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1.
Ann Palliat Med ; 10(10): 11074-11082, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34763469

RESUMO

BACKGROUND: γ-aminobutyric acid (GABA) is a naturally occurring non-protein amino acid in the nervous system and has a wide range of physiological functions in the body. Walnut peptide (WP) contains high levels of arginine, aspartic acid, and glutamate, and has been shown to improve cognitive deficits and memory impairment in mice, while restoring antioxidant enzyme levels and reducing brain inflammatory mediators. METHODS: This study investigated the effects of GABA and WP, either alone or in combination, on sleep disturbances in mice. The pentobarbital-prolonged sleep test, pentobarbital-threshold sleep test, and barbital-induced sleep test were conducted to assess the effects of GABA and WP on sleep quality by gavage for 30 days as follows: GABA (102.25 mg/kg), WP (102.25 mg/kg), GABA (33.95, 102.25, 306.75 mg/kg)/WP (102.25 mg/kg) mixture. Furthermore, neurotransmitter tests were performed using mice brain tissue to investigate the possible mechanisms of GABA and WP on sleep status. RESULTS: The results showed that the combined use of GABA and WP significantly increased sleep duration compared with single administration of either WP or GABA. Increasing doses of GABA in mice treated with combined GABA and WP elevated the sleep rate to 50.00%, 64.28%, and 64.28%, respectively, compared to mice treated with GABA alone (35.71%) or mice treated with WP alone (28.57%). In mice that received a combination of GABA and WP orally, the latency time was significantly decreased after 30 days compared to control mice (P<0.05). Additionally, in mice treated with GABA, WP, or the combination of GABA and WP, the concentrations of GABA and acetylcholine (Ach) in the brain were significantly elevated and the concentration of serotonin (5-HT) was decreased compared to untreated mice. CONCLUSIONS: These results demonstrated that the combined administration of GABA and WP could prolong the sleep duration, increase sleep rate, and shorten the sleep latency more effectively than the administration of either GABA or WP alone. The mechanisms of action may be related to the regulation of neurotransmitters in the brain tissue by the combination of GABA and WP.


Assuntos
Juglans , Animais , Camundongos , Pentobarbital , Peptídeos , Sono , Ácido gama-Aminobutírico
2.
Am J Vet Res ; 83(1): 95-99, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34757922

RESUMO

OBJECTIVE: To determine whether intrarenal injection of sodium pentobarbital is a viable method for euthanasia in anesthetized client-owned cats and assess potential factors associated with time to cardiopulmonary arrest (TCPA) for such treated cats. ANIMALS: 131 client-owned cats. PROCEDURES: In this retrospective study, client-owned cats presented for euthanasia between March 1, 2009, and January 15, 2010, were evaluated by veterinarians to determine suitability of intrarenal injection versus other methods of euthanasia. Cats included were anesthetized and then received 6 mL of sodium pentobarbital (390 mg/mL) by intrarenal injection. Results for TCPA were compared for cats grouped on the basis of variables of interest. RESULTS: 131 cats were included, of which 74 (79%) had a TCPA < 1 minute and 28 (21%) had a TCPA between 1.5 and 8 minutes after intrarenal injection. Most (124/131 [95%]) cats had no observable reaction to the intrarenal injection other than cardiopulmonary arrest. Median TCPA was longer for cats without (1 min; 25/131 [19%]) versus with (0 min; 106/131 [81%]) palpable kidney swelling upon injection. CLINICAL RELEVANCE: The effects of intrarenal injection of sodium pentobarbital in cats of the present study were similar to those typically observed with IV administration of euthanasia solution. When this intrarenal injection method is used, cardiopulmonary arrest with few agonal reactions can be expected to occur quickly in most patients. The intrarenal injection method is suited for euthanasia of anesthetized cats with easily located kidneys when IV access may be difficult.


Assuntos
Eutanásia Animal , Pentobarbital , Animais , Gatos , Injeções/veterinária , Pentobarbital/farmacologia , Estudos Retrospectivos , Sódio
3.
Sci Rep ; 11(1): 16313, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381098

RESUMO

The first night effect (FNE) is a type of sleep disturbance caused by an unfamiliar environment, which leads to difficulty falling asleep and reduced sleep duration. Previously, we reported that Lactobacillus fermentum PS150 (PS150) improves sleep conditions in a pentobarbital-induced sleep mouse model. In this study, we aimed to evaluate the effect of PS150 on the FNE in mice. Briefly, mice were implanted with electrodes and orally administered PS150 for four weeks, and then the FNE was induced by cage changing. Analysis of polysomnographic signals revealed that intervention with PS150 restored non-rapid eye movement (NREM) sleep length under the FNE. Compared to diphenhydramine, a commonly used sleep aid, PS150 had no unwanted side effects, such as rapid eye movement (REM) sleep deprivation and fragmented sleep. Moreover, temporal analysis revealed that PS150 efficiently reduced both sleep latency and time spent restoring normal levels of REM sleep. Taken together, these results suggest that PS150 efficiently ameliorates sleep disturbance caused by the FNE. Additionally, V3-V4 16S rRNA sequencing revealed significant increases in Erysipelotrichia, Actinobacteria, and Coriobacteriia in fecal specimens of the PS150-treated group, indicating that PS150 induces gut microbiota remodeling.


Assuntos
Lactobacillus fermentum/fisiologia , Sono REM/fisiologia , Animais , Modelos Animais de Doenças , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pentobarbital/farmacologia , Polissonografia/métodos , RNA Ribossômico 16S/genética , Privação do Sono/induzido quimicamente , Privação do Sono/microbiologia , Privação do Sono/fisiopatologia , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Distúrbios do Início e da Manutenção do Sono/microbiologia , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Transtornos do Sono-Vigília/induzido quimicamente , Transtornos do Sono-Vigília/microbiologia , Transtornos do Sono-Vigília/fisiopatologia , Sono REM/efeitos dos fármacos
4.
Cochrane Database Syst Rev ; 8: CD011786, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34397100

RESUMO

BACKGROUND: This is an updated version of a Cochrane Review published in 2017. Paediatric neurodiagnostic investigations, including brain neuroimaging and electroencephalography (EEG), play an important role in the assessment of neurodevelopmental disorders. The use of an appropriate sedative agent is important to ensure the successful completion of the neurodiagnostic procedures, particularly in children, who are usually unable to remain still throughout the procedure. OBJECTIVES: To assess the effectiveness and adverse effects of chloral hydrate as a sedative agent for non-invasive neurodiagnostic procedures in children. SEARCH METHODS: We searched the following databases on 14 May 2020, with no language restrictions: the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 12 May 2020). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including Cochrane Epilepsy. SELECTION CRITERIA: Randomised controlled trials that assessed chloral hydrate agent against other sedative agent(s), non-drug agent(s), or placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated studies identified by the search for their eligibility, extracted data, and assessed risk of bias. Results were expressed in terms of risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, with 95% confidence intervals (CIs). MAIN RESULTS: We included 16 studies with a total of 2922 children. The methodological quality of the included studies was mixed. Blinding of the participants and personnel was not achieved in most of the included studies, and three of the 16 studies were at high risk of bias for selective reporting. Evaluation of the efficacy of the sedative agents was also underpowered, with all the comparisons performed in small studies. Fewer children who received oral chloral hydrate had sedation failure compared with oral promethazine (RR 0.11, 95% CI 0.01 to 0.82; 1 study; moderate-certainty evidence). More children who received oral chloral hydrate had sedation failure after one dose compared to intravenous pentobarbital (RR 4.33, 95% CI 1.35 to 13.89; 1 study; low-certainty evidence), but there was no clear difference after two doses (RR 3.00, 95% CI 0.33 to 27.46; 1 study; very low-certainty evidence). Children with oral chloral hydrate had more sedation failure compared with rectal sodium thiopental (RR 1.33, 95% CI 0.60 to 2.96; 1 study; moderate-certainty evidence) and music therapy (RR 17.00, 95% CI 2.37 to 122.14; 1 study; very low-certainty evidence). Sedation failure rates were similar between groups for comparisons with oral dexmedetomidine, oral hydroxyzine hydrochloride, oral midazolam and oral clonidine. Children who received oral chloral hydrate had a shorter time to adequate sedation compared with those who received oral dexmedetomidine (MD -3.86, 95% CI -5.12 to -2.6; 1 study), oral hydroxyzine hydrochloride (MD -7.5, 95% CI -7.85 to -7.15; 1 study), oral promethazine (MD -12.11, 95% CI -18.48 to -5.74; 1 study) (moderate-certainty evidence for three aforementioned outcomes), rectal midazolam (MD -95.70, 95% CI -114.51 to -76.89; 1 study), and oral clonidine (MD -37.48, 95% CI -55.97 to -18.99; 1 study) (low-certainty evidence for two aforementioned outcomes). However, children with oral chloral hydrate took longer to achieve adequate sedation when compared with intravenous pentobarbital (MD 19, 95% CI 16.61 to 21.39; 1 study; low-certainty evidence), intranasal midazolam (MD 12.83, 95% CI 7.22 to 18.44; 1 study; moderate-certainty evidence), and intranasal dexmedetomidine (MD 2.80, 95% CI 0.77 to 4.83; 1 study, moderate-certainty evidence). Children who received oral chloral hydrate appeared significantly less likely to complete neurodiagnostic procedure with child awakening when compared with rectal sodium thiopental (RR 0.95, 95% CI 0.83 to 1.09; 1 study; moderate-certainty evidence). Chloral hydrate was associated with a higher risk of the following adverse events: desaturation versus rectal sodium thiopental (RR 5.00, 95% 0.24 to 102.30; 1 study), unsteadiness versus intranasal dexmedetomidine (MD 10.21, 95% CI 0.58 to 178.52; 1 study), vomiting versus intranasal dexmedetomidine (MD 10.59, 95% CI 0.61 to 185.45; 1 study) (low-certainty evidence for aforementioned three outcomes), and crying during administration of sedation versus intranasal dexmedetomidine (MD 1.39, 95% CI 1.08 to 1.80; 1 study, moderate-certainty evidence). Chloral hydrate was associated with a lower risk of the following: diarrhoea compared with rectal sodium thiopental (RR 0.04, 95% CI 0.00 to 0.72; 1 study), lower mean diastolic blood pressure compared with sodium thiopental (MD 7.40, 95% CI 5.11 to 9.69; 1 study), drowsiness compared with oral clonidine (RR 0.44, 95% CI 0.30 to 0.64; 1 study), vertigo compared with oral clonidine (RR 0.15, 95% CI 0.01 to 2.79; 1 study) (moderate-certainty evidence for aforementioned four outcomes), and bradycardia compared with intranasal dexmedetomidine (MD 0.17, 95% CI 0.05 to 0.59; 1 study; high-certainty evidence). No other adverse events were significantly associated with chloral hydrate, although there was an increased risk of combined adverse events overall (RR 7.66, 95% CI 1.78 to 32.91; 1 study; low-certainty evidence). AUTHORS' CONCLUSIONS: The certainty of evidence for the comparisons of oral chloral hydrate against several other methods of sedation was variable. Oral chloral hydrate appears to have a lower sedation failure rate when compared with oral promethazine. Sedation failure was similar between groups for other comparisons such as oral dexmedetomidine, oral hydroxyzine hydrochloride, and oral midazolam. Oral chloral hydrate had a higher sedation failure rate when compared with intravenous pentobarbital, rectal sodium thiopental, and music therapy. Chloral hydrate appeared to be associated with higher rates of adverse events than intranasal dexmedetomidine. However, the evidence for the outcomes for oral chloral hydrate versus intravenous pentobarbital, rectal sodium thiopental, intranasal dexmedetomidine, and music therapy was mostly of low certainty, therefore the findings should be interpreted with caution. Further research should determine the effects of oral chloral hydrate on major clinical outcomes such as successful completion of procedures, requirements for an additional sedative agent, and degree of sedation measured using validated scales, which were rarely assessed in the studies included in this review. The safety profile of chloral hydrate should be studied further, especially for major adverse effects such as oxygen desaturation.


Assuntos
Hidrato de Cloral/administração & dosagem , Técnicas de Diagnóstico Neurológico , Hipnóticos e Sedativos/administração & dosagem , Criança , Hidrato de Cloral/efeitos adversos , Humanos , Hidroxizina/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Midazolam/administração & dosagem , Midazolam/efeitos adversos , Pentobarbital/administração & dosagem
5.
Nutrients ; 13(8)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445005

RESUMO

Caffeine, a natural stimulant, is known to be effective for weight loss. On this basis, we screened the arousal-inducing effect of five dietary supplements with a weight loss effect (Garcinia cambogia, Coleus forskohlii, Camellia sinensis L., Irvingia gabonensis, and Malus pumila M.), of which the G. cambogia peel extract (GC) showed a significant arousal-inducing effect in the pentobarbital-induced sleep test in mice. This characteristic of GC was further evaluated by analysis of electroencephalogram and electromyogram in C57L/6N mice, and it was compared to that of the positive control, caffeine. Administration of GC (1500 mg/kg) significantly increased wakefulness and decreased non-rapid eye movement sleep, similar to that of caffeine (25 mg/kg), with GC and caffeine showing a significant increase in wakefulness at 2 and 6 h, respectively. Compared to that of caffeine, the shorter duration of efficacy of GC could be advantageous because of the lower possibility of sleep disturbance. Furthermore, the arousal-inducing effects of GC (1500 mg/kg) and caffeine (25 mg/kg) persisted throughout the chronic (3 weeks) administration study. This study, for the first time, revealed the arousal-inducing effect of GC. Our findings suggest that GC might be a promising natural stimulant with no side effects. In addition, it is preferential to take GC as a dietary supplement for weight loss during the daytime to avoid sleep disturbances owing to its arousal-inducing effect.


Assuntos
Nível de Alerta/efeitos dos fármacos , Ondas Encefálicas/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Eletroencefalografia , Garcinia cambogia , Extratos Vegetais/farmacologia , Animais , Fármacos Antiobesidade/farmacologia , Encéfalo/fisiologia , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/isolamento & purificação , Frutas , Garcinia cambogia/química , Hipnóticos e Sedativos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Pentobarbital/farmacologia , Extratos Vegetais/isolamento & purificação , Sono/efeitos dos fármacos
6.
Leg Med (Tokyo) ; 53: 101928, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34119997

RESUMO

A study was undertaken of 51 cases where barbiturates were detected in post-mortem blood samples from 2000 to 2019 at Forensic Science South Australia, Adelaide, Australia. The cause of death was drug toxicity in only 27 (53%) (M:F = 19:8; age range 19-74yrs, mean 46yrs). In 17 cases, barbiturate toxicity was the primary cause of death, 14 due to pentobarbitone and 3 to phenobarbitone. All were suicides. Barbiturates were obtained by online purchase from overseas sources in 9 cases (33%), and through veterinary practice in 2 cases (7%). Drug toxicity deaths where barbiturates were detected rose from 1 in 2000-2004 to 11 in 2015-2019, and those where deaths were primarily due to barbiturate toxicity rose from 1 in 2000-2004 to 9 in 2015-2019. However, the mere detection of barbiturates in post mortem samples did not equate with illicit use, as 23 of the deaths (45%) were due to natural causes in individuals prescribed barbiturates for epilepsy. The usefulness of examining subset populations separate from accrued national data is also demonstrated in the significantly younger age of decedents in South Australia dying from deliberately administered barbiturates (46 yrs) compared to the national average of 57.9 yrs. The reasons for this difference will require further investigation as this may impact upon local suicide prevention strategies.


Assuntos
Suicídio , Adulto , Idoso , Austrália , Barbitúricos , Humanos , Pessoa de Meia-Idade , Pentobarbital , Adulto Jovem
7.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072024

RESUMO

Overweight, obesity, and psychiatric disorders are serious health problems. To evidence the anxiolytic-like effects and lipid reduction in mice receiving a high-calorie diet and Bertholletia excelsa seeds in a nonpolar extract (SBHX, 30 and 300 mg/kg), animals were assessed in open-field, hole-board, and elevated plus-maze tests. SBHX (3 and 10 mg/kg) potentiated the pentobarbital-induced hypnosis. Chronic administration of SBHX for 40 days was given to mice fed with a hypercaloric diet to determine the relationship between water and food intake vs. changes in body weight. Testes, epididymal white adipose tissue (eWAT), and liver were dissected to analyze fat content, triglycerides, cholesterol, and histological effects after administering the hypercaloric diet and SBHX. Fatty acids, such as palmitoleic acid (0.14%), palmitic acid (21.42%), linoleic acid (11.02%), oleic acid (59.97%), and stearic acid (7.44%), were identified as constituents of SBHX, producing significant anxiolytic-like effects and preventing body-weight gain in mice receiving the hypercaloric diet without altering their water or food consumption. There was also a lipid-lowering effect on the testicular tissue and eWAT and a reduction of adipocyte area in eWAT. Our data evidence beneficial properties of B. excelsa seeds influencing global health concerns such as obesity and anxiety.


Assuntos
Ansiedade/metabolismo , Bertholletia/metabolismo , Lipídeos/química , Sobrepeso/metabolismo , Sementes , Tecido Adiposo Branco/metabolismo , Animais , Peso Corporal , Sistema Nervoso Central , Ingestão de Alimentos , Epididimo/metabolismo , Ácidos Graxos/metabolismo , Hipnose , Masculino , Aprendizagem em Labirinto , Camundongos , Pentobarbital , Testículo/metabolismo
8.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805468

RESUMO

The aim of this study was to investigate the effect of Lactobacillus brevis-fermented γ-aminobutyric acid (LB-GABA) on sleep behaviors in invertebrate and vertebrate models. In Drosophila melanogaster, LB-GABA-treated group showed an 8-9%-longer sleep duration than normal group did. LB-GABA-treated group also showed a 46.7% lower level of nighttime activity with a longer (11%) sleep duration under caffeine-induced arousal conditions. The LB-GABA-mediated inhibition of activity was confirmed as a reduction of total movement of flies using a video tracking system. In the pentobarbital-induced sleep test in mice, LB-GABA (100 mg/kg) shortened the time of onset of sleep by 32.2% and extended sleeping time by 59%. In addition, mRNA and protein level of GABAergic/Serotonergic neurotransmitters were upregulated following treatment with LB-GABA (2.0%). In particular, intestine- and brain-derived GABAA protein levels were increased by sevenfold and fivefold, respectively. The electroencephalography (EEG) analysis in rats showed that LB-GABA significantly increased non-rapid eye movement (NREM) (53%) with the increase in theta (θ, 59%) and delta (δ, 63%) waves, leading to longer sleep time (35%), under caffeine-induced insomnia conditions. LB-GABA showed a dose-dependent agonist activity on human GABAA receptor with a half-maximal effective concentration (EC50) of 3.44 µg/mL in human embryonic kidney 293 (HEK293) cells.


Assuntos
Sono/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia , Animais , Cafeína/farmacologia , Proteínas de Drosophila/genética , Drosophila melanogaster , Eletroencefalografia , Fermentação , Agonistas de Receptores de GABA-A/farmacologia , Células HEK293 , Humanos , Hipnóticos e Sedativos/farmacologia , Lactobacillus brevis/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Neurotransmissores/metabolismo , Pentobarbital/farmacologia , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Receptores de Neurotransmissores/genética , Receptores de Neurotransmissores/metabolismo , Sono/fisiologia , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Ácido gama-Aminobutírico/metabolismo
9.
Arq Neuropsiquiatr ; 79(3): 216-221, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33886795

RESUMO

BACKGROUND: Sleep disorders induce anxiety and forgetfulness and change habits. The chemical hypnotic drugs currently used have serious side effects and, therefore, people are drawn towards using natural compounds such as plant-based healing agents. Abscisic acid (ABA) is produced in a variety of mammalian tissues and it is involved in many neurophysiological functions. OBJECTIVE: To investigate the possible effect of ABA on pentobarbital-induced sleep and its possible signaling through GABA-A and PPAR (γ and ß) receptors, in male Wistar rats. METHODS: The possible effect of ABA (5 and 10 µg/rat, intracerebroventricularly) on sleep onset latency time and duration was evaluated in a V-maze model of sleep. Pentobarbital sodium (40 mg/kg, intraperitoneally) was injected to induce sleep 30 min after administration of ABA. PPARß (GSK0660, 80 nM/rat), PPARγ (GW9662, 3 nM/rat) or GABA-A receptor (bicuculline, 6 µg/rat) antagonists were given 15 min before ABA injection. Diazepam (2 mg/kg, intraperitoneally) was used as a positive control group. RESULTS: ABA at 5 µg significantly boosted the pentobarbital-induced subhypnotic effects and promoted induction of sleep onset in a manner comparable to diazepam treatment. Furthermore, pretreatment with bicuculline significantly abolished the ABA effects on sleep parameters, while the amplifying effects of ABA on the induction of sleep onset was not significantly affected by PPARß or PPARγ antagonists. The sleep prolonging effect of ABA was significantly prevented by both PPAR antagonists. CONCLUSIONS: The data showed that ABA boosts pentobarbital-induced sleep and that GABA-A, PPARß and PPARγ receptors are, at least in part, involved in ABA signaling.


Assuntos
Ácido Abscísico/farmacologia , PPAR gama/metabolismo , PPAR beta/metabolismo , Receptores de GABA-A/metabolismo , Sono , Animais , Masculino , Pentobarbital/farmacologia , Reguladores de Crescimento de Plantas/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais
10.
Amino Acids ; 53(3): 417-427, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33609179

RESUMO

This study aimed to investigate whether inhibition of endoplasmic reticulum stress (ERS) mediated the ameliorative effect of apelin on acute heart failure (AHF). Rabbit model of AHF was induced by sodium pentobarbital. Cardiac dysfunction and injury were detected in the rabbit models of AHF, including impaired hemodynamic parameters and increased levels of CK-MB and cTnI. Apelin treatment dramatically improved cardiac impairment caused by AHF. ERS, indexed by increased GRP78, CHOP, and cleaved-caspase12 protein levels, was simultaneously attenuated by apelin. Apelin also could ameliorate increased protein levels of cleaved-caspase3 and Bax, and improved decreased protein levels of Bcl-2. Two common ERS stimulators, tunicamycin (Tm) and dithiothreitol (DTT) blocked the ameliorative effect of apelin on AHF. Phosphorylated Akt levels increased after apelin treatment in the rabbit models of AHF. The Akt signaling inhibitors wortmannin and LY294002 could block the cardioprotective effect of apelin, which could be relieved by ERS inhibitor 4-phenyl butyric acid (4-PBA). The aforementioned beneficial effects of apelin could all be blocked by APJ receptor antagonist F13A. 4-PBA and SC79, an Akt activator, can restore the ameliorative effect of apelin on AHF blocked by F13A. Apelin treatment dramatically ameliorated cardiac impairment caused by AHF, which might be mediated by APJ/Akt/ERS signaling pathway. These results will shed new light on AHF therapy.


Assuntos
Apelina/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Doença Aguda , Animais , Receptores de Apelina/antagonistas & inibidores , Receptores de Apelina/metabolismo , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Coração/fisiopatologia , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Miocárdio/metabolismo , Pentobarbital/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Coelhos , Transdução de Sinais/efeitos dos fármacos
11.
J Control Release ; 332: 30-39, 2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33600879

RESUMO

Focused ultrasound (FUS) offers an attractive tool for non-invasive neuromodulation, addressing a clinical need to develop more minimally invasive approaches that are safer, more tolerable and versatile. In combination with a cavitation agent, the effects of ultrasound can be amplified and localized for therapy. Using c-Fos expression mapping, we show how ultrasound-sensitive nanodroplets can be used to induce either neurosuppression or neurostimulation, without disrupting the blood-brain barrier in rats. By repurposing a commercial ultrasound contrast agent, Definity, lipid-shell decafluorobutane-core nanodroplets of 212.5 ± 2.0 nm were fabricated and loaded with or without pentobarbital. FUS was delivered with an atlas-based targeting system at 1.66 MHz to the motor cortex of rats, using a feedback-controller to detect successful nanodroplet vaporization and drug release. Neuromodulation was quantified through changes in sensorimotor function and c-Fos expression. Following FUS-triggered delivery, sham nanodroplets induced a 22.6 ± 21% increase in local c-Fos expression, whereas pentobarbital-loaded nanodroplets induced a 21.7 ± 13% decrease (n = 6). Nanodroplets, combined with FUS, offer an adaptable tool for neuromodulation, through local delivery of small molecule anesthetics or targeted mechanical effects.


Assuntos
Barreira Hematoencefálica , Meios de Contraste , Animais , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Pentobarbital , Ratos , Ultrassonografia
12.
Int J Exp Pathol ; 102(1): 51-56, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33410572

RESUMO

This study aims to compare the influence of different anaesthesia methods on the mechanisms involved in the development of hepatoblastoma (HB). HB rabbit models were constructed and divided into three groups: disoprofol, pentobarbital sodium and HB groups. After anaesthesia, rabbit blood was collected from the tail vein. Haematological analysis (platelets) and an ELISA was used to measure the thrombopoietin (TPO) and 5-hydroxytryptamine (5-HT). Flow cytometry was used to determine expression of P-selectin and PAF. The expression of 5-HTR2B, PCNA, vWF, P70s6k, 4E-BP1, mTOR and FRAP was determined in the tumour itself or in vascular tissues obtained from the rabbits. The platelet content in the disoprofol group. The content or expression of TPO, 5-HT, P-selectin, PAF, 5-HTR2B, PCNA, vWF, P70s6k, 4E-BP1, mTOR and FRAP was significantly higher in the disoprofol group compared to pentobarbital sodium and HB groups. Expression of these molecules was much higher in the pentobarbital sodium group compared with the HB group. These findings suggest that disoprofol anaesthesia can promote HB development via the mTOR/p70S6K1 and FRAP signalling pathway.


Assuntos
Hepatoblastoma/patologia , Hipnóticos e Sedativos/efeitos adversos , Neoplasias Hepáticas/patologia , Pentobarbital/efeitos adversos , Ativação Plaquetária/efeitos dos fármacos , Propofol/efeitos adversos , Animais , Coelhos , Transdução de Sinais/efeitos dos fármacos
13.
J Mol Neurosci ; 71(3): 596-606, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32789565

RESUMO

KLF4 is a zinc-finger transcription factor that plays an essential role in many biological processes, including neuroinflammation, neuron regeneration, cell proliferation, and apoptosis. Through effects on these processes, KLF4 has likely roles in Alzheimer's disease, Parkinson's disease, and traumatic brain injury. However, little is known about the role of KLF4 in more immediate behavioral processes that similarly depend upon broad changes in brain excitability, such as the sleep process. Here, behavioral approaches, western blot, and immunohistochemical experiments were used to explore the role of KLF4 on sedation and the potential mechanisms of those effects. The results showed that overexpression of KLF4 prolonged loss of righting reflex (LORR) duration in pentobarbital-treated mice and increased c-Fos expression in the lateral hypothalamus (LH) and the ventrolateral preoptic nucleus (VLPO), while it decreased c-Fos expression in the tuberomammillary nucleus (TMN). Moreover, overexpression of KLF4 reduced the expression of p53 in the hypothalamus and increased the expression of STAT3 in the hypothalamus. Therefore, these results suggest that KLF4 exerts sedative effects through the regulation of p53 and STAT3 expression, and it indicates a role of KLF4 ligands in the treatment of sleep disorders.


Assuntos
Hipnóticos e Sedativos/farmacologia , Hipotálamo/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Pentobarbital/farmacologia , Animais , Hipotálamo/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Reflexo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
14.
Clin Toxicol (Phila) ; 59(3): 224-230, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32633579

RESUMO

INTRODUCTION: There have been increasing reports documenting barbiturate-related deaths, despite routine prescribing for only relatively rare indications. The aims of the current study were to examine trends in barbiturate-related deaths in Australia from 2000 to 2019 and determine the case characteristics and circumstances of barbiturate-related deaths. METHODS: All barbiturate-related deaths identified in the Australian National Coronial Information System were examined. Information was collected on cause, manner, demographics, location, psychosocial factors, circumstances of deaths and toxicology. We examined these based on the age categories 18-44 years, 45-64 years and ≥65 years. RESULTS: We identified 511 cases. Mean age was 57.9 years (SD 20.2, range 18-100) and 56% were male. Intentional poisoning was the most common cause of death (87.5%) and was slightly higher in the oldest age group (92.1%) and lowest in the youngest age group (81.1%). Pentobarbitone was the most common barbiturate (75.7%) and pentobarbitone-related deaths increased from 0% in 2000 to 93.6% in 2017. There were notable differences between age categories, with the youngest age group recording more severe psychiatric histories. In contrast, the oldest age group were more likely to have severe physical health problems, such as cancer, chronic non-cancer pain, neurological conditions and significant cardiopulmonary morbidity. Euthanasia resources were commonly documented (33.9%), most frequently in the oldest age group (52.3%). CONCLUSION: Barbiturate-related deaths in Australia are increasing, particularly pentobarbitone-related deaths. Most deaths were intentional and involved adults across the lifespan. Younger people were more likely to have significant mental health problems, whilst the oldest age group were more likely to have severe physical health conditions.


Assuntos
Barbitúricos/toxicidade , Overdose de Drogas/mortalidade , Hipnóticos e Sedativos/toxicidade , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pentobarbital/toxicidade , Psicologia , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
15.
Molecules ; 25(20)2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33066512

RESUMO

Gardenia jasminoides Ellis is a famous fragrant flower in China. Previous pharmacological research mainly focuses on its fruit. In this study, the essential oil of the flower of 'Shanzhizi', which was a major variety for traditional Chinese medicine use, was extracted by hydro distillation and analyzed by GC-MS. Mouse anxiety models included open field, elevated plus maze (EPM), and light and dark box (LDB), which were used to evaluate its anxiolytic effect via inhalation. The involvement of monoamine system was studied by pretreatment with neurotransmitter receptor antagonists WAY100635, flumazenil and sulpiride. The monoamine neurotransmitters contents in the prefrontal cortex (PFC) and hippocampus after aroma inhalation were also analyzed. The results showed that inhalation of G. jasminoides essential oil could significantly elevated the time and entries into open arms in EPM tests and the time explored in the light chamber in LDB tests with no sedative effect. WAY100635 and sulpiride, but not flumazenil, blocked its anxiolytic effect. Inhalation of G. jasminoides essential oil significantly down-regulated the 5-HIAA/5-HT in the PFC and reduced the 5-HIAA content in hippocampus compared to the control treatment. In conclusion, inhalation of gardenia essential oil showed an anxiolytic effect in mice. Monoamine, especially the serotonergic system, was involved in its anxiolytic effect.


Assuntos
Ansiolíticos/farmacologia , Gardenia/química , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Administração por Inalação , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/química , Monoaminas Biogênicas/análise , Cicloexanos/farmacologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Teste de Labirinto em Cruz Elevado , Flumazenil/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Masculino , Camundongos Endogâmicos ICR , Óleos Voláteis/administração & dosagem , Pentobarbital/farmacologia , Piperazinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptores de Neurotransmissores/antagonistas & inibidores , Sono/efeitos dos fármacos , Sulpirida/farmacologia , Transmissão Sináptica/efeitos dos fármacos
17.
PLoS One ; 15(9): e0238123, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881944

RESUMO

An effective and pain-free killing method is required to achieve the goal of euthanasia, a "good death". Overdose of sodium pentobarbital (PB) by intraperitoneal (IP) injection is a widely accepted technique in laboratory rats, but questions remain regarding pain associated with administration. As PB rapidly causes sedation and loss of consciousness, most studies have relied on indirect evidence of pain. The objective of this study was to assess pain associated with IP PB using an appropriate vehicle control. Adult male and female Sprague Dawley (SD) and female Wistar rats (N = 84) were block randomised by sex and strain to receive one of three treatments: 1) 800 mg/kg PB (pH 11), 2) saline or 3) vehicle controls (pH 11 or 12.5). Behavior (Rat Grimace Scale (RGS), writhing, back arching) was evaluated at baseline, before loss of righting reflex (LORR, PB group), and at 80s, 151s and 10 min post-injection (PI; saline and vehicle control groups). In the PB group, mean time to LORR was 78 ± 7.9 seconds. In the vehicle control groups, RGS scores were increased at 151s PI (SD: p = 0.0002, 95%CI 0.73 to 0.20) from baseline, as was relative frequency of writhing (SD: p < 0.0001; Wistar; p = 0.0004). RGS scores remained elevated 10 mins PI (SD: p = 0.0005, 95%CI 0.71 to 0.18; Wistar: p = 0.0234, 95%CI 0.91 to 0.07) but the relative frequency of writhing did not (p > 0.999). The RGS scores and the relative frequency of writhing remained low in the PB and saline groups (p > 0.05). These results show that, vehicle controls for IP PB result in signs associated with pain, pain may not be experienced following IP PB when LORR occurs quickly, and that the effects of PB limit behavioral pain assessments.


Assuntos
Hipnóticos e Sedativos/administração & dosagem , Dor/tratamento farmacológico , Pentobarbital/administração & dosagem , Animais , Comportamento Animal , Feminino , Injeções Intraperitoneais , Fígado/patologia , Masculino , Músculos/patologia , Dor/patologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar
18.
Am J Physiol Regul Integr Comp Physiol ; 319(5): R526-R540, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32903040

RESUMO

The goal of this study was to examine the effects of systemic morphine on the pattern and morphology of gasping breathing during respiratory autoresuscitation from transient anoxia. We hypothesized that systemic morphine levels sufficient to cause significant depression of eupnea would also cause depression of gasping breathing. Respiratory and cardiovascular variables were studied in 20 spontaneously breathing pentobarbital-anaesthetized adult male rats. Sham (saline) injections caused no significant change in resting respiratory or cardiovascular variables (n = 10 rats). Morphine, on the other hand, caused significant depression of eupneic breathing, with ventilation and peak inspiratory flow decreased by ∼30-60%, depending on the background condition (n = 10 rats). In contrast, morphine did not depress gasping breathing. Duration of primary apnea, time to restore eupnea, the number and amplitude of gasping breaths, average and maximum peak flows, and volume of gasping breaths were not significantly different postinjection in either condition. Blood pressures were all significantly lower following morphine injection at key time points in the process of autoresuscitation. Last, rate of successful recovery from anoxia was 80% in the morphine group (8/10 rats) compared with 100% (10/10 rats) in the sham group, postinjection. We conclude that the mechanisms and/or anatomic correlates underlying generation of gasping rhythm are distinct from those underlying eupnea, allowing gasping to remain robust to systemic morphine levels causing significant depression of eupnea. Morphine nevertheless decreases likelihood of recovery from transient anoxia, possibly as a result of decreased tissue perfusion pressures at critical time points during the process of respiratory autoresuscitation.


Assuntos
Morfina/efeitos adversos , Respiração/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Animais , Apneia , Relação Dose-Resposta a Droga , Hipnóticos e Sedativos/farmacologia , Hipóxia , Masculino , Morfina/administração & dosagem , Pentobarbital/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
19.
PLoS One ; 15(8): e0236594, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760073

RESUMO

Microglia, the resident immune cells of the brain, are highly ramified and motile and their morphology is strongly linked to their function. Microglia constantly monitor the brain parenchyma and are crucial for maintaining brain homeostasis and fine-tuning neuronal networks. Besides affecting neurons, anesthetics may have wide-ranging effects mediated by non-neuronal cells and in particular microglia. We thus examined the effect of two commonly used anesthetic agents, ketamine/xylazine and barbiturates, on microglial motility and morphology. A combination of two-photon in vivo imaging and electroencephalography (EEG) recordings in unanesthetized and anesthetized mice as well as automated analysis of ex vivo sections were used to assess morphology and dynamics of microglia. We found that administration of ketamine/xylazine and pentobarbital anesthesia resulted in quite distinct EEG profiles. Both anesthetics reduced microglial motility, but only ketamine/xylazine administration led to reduction of microglial complexity in vivo. The change of cellular dynamics in vivo was associated with a region-dependent reduction of several features of microglial cells ex vivo, such as the complexity index and the ramification length, whereas thiopental altered the size of the cytoplasm. Our results show that anesthetics have considerable effects on neuronal activity and microglial morphodynamics and that barbiturates may be a preferred anesthetic agent for the study of microglial morphology. These findings will undoubtedly raise compelling questions about the functional relevance of anesthetics on microglial cells in neuronal physiology and anesthesia-induced neurotoxicity.


Assuntos
Anestésicos/farmacologia , Moduladores GABAérgicos/farmacologia , Ketamina/farmacologia , Microglia/efeitos dos fármacos , Pentobarbital/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tiopental/farmacologia , Xilazina/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos
20.
Biomed Res Int ; 2020: 6109497, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32626750

RESUMO

Objectives: To evaluate the effects of pentobarbital dosages on lower urinary tract function and to define an appropriate dosage of sodium pentobarbital that would be suitable for urodynamic studies in which recovery from anesthesia and long term survive were needed for subsequent experiment. Methods: Twenty-four 8-week-old, female, virgin, Sprague-Dawley rats (200-250 g) were used in this study. Rats in study groups received gradient doses of pentobarbital intraperitoneally, and those in the control group received urethane intraperitoneally. External urethral sphincter electromyography (EUS-EMG) was recorded simultaneously during cystometry and leak point pressure tests. The toe-pinch reflex was used to determine the level of anesthesia. Results: Micturition was normally induced in both the urethane group and 32 mg/kg pentobarbital group. However, in groups of 40 mg/kg or 36 mg/kg pentobarbital, micturition failed to be induced; instead, nonvoiding contractions accompanied by EUS-EMG tonic activity were observed. There were no significant differences in leak point pressure or EUS-EMG amplitude or frequency between the urethane and 32 mg/kg pentobarbital groups. Conclusions: This study confirmed significant dose-dependent effects of pentobarbital on lower urinary tract function and 32 mg/kg pentobarbital as an appropriate dosage for recovery urodynamic testing, which enable the achievement of expected essential micturition under satisfactory anesthesia in female rats.


Assuntos
Anestésicos Intravenosos , Pentobarbital , Bexiga Urinária/efeitos dos fármacos , Urodinâmica/efeitos dos fármacos , Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/farmacologia , Animais , Eletromiografia/efeitos dos fármacos , Feminino , Pentobarbital/administração & dosagem , Pentobarbital/farmacologia , Ratos , Ratos Sprague-Dawley , Uretana/administração & dosagem , Uretana/farmacologia , Uretra/efeitos dos fármacos , Uretra/fisiologia , Bexiga Urinária/fisiologia , Micção/efeitos dos fármacos , Micção/fisiologia
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