Effects of Intravenous Anesthetic Agents on Glutamate Release

2000 ◽  
Vol 92 (4) ◽  
pp. 1067-1073 ◽  
Author(s):  
Donal J. Buggy ◽  
Beverley Nicol ◽  
David J. Rowbotham ◽  
David G. Lambert
Keyword(s):  
Glutamate Release ◽  
Receptor Activation ◽  
Gamma Aminobutyric Acid ◽  
Half Maximum ◽  
Intravenous Anesthetic ◽  
Anesthetic Agents ◽  
Acid Type ◽  
Maximum Inhibition ◽  
Dependent Inhibition ◽  
Anesthetic Action

Background Many anesthetic agents are known to enhance the alpha1beta2gamma2S gamma-aminobutyric acid type A (GABAA) chloride current; however, they also depress excitatory neurotransmission. The authors evaluated two hypotheses: intravenous anesthetic agents inhibit glutamate release and any observed inhibition may be secondary to GABAA receptor activation. Methods Cerebrocortical slices were prepared from Wistar rats. After perfusion in oxygenated Krebs buffer for 60 min at 37 degrees C, samples for glutamate assay were obtained at 2-nmin intervals. After 6 min, a 2-min pulse of 46 mM K+ was applied to the slices (S1); this was repeated after 30 min (S2). Bicuculline (1-100 microM) was applied when the S1 response returned to basal level, and 10 min later, thiopental (1-300 micro/M), propofol (10 microM), or ketamine (30 microM) were also applied until the end of S2. Perfusate glutamate concentrations were measured fluorometrically, and the area under the glutamate release curves was expressed as a ratio (S2/S1). Results Potassium (46 mM) evoked a monophasic release of glutamate during S1 and S2, with a mean control S2/S1 ratio of 1.07 +/- 0.33 (mean +/- SD, n = 96). Ketamine and thiopental produced a concentration-dependent inhibition of K+-evoked glutamate release with half-maximum inhibition of release values of 18.2 and 10.9 /microM, respectively. Release was also inhibited by propofol. Bicuculline produced a concentration dependent reversal of thiopental inhibition of glutamate release with a half-maximum reversal of the agonist effect of 10.3 microM. Bicuculline also reversed the effects of propofol but not those of ketamine. Conclusions The authors' data indicate that thiopental, propofol, and ketamine inhibit K+-evoked glutamate release from rat cerebrocortical slices. The inhibition produced by thiopental and propofol is mediated by activation of GABAA receptors, revealing a subtle interplay between GABA-releasing (GABAergic) and glutamatergic transmission in anesthetic action.

Droperidol Inhibits GABAAand Neuronal Nicotinic Receptor Activation

2002 ◽  
Vol 96 (4) ◽  
pp. 987-993 ◽  
Author(s):  
Pamela Flood ◽  
Kristen M. Coates
Keyword(s):  
Type A ◽  
Receptor Activation ◽  
Aminobutyric Acid ◽  
Hill Coefficient ◽  
High Dose ◽  
Gamma Aminobutyric Acid ◽  
Anesthetic Drugs ◽  
Gaba Inhibition ◽  
Acid Type ◽  
Anesthetic Action

Background Droperidol is used in neuroleptanesthesia and as an antiemetic. Although its antiemetic effect is thought to be caused by dopaminergic inhibition, the mechanism of droperidol's anesthetic action is unknown. Because gamma-aminobutyric acid type A (GABAA) and neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as putative targets of other general anesthetic drugs, the authors tested the ability of droperidol to modulate these receptors. Methods gamma-Aminobutyric acid type A alpha1beta1gamma2 receptor, alpha7 and alpha4beta2 nAChRs were expressed in Xenopus oocytes and studied with two-electrode voltage clamp recording. The authors tested the ability of droperidol at concentrations from 1 nm to 100 microm to modulate activation of these receptors by their native agonists. Results Droperidol inhibited the GABA response by a maximum of 24.7 +/- 3.0%. The IC50 for inhibition was 12.6 +/- 0.47 nm droperidol. At high concentrations, droperidol (100 microm) activates the GABAA receptor in the absence of GABA. Inhibition of the GABA response is significantly greater at hyperpolarized membrane potentials. The activation of the alpha7 nAChR is also inhibited by droperidol, with an IC50 of 5.8 +/- 0.53 microm. The Hill coefficient is 0.95 +/- 0.1. Inhibition is noncompetitive, and membrane voltage dependence is insignificant. Conclusions Droperidol inhibits activation of both the GABAA alpha1beta1gamma2 and alpha7 nAChR. The submaximal GABA inhibition occurs within a concentration range such that it might be responsible for the anxiety, dysphoria, and restlessness that limit the clinical utility of high-dose droperidol anesthesia. Inhibition of the alpha7 nAChR might be responsible for the anesthetic action of droperidol.

scholarly journals Natural Product Isoliquiritigenin Activates GABAB Receptors to Decrease Voltage-Gate Ca2+ Channels and Glutamate Release in Rat Cerebrocortical Nerve Terminals

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1537
Author(s):  
Tzu-Yu Lin ◽  
Cheng-Wei Lu ◽  
Pei-Wen Hsieh ◽  
Kuan-Ming Chiu ◽  
Ming-Yi Lee ◽  
...  
Keyword(s):  
Gabab Receptor ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Gabab Receptors ◽  
Nerve Terminals ◽  
Type B ◽  
Kinase C ◽  
Acid Type ◽  
Dependent Inhibition ◽  
Ca2 Channels

Reduction in glutamate release is a key mechanism for neuroprotection and we investigated the effect of isoliquiritigenin (ISL), an active ingredient of Glycyrrhiza with neuroprotective activities, on glutamate release in rat cerebrocortical nerve terminals (synaptosomes). ISL produced a concentration-dependent inhibition of glutamate release and reduced the intraterminal [Ca2+] increase. The inhibition of glutamate release by ISL was prevented after removing extracellular Ca2+ or blocking P/Q-type Ca2+ channels. This inhibition was mediated through the γ-aminobutyric acid type B (GABAB) receptors because ISL was unable to inhibit glutamate release in the presence of baclofen (an GABAB agonist) or CGP3548 (an GABAB antagonist) and docking data revealed that ISL interacted with GABAB receptors. Furthermore, the ISL inhibition of glutamate release was abolished through the inhibition of Gi/o-mediated responses or Gβγ subunits, but not by 8-bromoadenosine 3′, 5′-cyclic monophosphate or adenylate cyclase inhibition. The ISL inhibition of glutamate release was also abolished through the inhibition of protein kinase C (PKC), and ISL decreased the phosphorylation of PKC. Thus, we inferred that ISL, through GABAB receptor activation and Gβγ-coupled inhibition of P/Q-type Ca2+ channels, suppressed the PKC phosphorylation to cause a decrease in evoked glutamate release at rat cerebrocortical nerve terminals.

scholarly journals Modifications in Gamma-aminobutyric Acid type A Receptor Subunit Gene Expression During Macrophage Differentiation and Propofol Administration in THP-1 Cells

2021 ◽  
Author(s):  
Tsukasa Kochiyama ◽  
Izumi Kawagoe ◽  
Ai Yamaguchi ◽  
Masataka Fukuda ◽  
Masakazu Hayashida
Keyword(s):  
Gene Expression ◽  
Immune Cells ◽  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Subunit ◽  
Gamma Aminobutyric Acid ◽  
Subunit Gene ◽  
Macrophage Differentiation ◽  
Anesthetic Agents ◽  
Acid Type

Abstract Background: Gamma-aminobutyric acid type A (GABAA) receptors are thought to play a role in the functioning of the immune system. GABAA receptors have 19 types of subunits, the components of which determine their physiological functions. However, the subunits that are expressed in immune cells during inflammation have not been fully investigated. Recent reports have shown that anesthetic agents may affect the gene expression of GABAA receptors subunits in immune cells. Therefore, we aimed to investigate the changes in GABAA receptor subunit gene expression during macrophage differentiation and propofol administration in order to clarify the relationship between the expression of GABAA receptors and the immunomodulatory effect of propofol.Methods: Human acute monocytic leukemia (THP-1) cells were differentiated into macrophage-like cells (M0 THP-1); subsequently, M0 THP-1 cells were differentiated into inflammatory M1 macrophage-like cells (M1 THP-1). Propofol was administered during the differentiation into M1 THP-1 cells. Using reverse transcriptase polymerase chain reaction, we examined which GABAA receptor subunit genes were expressed and whether there were changes in the gene expression during macrophage differentiation and propofol administration in THP-1 cells.Results: The expression of the α1, α4, β1, β2, γ1, and γ2 subunits increased during differentiation into M0 THP-1 cells. The expression of the α1, α4, β1, β2, γ2, and δ subunits decreased and that of the γ1 subunit increased during differentiation into M1 THP-1 cells. The gene expression of the α1, α4, and β2 subunits increased upon administering propofol during differentiation into M1 THP-1 cells.Conclusions: The gene expression of GABAA receptor subunits changed during macrophage differentiation in THP-1 cells. The expressions of α1 and α4 increased following propofol administration during the differentiation into M1 THP-1 cells, which may indicate that the GABAA receptor is involved in the immunosuppressive effects of propofol. This study can help in the choice of anesthetic agents for proinflammatory conditions such as highly-invasive surgery.

scholarly journals A Conserved Tyrosine in the β2Subunit M4 Segment Is a Determinant of γ-Aminobutyric Acid Type A Receptor Sensitivity to Propofol

2007 ◽  
Vol 107 (3) ◽  
pp. 412-418 ◽  
Author(s):  
James E. Richardson ◽  
Paul S. Garcia ◽  
Kate K. O'Toole ◽  
Jason M. C. Derry ◽  
Shannon V. Bell ◽  
...  
Keyword(s):  
Binding Site ◽  
Type A ◽  
Receptor Activation ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
General Anesthetics ◽  
Receptor Function ◽  
293 Cells ◽  
Acid Type ◽  
Normal Sensitivity

Background The gamma-aminobutyric acid type A receptor (GABAA-R) beta subunits are critical targets for the actions for several intravenous general anesthetics, but the precise nature of the anesthetic binding sites are unknown. In addition, little is known about the role the fourth transmembrane (M4) segment of the receptor plays in receptor function. The aim of this study was to better define the propofol binding site on the GABAA-R by conducting a tryptophan scan in the M4 segment of the beta2 subunit. Methods Seven tryptophan mutations were introduced into the C-terminal end of the M4 segment of the GABAA-R beta2 subunit. GABAA-R subunit complementary DNAs were transfected into human embryonic kidney 293 cells grown on glass coverslips. After transfection (36-72 h), coverslips were transferred to a perfusion chamber to assay receptor function. Cells were whole cell patch clamped and exposed to GABA, propofol, etomidate, and pregnenolone. Chemicals were delivered to the cells using two 10-channel infusion pumps and a rapid solution exchanger. Results All tryptophan mutations were well tolerated, and with one exception, all resulted in minimal changes in receptor activation by GABA. One mutation, beta2(Y444W), selectively suppressed the ability of propofol to enhance receptor function while retaining normal sensitivity to etomidate and pregnenolone. Conclusions This is the first report of a mutation that selectively reduces propofol sensitivity without altering the action of etomidate. The reduction in propofol sensitivity is consistent with the loss of a hydrogen bond within the propofol binding site. These results also suggest a possible orientation of the propofol molecule within its binding site.

Neonatal Exposure to a Combination of N -Methyl-d-aspartate and γ-Aminobutyric Acid Type A Receptor Anesthetic Agents Potentiates Apoptotic Neurodegeneration and Persistent Behavioral Deficits

2007 ◽  
Vol 107 (3) ◽  
pp. 427-436 ◽  
Author(s):  
Anders Fredriksson ◽  
Emma Pontén ◽  
Torsten Gordh ◽  
Per Eriksson
Keyword(s):  
Type A ◽  
Brain Cell ◽  
Aminobutyric Acid ◽  
Growth Spurt ◽  
High Dose ◽  
Gamma Aminobutyric Acid ◽  
Behavioral Deficits ◽  
Anesthetic Agents ◽  
Acid Type ◽  
The Brain

Background During the brain growth spurt, the brain develops and modifies rapidly. In rodents this period is neonatal, spanning the first weeks of life, whereas in humans it begins during the third trimester and continues 2 yr. This study examined whether different anesthetic agents, alone and in combination, administered to neonate mice, can trigger apoptosis and whether behavioral deficits occur later in adulthood. Methods Ten-day-old mice were injected subcutaneously with ketamine (25 mg/kg), thiopental (5 mg/kg or 25 mg/kg), propofol (10 mg/kg or 60 mg/kg), a combination of ketamine (25 mg/kg) and thiopental (5 mg/kg), a combination of ketamine (25 mg/kg) and propofol (10 mg/kg), or control (saline). Fluoro-Jade staining revealed neurodegeneration 24 h after treatment. The behavioral tests--spontaneous behavior, radial arm maze, and elevated plus maze (before and after anxiolytic)--were conducted on mice aged 55-70 days. Results Coadministration of ketamine plus propofol or ketamine plus thiopental or a high dose of propofol alone significantly triggered apoptosis. Mice exposed to a combination of anesthetic agents or ketamine alone displayed disrupted spontaneous activity and learning. The anxiolytic action of diazepam was less effective when given to adult mice that were neonatally exposed to propofol. Conclusion This study shows that both a gamma-aminobutyric acid type A agonist (thiopental or propofol) and an N-methyl-D-aspartate antagonist (ketamine) during a critical stage of brain development potentiated neonatal brain cell death and resulted in functional deficits in adulthood. The use of thiopental, propofol, and ketamine individually elicited no or only minor changes.

Cardiovascular Complications of Sleep Disorders: A Better Night’s Sleep for a Healthier Heart / From Bench to Bedside

2020 ◽  
Vol 19 (2) ◽  
pp. 210-232 ◽  
Author(s):  
Theodora A. Manolis ◽  
Antonis A. Manolis ◽  
Evdoxia J. Apostolopoulos ◽  
Helen Melita ◽  
Antonis S. Manolis
Keyword(s):  
Sleep Disorders ◽  
Disease Risk ◽  
Behavioral Therapy ◽  
Benzodiazepine Receptor ◽  
Cardiovascular Complications ◽  
Gamma Aminobutyric Acid ◽  
Acid Type ◽  
Increased Risk ◽  
Cv Disease ◽  
Meta Analyses

: Sleep is essential to and an integral part of life and when lacking or disrupted, a multitude of mental and physical pathologies ensue, including cardiovascular (CV) disease, which increases health care costs. Several prospective studies and meta-analyses show that insomnia, short (<7h) or long (>9h) sleep and other sleep disorders are associated with an increased risk of hypertension, metabolic syndrome, myocardial infarction, heart failure, arrhythmias, CV disease risk and/or mortality. The mechanisms by which insomnia and other sleep disorders lead to increased CV risk may encompass inflammatory, immunological, neuro-autonomic, endocrinological, genetic and microbiome perturbations. Guidelines are emerging that recommend a target of >7 h of sleep for all adults >18 years for optimal CV health. Treatment of sleep disorders includes cognitive-behavioral therapy considered the mainstay of non-pharmacologic management of chronic insomnia, and drug treatment with benzodiazepine receptor agonists binding to gamma aminobutyric acid type A (benzodiazepine and non-benzodiazepine agents) and some antidepressants. However, observational studies and meta-analyses indicate an increased mortality risk of anxiolytics and hypnotics, although bias may be involved due to confounding and high heterogeneity in these studies. Nevertheless, it seems that the risk incurred by the non-benzodiazepine hypnotic agents (Z drugs) may be relatively less than the risk of anxiolytics, with evidence indicating that at least one of these agents, zolpidem, may even confer a lower risk of mortality in adjusted models. All these issues are herein reviewed.

[11C]Flumazenil Positron Emission Tomography Analyses of Brain Gamma-Aminobutyric Acid Type A Receptors in Angelman Syndrome

2008 ◽  
Vol 152 (4) ◽  
pp. 546-549.e3 ◽  
Author(s):  
Naoko Asahina ◽  
Tohru Shiga ◽  
Kiyoshi Egawa ◽  
Hideaki Shiraishi ◽  
Shinobu Kohsaka ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Angelman Syndrome ◽  
Type A ◽  
Emission Tomography ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Positron Emission ◽  
Acid Type
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