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Gabaa inhibitor

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https://www.readbyqxmd.com/read/29677536/sedative-and-hypnotic-effects-of-schisandrin-b-through-increasing-gaba-glu-ratio-and-upregulating-the-expression-of-gaba-a-in-mice-and-rats
#1
Ning Li, Jiale Liu, Mengyang Wang, Zepeng Yu, Kuo Zhu, Jiaqi Gao, Chunmei Wang, Jinghui Sun, Jianguang Chen, He Li
Schisandrin B (SchB) is an active lignan component from Schisandra chinensis Turcz. Baill that has been long used as Traditional Chinese Medical Herb in the prescriptions for "tranquilizing the mind and overcoming anxiety". Given that SchB is one of the most abundant ingredients of Schisandra chinensis Baill, we examined the sedative and hypnotic effects of SchB and explored the underlying mechanism. The results showed that SchB can significantly decrease mouse locomotor activities and improved sleeping quality index, including increased number of sleeping mice treated with the subthreshold dose of pentobarbital sodium, increased sleep time, shortened sleep latency and prolonged sleep duration...
April 17, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29667225/activation-of-central-gaba-b-receptors-offsets-the-cyclosporine-counteraction-of-endotoxic-cardiovascular-outcomes-in-conscious-rats
#2
Marwa Y Sallam, Sahar M El-Gowilly, Abdel-Galil A Abdel-Galil, Mahmoud M El-Mas
We have previously shown that cyclosporine (CSA) counteracts cardiovascular manifestations induced by endotoxemia (lipopolysaccharide, LPS) such as hypotension and cardiac autonomic dysfunction in conscious rats. In this study we investigated whether the facilitation of central γ-amino butyric acid (GABA) neurotransmission blunts these favorable influences of CSA. The LPS-CSA interaction was determined in the absence and presence of drugs that activate GABAA or GABAB receptors or elevate synaptic GABA levels in the central nervous system...
April 18, 2018: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/29665500/aromatase-inhibition-by-letrozole-attenuates-kainic-acid-induced-seizures-but-not-neurotoxicity-in-mice
#3
Ramsha Iqbal, Gaurav K Jain, Fouzia Siraj, Divya Vohora
Evidence shows neurosteroids play a key role in regulating epileptogenesis. Neurosteroids such as testosterone modulate seizure susceptibility through its transformation to metabolites which show proconvulsant and anticonvulsant effects, respectively. Reduction of testosterone by aromatase generates proconvulsant 17-β estradiol. Alternatively, testosterone is metabolized into 5α-dihydrotestosterone (5α-DHT) by 5α-reductase, which is then reduced by 3α-hydroxysteroid oxidoreductase enzyme (3α-HSOR) to form anticonvulsant metabolite 3α-androstanediol (3α-Diol), a potent GABAA receptor modulating neurosteroid...
April 9, 2018: Epilepsy Research
https://www.readbyqxmd.com/read/29621596/a-novel-action-of-lacosamide-on-gaba-a-currents-sets-the-ground-for-a-synergic-interaction-with-levetiracetam-in-treatment-of-epilepsy
#4
Gabriele Ruffolo, Carlo Di Bonaventura, Pierangelo Cifelli, Cristina Roseti, Jinane Fattouch, Alessandra Morano, Cristina Limatola, Eleonora Aronica, Eleonora Palma, Anna Teresa Giallonardo
Epilepsy is one of the most common chronic neurological diseases, and its pharmacological treatment holds great importance for both physicians and national authorities, especially considering the high proportion of drug-resistant patients (about 30%). Lacosamide (LCM) is an effective and well-tolerated new-generation antiepileptic drug (AED), currently licensed as add-on therapy for partial-onset seizures. However, LCM mechanism of action is still a matter of debate, although its effect on the voltage sensitive sodium channels is by far the most recognized...
April 2, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29565038/gabaergic-inhibitory-neurons-as-therapeutic-targets-for-cognitive-impairment-in-schizophrenia
#5
REVIEW
Meng-Yi Xu, Albert H C Wong
Schizophrenia is considered primarily as a cognitive disorder. However, functional outcomes in schizophrenia are limited by the lack of effective pharmacological and psychosocial interventions for cognitive impairment. GABA (gamma-aminobutyric acid) interneurons are the main inhibitory neurons in the central nervous system (CNS), and they play a critical role in a variety of pathophysiological processes including modulation of cortical and hippocampal neural circuitry and activity, cognitive function-related neural oscillations (eg, gamma oscillations) and information integration and processing...
March 22, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29559921/nitric-oxide-orchestrates-a-power-law-modulation-of-sympathetic-firing-behaviors-in-neonatal-rat-spinal-cords
#6
Chun-Kuei Su, Yi-Yin Chen, Chiu-Ming Ho
Nitric oxide (NO) is a diffusible gas and has multifarious effects on both pre- and postsynaptic events. As a consequence of complex excitatory and inhibitory integrations, NO effects on neuronal activities are heterogeneous. Using in vitro preparations of neonatal rats that retain the splanchnic sympathetic nerves and the thoracic spinal cord as an experimental model, we report here that either enhancement or attenuation of NO production in the neonatal rat spinal cords could increase, decrease, or not change the spontaneous firing behaviors recorded from splanchnic sympathetic single fibers...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29559911/vortioxetine-treatment-reverses-subchronic-pcp-treatment-induced-cognitive-impairments-a-potential-role-for-serotonin-receptor-mediated-regulation-of-gaba-neurotransmission
#7
Alan L Pehrson, Christian S Pedersen, Kirstine Sloth Tølbøl, Connie Sanchez
Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine's effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected vortioxetine's cognitive effects to those on GABA and glutamate neurotransmission...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29543349/corticosterone-and-serotonin-similarly-influence-gabaergic-and-purinergic-pathways-to-affect-cortical-inhibitory-networks
#8
Caitlin A Wotton, Elizabeth F Quon, Ashley C Palmer, Lane K Bekar
Both serotonin (5HT) and stress exert changes in cortical inhibitory tone to shape activity of cortical networks. As astrocytes are also known to affect inhibition through established purinergic pathways, we assessed the role of GABA and purinergic pathways in rapid corticosterone (CORT) and 5HT effects on cortical inhibition. We used a paired-pulse paradigm (P1 & P2) in acutely isolated mouse brain slices to evaluate changes in cortical evoked inhibition. Normally, 5HT decreases amplitude of the first pulse P1, while increasing the amplitude of P2 (increase frequency transmission)...
March 15, 2018: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/29532486/glyoxalase-glo1-inhibition-or-genetic-overexpression-does-not-alter-ethanol-s-locomotor-effects-implications-for-glo1-as-a-therapeutic-target-in-alcohol-use-disorders
#9
Amanda M Barkley-Levenson, Frances A Lagarda, Abraham A Palmer
BACKGROUND: Glyoxalase 1 (GLO1) is an enzyme that metabolizes methylglyoxal (MG), which is a competitive partial agonist at GABAA receptors. Inhibition of GLO1 increases concentrations of MG in the brain and decreases binge-like ethanol drinking. The present study assessed whether inhibition of GLO1, or genetic over expression of Glo1, would also alter the locomotor effects of ethanol, which might explain reduced ethanol consumption following GLO1 inhibition. We used the prototypical GABAA receptor agonist muscimol as a positive control...
March 12, 2018: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/29529524/estradiol-and-luteinizing-hormone-regulate-recognition-memory-following-subchronic-phencyclidine-evidence-for-hippocampal-gaba-action
#10
Alexander J Riordan, Ari W Schaler, Jenny Fried, Tracie A Paine, Janice E Thornton
The cognitive symptoms of schizophrenia are poorly understood and difficult to treat. Estrogens may mitigate these symptoms via unknown mechanisms. To examine these mechanisms, we tested whether increasing estradiol (E) or decreasing luteinizing hormone (LH) could mitigate short-term episodic memory loss in a phencyclidine (PCP) model of schizophrenia. We then assessed whether changes in cortical or hippocampal GABA may underlie these effects. Female rats were ovariectomized and injected subchronically with PCP...
February 27, 2018: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/29520058/histone-deacetylases-mediate-gaba-a-receptor-expression-physiology-and-behavioral-maladaptations-in-rat-models-of-alcohol-dependence
#11
John Peyton Bohnsack, Benjamin A Hughes, Todd K O'Buckley, Kamyra Edokpolor, Joyce Besheer, A Leslie Morrow
Alcohol use disorders are chronic debilitating diseases characterized by severe withdrawal symptoms that contribute to morbidity and relapse. GABAA receptor (GABAA R) adaptations have long been implicated in the chronic effects of alcohol and contribute to many withdrawal symptoms associated with alcohol dependence. In rodents, GABAA R hypofunction results from decreases in Gabra1 expression, although the underlying mechanism controlling Gabra1 expression after chronic ethanol exposure is still unknown. We found that chronic ethanol exposure using either ethanol gavage or two-bottle choice voluntary access paradigms decreased Gabra1 expression and increased Hdac2 and Hdac3 expression...
February 27, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29460030/succinic-semialdehyde-dehydrogenase-deficiency-a-disorder-of-gaba-metabolism-an-update-on-pharmacological-and-enzyme-replacement-therapeutic-strategies
#12
Kara R Vogel, Garrett R Ainslie, Dana C Walters, Alice McConnell, Sameer C Dhamne, Alexander Rotenberg, Jean-Baptiste Roullet, K Michael Gibson
We present an update to the status of research on succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD), a rare disorder of GABA metabolism. This is an unusual disorder featuring the accumulation of both GABA and its neuromodulatory analog, gamma-hydroxybutyric acid (GHB), and recent studies have advanced the potential clinical application of NCS-382, a putative GHB receptor antagonist. Animal studies have provided proof-of-concept that enzyme replacement therapy could represent a long-term therapeutic option...
February 19, 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29411793/expeditious-synthesis-of-polyacetylenic-water-hemlock-toxins-and-their-effects-on-the-major-gabaa-receptor-isoform
#13
Martin Berger, Yong Chen, Konstantina Bampali, Margot Ernst, Nuno Maulide
Classical synthetic approaches to highly unsaturated polyene/yne natural products rely on iterative cross-coupling of linear fragments. Herein, we present an expeditious and unified approach to the unsaturated backbone of polyacetylenes via domino cuprate addition/4π-electrocyclic ring opening of a stereodefined cyclobutene intermediate. This sets the stage for a detailed biological assessment of the role of Virol A and Cicutoxin as inhibitors of GABA induced chloride currents, providing further insight into the interaction of these highly potent toxins towards the GABAA receptor, including the structure-activity relationship of the derivatives...
February 7, 2018: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/29376464/the-flavonoid-2-methoxy-6-methylflavone-affords-neuroprotection-following-focal-cerebral-ischaemia
#14
Andrew N Clarkson, Lily Boothman-Burrell, Zita Dósa, Raghavendra Y Nagaraja, Liang Jin, Kim Parker, Petra S van Nieuwenhuijzen, Silke Neumann, Emma K Gowing, Navnath Gavande, Philip K Ahring, Mai M Holm, Jane R Hanrahan, Joseph A Nicolazzo, Kimmo Jensen, Mary Chebib
Tonic inhibitory currents, mediated by extrasynaptic GABAA receptors, are elevated at a delay following stroke. Flavonoids minimise the extent of cellular damage following stroke, but little is known about their mode of action. We demonstrate that the flavonoid, 2'-methoxy-6-methylflavone (0.1-10 µM; 2'MeO6MF), increases GABAA receptor tonic currents presumably via δ-containing GABAA receptors. Treatment with 2'MeO6MF 1-6 h post focal ischaemia dose dependently decreases infarct volume and improves functional recovery...
January 1, 2018: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/29330041/acute-epileptiform-activity-induced-by-gabazine-involves-proteasomal-rather-than-lysosomal-degradation-of-k-ca-2-2-channels
#15
Steffen Müller, Xiati Guli, Judith Hey, Anne Einsle, Daniela Pfanz, Victor Sudmann, Timo Kirschstein, Rüdiger Köhling
Voltage-independent, Ca2+ -activated K+ channels (KCa 2.2, previously named SK2) are typically activated during a train of action potentials, and hence, are powerful regulators of cellular excitability by generating an afterhyperpolarizing potential (AHP) following prolonged excitation. In the acute in vitro epilepsy model induced in hippocampal brain slice preparations by exposure to the GABAA receptor blocker gabazine (GZ), the AHP was previously shown to be significantly decreased. Here, we asked the question whether KCa 2...
April 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29316656/azemiopsin-a-selective-peptide-antagonist-of-muscle-nicotinic-acetylcholine-receptor-preclinical-evaluation-as-a-local-muscle-relaxant
#16
Irina V Shelukhina, Maxim N Zhmak, Alexander V Lobanov, Igor A Ivanov, Alexandra I Garifulina, Irina N Kravchenko, Ekaterina A Rasskazova, Margarita A Salmova, Elena A Tukhovskaya, Vladimir A Rykov, Gulsara A Slashcheva, Natalya S Egorova, Inessa S Muzyka, Victor I Tsetlin, Yuri N Utkin
Azemiopsin (Az), a linear peptide from the Azemiops feae viper venom, contains no disulfide bonds, is a high-affinity and selective inhibitor of nicotinic acetylcholine receptor (nAChR) of muscle type and may be considered as potentially applicable nondepolarizing muscle relaxant. In this study, we investigated its preclinical profile in regard to in vitro and in vivo efficacy, acute and chronic toxicity, pharmacokinetics, allergenic capacity, immunotoxicity and mutagenic potency. The peptide effectively inhibited (IC50 ~ 19 nM) calcium response of muscle nAChR evoked by 30 μM (EC100 ) acetylcholine but was less potent (IC50 ~ 3 μM) at α7 nAChR activated by 10 μM (EC50 ) acetylcholine and had a low affinity to α4β2 and α3-containing nAChR, as well as to GABAA or 5HT₃ receptors...
January 7, 2018: Toxins
https://www.readbyqxmd.com/read/29203576/dimethoxy-etomidate-a-nonhypnotic-etomidate-analog-that-potently-inhibits-steroidogenesis
#17
Megan McGrath, Celena Ma, Douglas E Raines
Cushing's syndrome is characterized by the overproduction of adrenocortical steroids. Steroidogenesis inhibitors are mainstays of medical therapy for Cushing's syndrome; unfortunately, adverse side effects and treatment failures are common with currently available drugs. The general anesthetic induction agent etomidate is among the most potent inhibitors of adrenocortical steroidogenesis. However, its use as a treatment of Cushing's syndrome is complicated by its sedative-hypnotic activity and ability to produce myoclonus, central nervous system actions thought to be mediated by the GABAA receptor...
February 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29200913/developmental-changes-in-gaba-a-tonic-inhibition-are-compromised-by-multiple-mechanisms-in-preadolescent-dentate-gyrus-granule-cells
#18
Sudip Pandit, Gyu Seung Lee, Jin Bong Park
The sustained tonic currents (Itonic ) generated by γ-aminobutyric acid A receptors (GABAA Rs) are implicated in diverse age-dependent brain functions. While various mechanisms regulating Itonic in the hippocampus are known, their combined role in Itonic regulation is not well understood in different age groups. In this study, we demonstrated that a developmental increase in GABA transporter (GAT) expression, combined with gradual decrease in GABAA R α5 subunit, resulted in various Itonic in the dentate gyrus granule cells (DGGCs) of preadolescent rats...
November 2017: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/29193847/genetic-loss-of-diazepam-binding-inhibitor-in-mice-impairs-social-interest
#19
A L Ujjainwala, C D Courtney, S G Rhoads, J S Rhodes, C A Christian
Neuropsychiatric disorders in which reduced social interest is a common symptom, such as autism, depression, and anxiety, are frequently associated with genetic mutations affecting γ-aminobutyric acid (GABA)ergic transmission. Benzodiazepine treatment, acting via GABA type-A receptors, improves social interaction in male mouse models with autism-like features. The protein diazepam binding inhibitor (DBI) can act as an endogenous benzodiazepine, but a role for DBI in social behavior has not been described. Here, we investigated the role of DBI in the social interest and recognition behavior of mice...
November 28, 2017: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/29167116/medullary-raphe-nuclei-activate-the-lumbosacral-defecation-center-through-the-descending-serotonergic-pathway-to-regulate-colorectal-motility-in-rats
#20
Hiroyuki Nakamori, Kiyotada Naitou, Yuuki Horii, Hiroki Shimaoka, Kazuhiro Horii, Hiroki Sakai, Akihiro Yamada, Hidemasa Furue, Takahiko Shiina, Yasutake Shimizu
Colorectal motility is regulated by two defecation centers located in the brain and spinal cord. In previous studies, we have shown that administration of serotonin (5-HT) in the lumbosacral spinal cord causes enhancement of colorectal motility. Because spinal 5-HT is derived from neurons of the medullary raphe nuclei, including the raphe magnus, raphe obscurus, and raphe pallidus, we examined whether stimulation of the medullary raphe nuclei enhances colorectal motility via the lumbosacral defecation center...
March 1, 2018: American Journal of Physiology. Gastrointestinal and Liver Physiology
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