoxicity in fetal and offspring rodents. However, the underlying mechanisms and targeted treatments remain largely to be determined. Isoflurane and propofol are among commonly used anesthetics. Thus, we set out to investigate whether propofol can mitigate the isoflurane-induced neurotoxicity in mice. METHODS: Pregnant C57BL/6 mice at gestational day 15 (G15) were randomly assigned to 4 groups: control, isoflurane, propofol, and isoflurane plus propofol. Levels of interleukin (IL)-6 and poly-ADP ribose polymerase (PARP) fragment were measured in the brains of G15 embryos, and levels of postsynaptic density (PSD)-95 and synaptophysin were determined in the hippocampal tissues of postnatal day 31 (P31) offspring using Western blotting and immunohistochemical staining. Learning and memory functions in P31 offspring were determined using a Morris water maze test. RESULTS: Isoflurane anesthesia in pregnant mice at G15 significantly increased brain IL-6 (222.6% ± 36.45% vs 100.5% ± 3.43%, P < .0001) and PARP fragment (384.2% ± 50.87% vs 99.59% ± 3.25%, P < .0001) levels in fetal mice and reduced brain PSD-95 (30.76% ± 2.03% vs 100.8% ± 2.25%, P < .0001) and synaptophysin levels in cornu ammonis (CA) 1 region (57.08% ± 4.90% vs 100.6% ± 2.20%, P < .0001) and dentate gyrus (DG; 56.47% ± 3.76% vs 99.76% ± 1.09%, P < .0001) in P31 offspring. Isoflurane anesthesia also impaired cognitive function in offspring at P31. Propofol significantly mitigated isoflurane-induced increases in brain IL-6 (117.5% ± 10.37% vs 222.6% ± 36.45%, P < .0001) and PARP fragment (205.1% ± 35.99% vs 384.2% ± 50.87%, P < .0001) levels in fetal mice, as well as reductions in PSD-95 (49.79% ± 3.43% vs 30.76% ± 2.03%, P < .0001) and synaptophysin levels in CA1 region (85.57% ± 2.97% vs 57.08% ± 4.90%, P < .0001) and DG (85.05% ± 1.87% vs 56.47% ± 3.76%, P < .0001) in hippocampus of P31 offspring. Finally, propofol attenuated isoflurane-induced cognitive impairment in offspring. CONCLUSIONS: These findings suggest that gestational isoflurane exposure in mice induces neuroinflammation and apoptosis in embryos and causes cognitive impairment in offspring. Propofol can attenuate these isoflurane-induced detrimental effects.


Assuntos
Anestésicos Inalatórios/toxicidade , Anestésicos Intravenosos/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/prevenção & controle , Isoflurano/antagonistas & inibidores , Isoflurano/toxicidade , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/prevenção & controle , Propofol/farmacologia , Animais , Animais Recém-Nascidos , Química Encefálica/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Disfunção Cognitiva/psicologia , Proteína 4 Homóloga a Disks-Large/metabolismo , Feminino , Feto , Interleucina-6/metabolismo , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Poli(ADP-Ribose) Polimerase-1/metabolismo , Gravidez , Sinaptofisina/metabolismo
12.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 273-278, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981285

RESUMO

Objective: To observe the effects of propofol on the activation of hepatic stellate cell line HSC2-T6 induced by transforming growth factor-beta 1 (TGF-ß1) and explore its possible mechanism.Methods: The cells were divided into control group, TGF-ß1 group, propofol group, TGF-ß1 + propofol group, rapamycin group, TGF-ß1 + propofol + rapamycin group. Cells were treated with rapamycin (5 µmol/L) for 1 hour, propofol (100 µmol/L) for 1 hour, then TGF-ß1 (5 ng/ml) was added to co-culture for 24 hours. Cell proliferation was measured by MTT assay. The concentrations of hyaluronic acid (HA), collagen IV (IV-C) and laminin (LN) in the supernatant of cell culture medium were measured by ELISA. The ultrastructure of cells was observed by transmission electron microscopy. The expressions of alpha-smooth muscle actin (α-SMA), mammalian rapamycin target protein (mTOR), phosphorylated mTOR (p-mTOR) and the autophagy related gene Beclin 1, LC3 and p62 were measured by Western blot. Results: Compared with control group, cell proliferation, the expression of α-SMA, the concentrations of HA, IV-C and LN in culture supernatant, the number of autophages, the expressions of Beclin-1 and LC3-II, the ratio of LC3-II/LC3-I in HSC2-T6 cells were increased significantly, while the expression of p-mTOR, the ratio of p-mTOR/mTOR and the expression of p62 protein were decreased significantly in TGF-ß1 group (All P<0.05). Compared with TGF-ß1 group, cell proliferation, the expression of α-SMA, the concentrations of HA, IV-C and LN in culture supernatant, the number of autophages, the expressions of Beclin-1 and LC3-II, the ratio of LC3-II/LC3-I in HSC2-T6 cells in TGF-ß1 group were decreased significantly, and the expression of p-mTOR, the ratio of p-mTOR/mTOR and expression of p62 protein were increased significantly in TGF-ß1 + propofol group (All P<0.05). Conclusion: Propofol inhibits the activation of hepatic stellate cells induced by TGF-beta 1, and its mechanism involves the mTOR-autophagy pathway.


Assuntos
Autofagia , Células Estreladas do Fígado , Propofol , Fator de Crescimento Transformador beta1 , Animais , Autofagia/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Propofol/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
13.
Medicine (Baltimore) ; 99(36): e21859, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899015

RESUMO

BACKGROUND: The purpose of this study was to evaluate the effects of adding ketamine to propofol on cognitive functions in patients undergoing sedation for colonoscopy. METHODS: In this randomized, double-blinded, and controlled study, 200 patients were randomly allocated to ketamine/propofol admixture group (Group KP, n = 100), and propofol group (Group P, n = 100). Patients in Group KP received 0.25 mg/kg of ketamine and 0.5 mg/kg of propofol. Patients in Group P received 0.5 mg/kg propofol. Cognitive functions were measured using CogState battery before and after the colonoscopy procedure. Ninety five patients in Group KP and 92 patients in Group P had completed the CogStates tests and were included in the data analysis. RESULTS: Compared with before procedure baseline, the performance on detection and identification tasks were significantly impaired after the procedure in both Group KP (P = .004, P = .001) and Group P patients (P = .005, P < .001). However, one-card learning accuracy and One-back memory was only impaired in Group KP patients (P = .006, P = .040) after the endoscopy but left intact in Group P patients. Group KP patients showed more severe impairment in one-card learning accuracy compared with Group P patients (P = .044). Group KP patients have better 5 minutes MAP (P = .005) and were also less likely to suffer from complications such as respiratory depression (P = .023) and hypotension (P = .015). OAA/S scores, BIS, MAP, complications, recovery times, and endoscopist and patient satisfaction were similar between the 2 groups. CONCLUSION: Although adding ketamine to propofol for sedation in colonoscopy provided fewer complications such as respiratory depression and hypotension, it also causes more impairment in cognitive functions.


Assuntos
Colonoscopia/métodos , Sedação Profunda/métodos , Hipnóticos e Sedativos/farmacologia , Ketamina/farmacologia , Complicações Cognitivas Pós-Operatórias/induzido quimicamente , Propofol/farmacologia , Adulto , Sedação Profunda/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Ketamina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Propofol/administração & dosagem , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Nature ; 585(7824): 303-308, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32879488

RESUMO

Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABAA) receptors to dampen neuronal activity in the brain1-5. However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABAA receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABAA receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABAA receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain.


Assuntos
Anestésicos Gerais/química , Anestésicos Gerais/farmacologia , Barbitúricos/química , Barbitúricos/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Microscopia Crioeletrônica , Receptores de GABA-A/química , Regulação Alostérica/efeitos dos fármacos , Anestésicos Gerais/metabolismo , Barbitúricos/metabolismo , Benzodiazepinas/metabolismo , Bicuculina/química , Bicuculina/metabolismo , Bicuculina/farmacologia , Sítios de Ligação , Ligação Competitiva/efeitos dos fármacos , Diazepam/química , Diazepam/metabolismo , Diazepam/farmacologia , Eletrofisiologia , Etomidato/química , Etomidato/metabolismo , Etomidato/farmacologia , Flumazenil/farmacologia , Antagonistas de Receptores de GABA-A/química , Antagonistas de Receptores de GABA-A/metabolismo , Antagonistas de Receptores de GABA-A/farmacologia , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Simulação de Dinâmica Molecular , Fenobarbital/química , Fenobarbital/metabolismo , Fenobarbital/farmacologia , Picrotoxina/química , Picrotoxina/metabolismo , Picrotoxina/farmacologia , Propofol/química , Propofol/metabolismo , Propofol/farmacologia , Receptores de GABA-A/metabolismo , Receptores de GABA-A/ultraestrutura , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologia
15.
PLoS One ; 15(9): e0238857, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32898195

RESUMO

BACKGROUND: Hypoxia-induced oxidative stress is one of the main mechanisms of myocardial injury, which frequently results in cardiomyocyte death and precipitates life-threatening heart failure. Propofol (2,6-diisopropylphenol), which is used to sedate patients during surgery, was shown to strongly affect the regulation of physiological processes, including hypoxia-induced oxidative stress. However, the exact mechanism is still unclear. METHODS: Expression of LRPPRC, SLIRP, and Bcl-2 after propofol treatment was measured by RT-qPCR and western blot analyses. The effects of propofol under hypoxia were determine by assessing mitochondrial homeostasis and mitochondrial function, including the ATP level and mitochondrial mass. Autophagy/mitophagy was measured by detecting the presence of LC3B, and autophagosomes were observed by transmission microscopy. RESULTS: Propofol treatment inhibited cleaved caspase-9 and caspase-3, indicating its inhibitory roles in mitochondrial-related apoptosis. Propofol treatment also transcriptionally activated LRPPRC, a mitochondrial-associated protein that exerts multiple functions by maintaining mitochondrial homeostasis, in a manner dependent on the presence of hypoxia-induced factor (HIF)-1α transcriptional activity in H9C2 and primary rat cardiomyocytes. LRPPRC induced by propofol maintained the mitochondrial membrane potential (MMP) and promoted mitochondrial function, including ATP synthesis and transcriptional activity. Furthermore, LRPPRC induced by propofol contributes, at least partially, to the inhibition of apoptotic cell death induced by hypoxia. CONCLUSION: Taken together, our results indicate that LRPPRC may have a protective antioxidant effect by maintaining mitochondrial homoeostasis induced by propofol and provide new insight into the protective mechanism of propofol against oxidative stress.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hipóxia/fisiopatologia , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Propofol/farmacologia , Substâncias Protetoras/farmacologia , Anestésicos Intravenosos/farmacologia , Animais , Apoptose , Células Cultivadas , Potencial da Membrana Mitocondrial , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-bcl-2 , Ratos , Espécies Reativas de Oxigênio
16.
Anesth Analg ; 131(4): 1270-1280, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32925348

RESUMO

BACKGROUND: Propofol is a common sedative-hypnotic drug traditionally used for inducing and maintaining general anesthesia. Recent studies have drawn attention to the nonanesthetic effects of propofol, but the potential mechanism by which propofol suppresses non-small-cell lung cancer (NSCLC) progression has not been fully elucidated. METHODS: For the in vitro experiments, we used propofol (0, 2, 5, and 10 µg/mL) to treat A549 cells for 1, 4, and 12 hours and Cell Counting Kit-8 (CCK-8) to detect proliferation. Apoptosis was measured with flow cytometry. We also transfected A549 cells with an microribonucleic acid-21 (miR-21) mimic or negative control ribonucleic acid (RNA) duplex and phosphatase and tensin homolog, deleted on chromosome 10 (PTEN) small interfering ribonucleic acid (siRNA) or negative control. PTEN, phosphorylated protein kinase B (pAKT), and protein kinase B (AKT) expression were detected using Western blotting, whereas miR-21 expression was examined by real-time polymerase chain reaction (RT-PCR). In vivo, nude mice were given injections of A549 cells to grow xenograft tumors; 8 days later, the mice were intraperitoneally injected with propofol (35 mg/kg) or soybean oil. Tumors were then collected from mice and analyzed by immunohistochemistry and Western blotting. RESULTS: Propofol inhibited growth (1 hour, P = .001; 4 hours, P ≤ .0001; 12 hours, P = .0004) and miR-21 expression (P ≤ .0001) and induced apoptosis (1 hour, P = .0022; 4 hours, P = .0005; 12 hours, P ≤ .0001) in A549 cells in a time and concentration-dependent manner. MiR-21 mimic and PTEN siRNA transfection antagonized the suppressive effects of propofol on A549 cells by decreasing PTEN protein expression (mean differences [MD] [95% confidence interval {CI}], -0.51 [-0.86 to 0.16], P = .0058; MD [95% CI], 0.81 [0.07-1.55], P = .0349, respectively), resulting in an increase in pAKT levels (MD [95% CI] = -0.82 [-1.46 to -0.18], P = .0133) following propofol exposure. In vivo, propofol treatment reduced NSCLC tumor growth (MD [95% CI] = -109.47 [-167.03 to -51.91], P ≤ .0001) and promoted apoptosis (MD [95% CI] = 38.53 [11.69-65.36], P = .0093). CONCLUSIONS: Our study indicated that propofol inhibited A549 cell growth, accelerated apoptosis via the miR-21/PTEN/AKT pathway in vitro, suppressed NSCLC tumor cell growth, and promoted apoptosis in vivo. Our findings provide new implications for propofol in cancer therapy and indicate that propofol is extremely advantageous in surgical treatment.


Assuntos
Anestésicos Intravenosos/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Propofol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células A549 , Anestésicos Intravenosos/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/efeitos dos fármacos , PTEN Fosfo-Hidrolase/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Br J Anaesth ; 125(4): 518-528, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32773216

RESUMO

BACKGROUND: Coherent alpha electroencephalogram (EEG) rhythms in the frontal cortex have been correlated with the hypnotic effects of propofol and dexmedetomidine, but less is known about frontal connectivity as a state-specific correlate of unresponsiveness as compared with long-range connectivity. We aimed to distinguish dose- and state-dependent effects of dexmedetomidine and propofol on EEG connectivity. METHODS: Forty-seven healthy males received either dexmedetomidine (n=23) or propofol (n=24) as target-controlled infusion with stepwise increments until loss of responsiveness (LOR). We attempted to arouse participants during constant dosing (return of responsiveness [ROR]), and the target concentration was then increased 50% to achieve presumed loss of consciousness. We collected 64-channel EEG data and prefrontal-frontal and anterior-posterior functional connectivity in the alpha band (8-14 Hz) was measured using coherence and weighted phase lag index (wPLI). Directed connectivity was measured with directed phase lag index (dPLI). RESULTS: Prefrontal-frontal EEG-based connectivity discriminated the states at the different drug concentrations. At ROR, prefrontal-frontal connectivity reversed to the level observed before LOR, indicating that connectivity changes were related to unresponsiveness rather than drug concentration. Unresponsiveness was associated with emergence of frontal-to-prefrontal dominance (dPLI: -0.13 to -0.40) in contrast to baseline (dPLI: 0.01-0.02). Coherence, wPLI, and dPLI had similar capability to discriminate the states that differed in terms of responsiveness and drug concentration. In contrast, anterior-posterior connectivity in the alpha band did not differentiate LOR and ROR. CONCLUSIONS: Local prefrontal-frontal EEG-based connectivity reflects unresponsiveness induced by propofol or dexmedetomidine, suggesting its utility in monitoring the anaesthetised state with these agents. CLINICAL TRIAL REGISTRATION: NCT01889004.


Assuntos
Dexmedetomidina/farmacologia , Eletroencefalografia/efeitos dos fármacos , Propofol/farmacologia , Adulto , Relação Dose-Resposta a Droga , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/fisiologia , Humanos , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia
18.
Br J Anaesth ; 125(3): 267-274, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32660717

RESUMO

BACKGROUND: Anaesthetic agents are likely to alter circulating cytokine concentrations. Because preceding studies have not been able to exclude the contribution of surgical trauma, perioperative stress, or both to circulating cytokine concentrations, the effects of anaesthesia remain unclear. The aim of this study was to quantify serum cytokines in healthy volunteers administered i.v. anaesthetic agents in the absence of surgical trauma and perioperative stress. METHODS: Serum samples obtained during previous standardised studies from healthy volunteers were compared before and 6-8 h after induction of anaesthesia with propofol (n=31), propofol/remifentanil (n=30), dexmedetomidine (n=17) or dexmedetomidine/remifentanil (n=15). Anaesthetic regimens were standardised and volunteers did not undergo any surgical intervention. Serum concentrations of interleukin (IL)2, IL4, IL6, IL10, IL17, IL18, IL21, IL22, IL23, C-X-C motif ligand 8, interferon gamma, E-selectin, L-selectin, major histocompatibility complex class I chain-polypeptide-related sequence (MIC)A, MICB, Granzyme A, and Granzyme B were quantified using a multiplexed antibody-based assay (Luminex). RESULTS: Samples were obtained from volunteers of either sex aged 18-70 yr. After anaesthesia with propofol alone, concentrations of IL4 (P=0.012), IL6 (P=0.027), IL21 (P=0.035), IL22 (P=0.002), C-X-C motif ligand 8 (P=0.004), MICB (P=0.046), and Granzyme A (P=0.045) increased. After anaesthesia with propofol and remifentanil, IL17 (P=0.013), interferon gamma (P=0.003), and MICA (P=0.001) decreased, but IL6 (P=0.006) and L-selectin (P=0.001) increased. After dexmedetomidine alone, IL18 (P=0.002), L-selectin (P=0.017), E-selectin (P=0.002), and Granzyme B (P=0.023) decreased. After dexmedetomidine with remifentanil no changes were observed. CONCLUSIONS: In healthy volunteers not undergoing surgery, different i.v. anaesthesia regimens were associated with differential effects on circulating cytokines.


Assuntos
Citocinas/sangue , Citocinas/efeitos dos fármacos , Dexmedetomidina/farmacologia , Hipnóticos e Sedativos/farmacologia , Propofol/farmacologia , Remifentanil/farmacologia , Adolescente , Adulto , Idoso , Analgésicos Opioides/farmacologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Adulto Jovem
19.
Artigo em Inglês | MEDLINE | ID: mdl-32549340

RESUMO

To illustrate a new technological advance in the standard drug-induced sleep endoscopy (DISE) model, a new machine was used, the Experimental 5 Video Stream System (5VsEs), which is capable of simultaneously visualizing all the decisional parameters on a single monitor, and recording and storing them in a single uneditable video. The DISE procedure was performed on 48 obstructive sleep apnea (OSA) or snoring patients. The parameters simultaneously recorded on a single monitor are (1) the pharmacokinetics and pharmacodynamics of propofol (through the target controlled infusion (TCI) pump monitor), (2) the endoscopic upper airway view, (3) the polygraphic pattern, and (4) the level of sedation (through the bispectral index (BIS) value). In parallel to the BIS recording, the middle latency auditory evoked potential (MLAEP) was also recorded and provided. Recorded videos from the 5VsEs machine were re-evaluated six months later by the same clinician and a second clinician to evaluate the concordance of the therapeutic indications between the two. After the six-month period, the same operator confirmed all their clinical decisions for 45 out of 48 videos. Three videos were no longer evaluable for technical reasons, so were excluded from further analysis. The comparison between the two operators showed a complete adherence in 98% of cases. The 5VsEs machine provides a multiparametric evaluation setting, defined as an "all in one glance" strategy, which allows a faster and more effective interpretation of all the simultaneous parameters during the DISE procedure, improving the diagnostic accuracy, and providing a more accurate post-analysis, as well as legal and research advantages.


Assuntos
Endoscopia , Hipnóticos e Sedativos , Propofol , Apneia Obstrutiva do Sono , Adulto , Feminino , Humanos , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Masculino , Propofol/farmacocinética , Propofol/farmacologia , Sono , Apneia Obstrutiva do Sono/diagnóstico , Ronco , Adulto Jovem
20.
Mol Pharmacol ; 98(3): 185-191, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32580996

RESUMO

Several general anesthetics (GAs) produce pain or irritation upon administration, and this occurs predominantly through the activation of the nociceptive ion channel, transient receptor potential ankyrin type 1 (TRPA1). However, the effects of GAs on agonist-mediated TRPA1 activity are unclear. Here we show that a diverse range of noxious and non-noxious volatile anesthetics, at clinically relevant concentrations, inhibit ligand-activated TRPA1 currents. These effects are species-specific; GAs blocks rodent TRPA1 without affecting the Drosophila ortholog. Furthermore, propofol inhibits rodent but not human TRPA1. Analysis of chimeric TRPA1 proteins and mutagenesis combined reveals two amino acid residues located in the S5 domain, Ser876 and Thr877, that are critical for the inhibitory effects of isoflurane and propofol. Introduction of these residues into Drosophila TRPA1 confers anesthetic inhibition. Furthermore, several residues lining the presumptive binding pocket for noxious GAs are not required for the inhibitory effects of GAs. We conclude that anesthetics inhibit TRPA1 by interacting at a site distinct from the activation site. The inhibitory effects of GAs at TRPA1 may contribute to the diverse pharmacological action of these drugs. SIGNIFICANCE STATEMENT: We show that both noxious and non-noxious general anesthetics inhibit agonist-evoked transient receptor potential ankyrin type 1 (TRPA1) activity and identify critical amino acid residues located in the pore domain. Inhibition of TRPA1 may affect pain and vascular signaling during anesthesia.


Assuntos
Hipnóticos e Sedativos/farmacologia , Mutação , Canal de Cátion TRPA1/genética , Canal de Cátion TRPA1/metabolismo , Animais , Drosophila melanogaster , Células HEK293 , Humanos , Isoflurano/farmacologia , Camundongos , Propofol/farmacologia , Domínios Proteicos , Ratos , Especificidade da Espécie , Canal de Cátion TRPA1/química
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