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Molecules (Basel, Switzerland) May 2021Overweight, obesity, and psychiatric disorders are serious health problems. To evidence the anxiolytic-like effects and lipid reduction in mice receiving a high-calorie...
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 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 seeds influencing global health concerns such as obesity and anxiety.
Topics: Adipose Tissue, White; Animals; Anxiety; Bertholletia; Body Weight; Central Nervous System; Eating; Epididymis; Fatty Acids; Hypnosis; Lipids; Male; Maze Learning; Mice; Overweight; Pentobarbital; Seeds; Testis
PubMed: 34072024
DOI: 10.3390/molecules26113212 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... Nov 2021To investigate the role of cisatracurium in diaphragm atrophy in mechanically ventilated (MV) rats and its possible mechanism.
OBJECTIVE
To investigate the role of cisatracurium in diaphragm atrophy in mechanically ventilated (MV) rats and its possible mechanism.
METHODS
30 adult male Sprague-Dawley (SD) rats were randomly assigned to 5 groups: Rats in the control (CON) group ( =6) were fasted for 30 h without any other intervention; rats in the MV group ( =6) were fasted for 6 h, and then mechanically ventilated for 24 h while receiving continuous infusion of sodium pentobarbital and 0.9% NaCl; rats in the MV+cisatracurium (MVC) group ( =6) were fasted for 6 h, and then mechanically ventilated for 24 h while receiving continuous infusion of sodium pentobarbital and cisatracurium; rats in the MV+chloroquine (QMV) group ( =6) and rats in the MV+cisatracurium+chloroquine (QMVC) group ( =6) received intraperitoneal injection of chloroquine (30 mg/kg), an autophagy inhibitor, at 24 h and 30 min prior to MV in addition to the treatments given to the MV group and the MVC group, respectively. The rats in each group were sacrificed 30 hours later, and costal diaphragm muscle specimens were collected. The cross-sectional area (CSA) of the diaphragm fibers was observed through HE staining, and the colocalizations of TOM20 and LC3 were assessed by immunofluorescence staining. The expression levels of PINK1, Parkin, P62 and LC3, the mitophagy-related proteins, and the expression levels of MAFbx and MURF-1, muscular-atrophy-related proteins, were evaluated by Western blot.
RESULTS
Respective comparisons of the MV group with the CON group and the MVC group with the MV group showed that the CSA decreased ( <0.05), the expression of MURF-1, MAFbx, PINK1, Parkin and LC3Ⅱ/Ⅰproteins increased ( <0.05), the number of co-expressed mitochondria of TOM20 and LC3 and the expression of LC3 increased and the expression of P62 protein decreased ( <0.05) in the MV and MVC groups. Respective comparisons of the QMV group with the MV group and the QMVC group with the MVC group showed that the CSA increased ( <0.05), the expression of MURF-1, MAFbx, PINK1, Parkin and LC3Ⅱ/Ⅰ proteins increased ( <0.05), the number of co-expressed mitochondria of TOM20 and LC3 and the expression of LC3 decreased and the expression of P62 protein decreased ( <0.05) in the QMV and QMVC group.
CONCLUSION
Mechanical ventilation for 24 h caused diaphragm atrophy in SD rats. Cisatracurium may aggravate diaphragm atrophy in mechanically ventilated rats through the autophagy-lysosome (AL) pathway, a process that may be related to the PINK1/Parkin-mediated mitophagy, and chloroquine may reduce diaphragmatic atrophy induced by cisatracurium by blocking the AL pathway.
Topics: Animals; Atracurium; Diaphragm; Male; Muscular Atrophy; Rats; Rats, Sprague-Dawley; Respiration, Artificial
PubMed: 34841764
DOI: 10.12182/20210660102 -
Anesthesiology Dec 2019Transgenic mouse studies suggest that γ-aminobutyric acid type A (GABAA) receptors containing β3 subunits mediate important effects of etomidate, propofol, and...
BACKGROUND
Transgenic mouse studies suggest that γ-aminobutyric acid type A (GABAA) receptors containing β3 subunits mediate important effects of etomidate, propofol, and pentobarbital. Zebrafish, recently introduced for rapid discovery and characterization of sedative-hypnotics, could also accelerate pharmacogenetic studies if their transgenic phenotypes reflect those of mammals. The authors hypothesized that, relative to wild-type, GABAA-β3 functional knock-out (β3) zebrafish would show anesthetic sensitivity changes similar to those of β3 mice.
METHODS
Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 mutagenesis was used to create a β3 zebrafish line. Wild-type and β3 zebrafish were compared for fertility, growth, and craniofacial development. Sedative and hypnotic effects of etomidate, propofol, pentobarbital, alphaxalone, ketamine, tricaine, dexmedetomidine, butanol, and ethanol, along with overall activity and thigmotaxis were quantified in 7-day postfertilization larvae using video motion analysis of up to 96 animals simultaneously.
RESULTS
Xenopus oocyte electrophysiology showed that the wild-type zebrafish β3 gene encodes ion channels activated by propofol and etomidate, while the β3 zebrafish transgene does not. Compared to wild-type, β3 zebrafish showed similar morphology and growth, but more rapid swimming. Hypnotic EC50s (mean [95% CI]) were significantly higher for β3 versus wild-type larvae with etomidate (1.3 [1.0 to 1.6] vs. 0.6 [0.5 to 0.7] µM; P < 0.0001), propofol (1.1 [1.0 to 1.4] vs. 0.7 [0.6 to 0.8] µM; P = 0.0005), and pentobarbital (220 [190 to 240] vs. 130 [94 to 179] μM; P = 0.0009), but lower with ethanol (150 [106 to 213] vs. 380 [340 to 420] mM; P < 0.0001) and equivalent with other tested drugs. Comparing β3 versus wild-type sedative EC50s revealed a pattern similar to hypnosis.
CONCLUSIONS
Global β3 zebrafish are selectively insensitive to the same few sedative-hypnotics previously reported in β3 transgenic mice, indicating phylogenetic conservation of β3-containing GABAA receptors as anesthetic targets. Transgenic zebrafish are potentially valuable models for sedative-hypnotic mechanisms research.
Topics: Anesthetics; Animals; Animals, Genetically Modified; Clustered Regularly Interspaced Short Palindromic Repeats; Female; Hypnotics and Sedatives; Locomotion; Mice; Mice, Knockout; Mice, Transgenic; Receptors, GABA-A; Xenopus laevis; Zebrafish
PubMed: 31567362
DOI: 10.1097/ALN.0000000000002963 -
Biomedicine & Pharmacotherapy =... Sep 2019The complex pathophysiology of brain disorders and the difficulty of delivering therapeutic agents to the brain remain major obstacles in the research and development of...
The complex pathophysiology of brain disorders and the difficulty of delivering therapeutic agents to the brain remain major obstacles in the research and development of new therapeutic methods for brain disorders. Therefore, delivering existing therapeutic agents to the central nervous system is expected to provide benefits in various diseases. In this study, we investigated whether inhaled central nervous system drugs reached the brain and affected mouse behaviour. Dizocilpine (MK-801), which increases locomotor activity in mice, was mainly used to study this hypothesis. First, we administered MK-801, an N-methyl-d-aspartate receptor antagonist, to mice via inhalation and examined whether it induced excessive activity similar to that observed after intraperitoneal administration. We also examined the time- and dose-dependency of drug induced changes in mouse behaviour after MK-801 inhalation. Next, we investigated whether inhalation of scopolamine, pentobarbital, and imipramine also affected mouse behaviour. Mice that inhaled MK-801 showed MK-801-induced hyperactivity similar to that observed following intraperitoneal administration. Furthermore, the extent of activity changed in a time- and dose-dependent manner after MK-801 inhalation. Inhalation of pentobarbital, scopolamine, and imipramine also changed mouse behaviour. These results demonstrate that inhalation of MK-801 exerts effects similar to those achieved with intraperitoneal and oral administration in mice. Thus, central nervous system agonists can reach the brain efficiently via inhalation. This finding may facilitate the development of improved therapies for brain disorders.
Topics: Animals; Behavior, Animal; Depression; Dizocilpine Maleate; Drug Administration Routes; Imipramine; Inhalation Exposure; Locomotion; Male; Mice, Inbred C57BL; Pentobarbital; Scopolamine
PubMed: 31177060
DOI: 10.1016/j.biopha.2019.109038 -
BioRxiv : the Preprint Server For... Sep 2023Cortical electroencephalograms (EEG) may help understanding of neuropsychiatric illness and new treatment mechanisms. The aperiodic component (1/ ) of EEG power spectra...
UNLABELLED
Cortical electroencephalograms (EEG) may help understanding of neuropsychiatric illness and new treatment mechanisms. The aperiodic component (1/ ) of EEG power spectra is often treated as noise, but recent studies suggest that changes to the aperiodic exponent of power spectra may reflect changes in excitation/inhibition (E/I) balance, a concept linked to antidepressant effects, epilepsy, autism, and other clinical conditions. One confound of previous studies is behavioral state, because factors associated with behavioral state other than E/I ratio may alter EEG parameters. Thus, to test the robustness of the aperiodic exponent as a predictor of E/I ratio, we analyzed active exploration in mice using video EEG following various pharmacological manipulations with the Fitting Oscillations & One Over F (FOOOF) algorithm. We found that GABA receptor (GABA R) positive allosteric modulators increased the aperiodic exponent, consistent with the hypothesis that an increased exponent signals enhanced cortical inhibition, but other drugs (ketamine and GABA R antagonists at sub-convulsive doses) did not follow the prediction. To tilt E/I ratio more selectively toward excitation, we suppressed the activity of parvalbumin (PV) interneurons with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Contrary to our expectations and studies demonstrating increased cortical activity following PV suppression, circuit disinhibition with the DREADD increased the aperiodic exponent. We conclude that the aperiodic exponent of EEG power spectra does not yield a universally reliable marker of E/I ratio. Alternatively, the concept of E/I state may be sufficiently oversimplified that it cannot be mapped readily onto an EEG parameter.
SIGNIFICANCE STATEBMENT
Neuropsychiatric illness is widely prevalent and debilitating. Causes are not well understood, but some hypotheses point toward altered excitation/inhibition (E/I) balance. Here, we use cortical electroencephalograms (EEG) in mice, given applicability of cortical EEG across species, and evaluate the impact of validated drugs, including anxiolytics (pentobarbital and diazepam), along with novel rapid-acting antidepressants (ketamine and allopregnanolone). We focus on analyzing the aperiodic component of EEG power spectra, which may be associated with changes in E/I ratio. We show that aperiodic exponent of EEG power spectra is not a reliable marker of E/I ratio. Moreover, the concept of E/I ratio may be too broad and complex to be defined by an EEG parameter.
PubMed: 37790570
DOI: 10.1101/2023.09.21.558828 -
Frontiers in Neuroscience 2020L. (hops) is a major constituent of beer. It exhibits neuroactive properties that make it useful as a sleeping aid. These effects are hypothesized to be mediated by an...
L. (hops) is a major constituent of beer. It exhibits neuroactive properties that make it useful as a sleeping aid. These effects are hypothesized to be mediated by an increase in GABA receptor function. In the quest to uncover the constituents responsible for the sedative and hypnotic properties of hops, recent evidence revealed that humulone, a prenylated phloroglucinol derivative comprising 35-70% of hops alpha acids, may act as a positive modulator of GABA receptors at low micromolar concentrations. This raises the question whether humulone plays a key role in hops pharmacological activity and potentially interacts with other modulators such as ethanol, bringing further enhancement in GABA receptor-mediated effects of beer. Here we assessed electrophysiologically the positive modulatory activity of humulone on recombinant GABA receptors expressed in HEK293 cells. We then examined humulone interactions with other active hops compounds and ethanol on GABA-induced displacement of [H]EBOB binding to native GABA receptors in rat brain membranes. Using BALB/c mice, we assessed humulone's hypnotic behavior with pentobarbital- and ethanol-induced sleep as well as sedation in spontaneous locomotion with open field test. We demonstrated for the first time that humulone potentiates GABA-induced currents in α1β3γ2 receptors. In radioligand binding to native GABA receptors, the inclusion of ethanol enhanced humulone modulation of GABA-induced displacement of [H]EBOB binding in rat forebrain and cerebellum as it produced a leftward shift in [H]EBOB displacement curves. Moreover, the additive modulatory effects between humulone, isoxanthohumol and 6-prenylnaringenin were evident and corresponded to the sum of [H]EBOB displacement by each compound individually. In behavioral tests, humulone shortened sleep onset and increased the duration of sleep induced by pentobarbital and decreased the spontaneous locomotion in open field at 20 mg/kg (.). Despite the absence of humulone effects on ethanol-induced sleep onset, sleep duration was increased dose-dependently down to 10 mg/kg (.). Our findings confirmed humulone's positive allosteric modulation of GABA receptor function and displayed its sedative and hypnotic behavior. Humulone modulation can be potentially enhanced by ethanol and hops modulators suggesting a probable enhancement in the intoxicating effects of ethanol in hops-enriched beer.
PubMed: 33177986
DOI: 10.3389/fnins.2020.594708 -
Frontiers in Psychiatry 2023The utilization of Propofol, a widely used intravenous sedative or anesthetic, is characterized by its quick onset, predictable control, and fleeting half-life during...
BACKGROUND
The utilization of Propofol, a widely used intravenous sedative or anesthetic, is characterized by its quick onset, predictable control, and fleeting half-life during both general anesthesia and intensive care unit sedation. Recent evidence, however, has highlighted propofol's propensity to induce euphoria, particularly in patients undergoing painless procedures such as gastrointestinal or gastric endoscopy. Given its widespread use in patients undergoing such procedures, this study aims to investigate the clinical evidence and factors that may influence propofol-induced euphoria in these settings.
METHODS
The Addiction Research Center Inventory-Chinese Version (ARCI-CV) scale was administered to 360 patients undergoing gastric or gastrointestinal endoscopy using propofol as a sedative. Patient characteristics including past medical history, depression, anxiety, alcohol abuse, and sleep disturbance were recorded through history taking and assessment using various questionnaires prior to the examination. The euphoric and sedative statuses were assessed at 30 min and 1 week post-examination.
RESULTS
The experimental results of a survey of 360 patients who underwent gastric or gastrointestinal endoscopy using propofol showed that the mean Morphine-Benzedrine Group (MBG) score before the procedure and after 30 min of the procedure was 4.23 and 8.67, respectively. The mean Pentobarbital-Chlorpromazine-Alcohol Group (PCAG) score before the procedure and after 30 min of the procedure was 3.24 and 6.22, respectively. These results showed that both MBG and PCAG scores increased significantly after the procedure. Certain factors, such as dreaming, propofol dose, duration of anesthesia, and etomidate dose, were all correlated with MBG both at 30 min and 1 week after the examination. In addition, etomidate had an effect of decreasing MBG scores and increasing PCAG scores both at 30 min and 1 week after the examination.
CONCLUSION
Taken together, propofol may elicit euphoria and potentially contribute to propofol addiction. There are several risk factors for the development of propofol addiction, including dreaming, propofol dose, duration of anesthesia, and etomidate dose. These findings suggest that propofol may have a euphoric effect and may have the potential for drug addiction and abuse.
PubMed: 37181900
DOI: 10.3389/fpsyt.2023.1001626 -
Pharmaceutical Biology Dec 2019The interruption of cerebral blood circulation may cause stroke characterized by high neurological deficits (NDs) as a result of neuronal dysfunction or destruction....
The interruption of cerebral blood circulation may cause stroke characterized by high neurological deficits (NDs) as a result of neuronal dysfunction or destruction. Heparin may exert a neuroprotective effect against cerebral ischaemia/reperfusion injury. The objective of this study was to investigate the mechanism underlying the effects of heparin pre-treatment on cerebral injury in the gerbil. A total of 80 healthy Mongolian gerbils were randomly divided into four groups to establish cerebral ischaemia model by bilateral carotid artery occlusion: control (no anaesthesia and surgery), sham (no occlusion), non-anticoagulation (occlusion), and anti-coagulation treatment groups (50 IU/100 g heparin pre-treated, occlusion). Gerbils were anesthetized with 40 mg/kg pentobarbital sodium through intraperitoneal injection before operation except for the control group. Then, the ND and histopathological damage (HD) scores were determined. The percentage of tumour necrosis factor (TNF)-α- and interleukin (IL)-1β-positive cells were calculated based on immunohistochemical results. The mRNA and protein levels of caspase-9, caspase-8, FasL, and calpain were evaluated with real-time polymerase chain reaction (RT-PCR) and western blotting, respectively. Compared with non-anticoagulation group, heparin pre-treatment (50 IU/100 g) delayed the onset of dyspnoea ( < 0.05), and showed a significant decrease in ND ( < 0.01), mortality rate ( < 0.05), HD ( < 0.01) and percentage of positive cells for TNF-α, IL-1β ( < 0.01) in cerebral ischaemia gerbils. Besides, the expression levels of caspase-9, caspase-8, FasL, and calpain were reduced after pre-treatment with 50 IU/100 g heparin. The damage caused to gerbil brain was reduced upon pre-treatment with heparin, possibly through the amelioration of neuronal cell apoptosis and expression of TNF-α and IL-1β. These findings are expected to provide a new breakthrough in the study and treatment of cerebral ischaemia.
Topics: Animals; Caspase 8; Caspase 9; Gerbillinae; Heparin; Hippocampus; Hypoxia; Interleukin-1beta; Reperfusion Injury; Tumor Necrosis Factor-alpha
PubMed: 31401926
DOI: 10.1080/13880209.2019.1648524 -
Experimental and Therapeutic Medicine May 2023Chronic fragmented sleep is a very common type of insomnia that affects the daily lives of numerous people around the world. However, its pathogenesis is not very clear...
Chronic fragmented sleep is a very common type of insomnia that affects the daily lives of numerous people around the world. However, its pathogenesis is not very clear and a corresponding rat model has not been reported for this purpose at present. The present study aimed to establish a rat model of chronic insomnia with sleep fragmentation using self-made multiple strings of unstable platforms surrounded by shallow water. During the establishment of the models, changes in body weight and differences in food and water intake in the daytime and at night were acquired. The rat models were assessed using several tests, including the Morris water maze test, pentobarbital sodium-induced sleep, infrared monitoring and electroencephalogram/electromyography during sleep. The expression levels of certain inflammatory factors and orexin A were detected in the serum and brain tissues using ELISAs, immunohistochemistry and immunofluorescence. The expression levels of orexin 1 receptor (orexin 1r) were also detected in the brain. Polysomnography indicated that the model rats were successfully prepared with reduced non-rapid eye movement (non-REM) sleep in the daytime, which was increased at night, and considerably lower REM duration during the day and night. The number of instances of sleep arousals were also increased in the day and at night, and the average duration of each sleep bout was decreased in the daytime. The body weights of the model rats increased at a normal rate. However, the reduction of body weight in the daytime and increased in body weight at night were significantly less than those of the control rats. The daytime food and water consumption of the model rats increased significantly compared with that of the control rats, but was similar to that of the control group at night. The Morris water maze test indicated that the model rats were slow to learn to escape the platforms and performed a lower number of target crossings. The pentobarbital-induced sleep experiment confirmed that the model rats exhibited a longer sleep latency and shorter sleep time. The serum IL-1β, IL-6, TNF-α and orexin A levels of the model rats were significantly increased, whereas their serum IL-10 levels were significantly decreased compared with those of the control rats. The expression levels of IL-1β, IL-6, orexin A and orexin 1r in the brain tissues of the model rats were also significantly increased. In conclusion, these data indicate that learning and memory function, sleep time, arousal times, diurnal and nocturnal body weight changes, food and water intake, and expression levels of the specific inflammatory factors orexin A and orexin 1r were altered in the model rats. This suggests the chronic insomnia rat model with sleep fragmentation was successfully established using multiple strings of unstable platforms surrounded by water.
PubMed: 37114171
DOI: 10.3892/etm.2023.11932 -
BioMed Research International 2021Picroside II is an important ingredient agent in Traditional Chinese medicine and hoped to reduce hepatocellular injury caused by severe acute pancreatitis (SAP). An...
Picroside II is an important ingredient agent in Traditional Chinese medicine and hoped to reduce hepatocellular injury caused by severe acute pancreatitis (SAP). An SAP-induced hepatocellular injury model was established in rats by using pentobarbital sodium. 27 rats were divided into 3 groups: the sham group (SG), model group (MG), and Picroside groups (PG). SAP-induced hepatocellular injury was assessed using hematoxylin and eosin staining. We measured hepatocellular enzymes (amylase (AMY), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)), oxidative stress factors (superoxidase dismutase (SOD) and malondialdehyde (MDA)), and inflammatory factors (tumor necrosis factor (TNF-), interleukin- (IL-) 6, and IL-10), apoptotic factors (BAX and cleaved caspase 3), and inflammatory signaling (Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3), p-JAK2, and p-STAT3) in hepatocellular tissues. The SAP-induced hepatocellular injury model was successfully established. Picroside II treatment repaired hepatocellular injury by reducing the activities of AMY, ALT, and AST; reducing the levels of MDA, TNF-, IL-1, IL-6, p-JAK2, p-STAT3, BAX, and cleaved caspase 3; and increasing the levels of SOD and IL-10. Picroside II exerted protective function for the SAP-induced hepatocellular injury model. Picroside II improved SAP-induced hepatocellular injury and antioxidant and anti-inflammatory properties by affecting JAK2/STAT3 phosphorylation signaling.
Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Bile Acids and Salts; Cholestasis; Cinnamates; Cytokines; Hepatocytes; Iridoid Glucosides; Janus Kinase 2; Liver; Male; Models, Biological; Pancreatitis; Phosphorylation; RNA, Messenger; Rats, Sprague-Dawley; STAT3 Transcription Factor; Signal Transduction; Rats
PubMed: 34368363
DOI: 10.1155/2021/9945149