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Gabaa inhibitor

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https://www.readbyqxmd.com/read/29872336/dexmedetomidine-attenuates-persistent-postsurgical-pain-by-upregulating-k-cl-cotransporter-2-in-the-spinal-dorsal-horn-in-rats
#1
Shuhong Dai, Yu Qi, Jie Fu, Na Li, Xu Zhang, Juan Zhang, Wei Zhang, Haijun Xu, Hai Zhou, Zhengliang Ma
Background: Dexmedetomidine (DEX) could have an analgesic effect on pain transmission through the modulation of brain-derived neurotrophic factor (BDNF). In addition, KCC2-induced shift in neuronal Cl- homeostasis is crucial for postsynaptic inhibition mediated by GABAA receptors. Accumulating evidence shows that nerve injury, peripheral inflammation and stress activate the spinal BDNF/TrkB signal, which results in the downregulation of KCC2 transport and expression, eventually leads to GAGAergic disinhibition and hyperalgesia...
2018: Journal of Pain Research
https://www.readbyqxmd.com/read/29859204/neuroprotective-effect-of-zolpidem-against-glutamate-induced-toxicity-is-mediated-via-the-pi3k-akt-pathway-and-inhibited-by-pk11195
#2
Maja Jazvinšćak Jembrek, Vedrana Radovanović, Josipa Vlainić, Lidija Vuković, Nikolina Hanžić
Excitotoxicity is a pathological process in which neuronal dysfunction and death are induced by excessive glutamate stimulation, the major fast excitatory neurotransmitter in the mammalian brain. Excitotoxicity-induced neurodegeneration is a contributing factor in ischemia-induced brain damage, traumatic brain injury, and various neurodegenerative diseases. It is triggered by calcium overload due to prolonged over-activation of ionotropic N-methyl-D-aspartate (NMDA) receptors. Enhanced Ca2+ release results in neuronal vulnerability through several intertwined mechanisms, including activation of proteolytic enzymes, increased production of reactive oxygen species (ROS), mitochondrial dysfunction and modulation of intracellular signalling pathways...
May 30, 2018: Toxicology
https://www.readbyqxmd.com/read/29758302/plasminogen-binding-inhibitors-demonstrate-unwanted-activities-on-gaba-a-and-glycine-receptors-in-human-ipsc-derived-neurons
#3
Lisbeth Kristensson, Anders Lundin, David Gustafsson, Jan Fryklund, Tomas Fex, Delsing Louise, Erik Ryberg
Plasminogen binding inhibitors (PBIs) reduce the risk of bleeding in hemorrhagic conditions. However, generic PBIs are also associated with an increased risk of seizures, an adverse effect linked to unwanted activities towards inhibitory neuronal receptors. Development of novel PBIs serve to remove compounds with such properties, but progress is limited by a lack of higher throughput methods with human translatability. Herein we apply human induced pluripotent stem cell (hiPSC) derived neurons in combination with dynamic mass redistribution (DMR) technology to demonstrate robust and reproducible modulation of both GABAA and glycine receptors...
May 11, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29704480/protective-effect-and-mechanism-of-injection-of-glutamate-into-cerebellum-fastigial-nucleus-on-chronic-visceral-hypersensitivity-in-rats
#4
Ling-Ling Zhen, Bei Miao, Ying-Ying Chen, Zhen Su, Man-Qiu Xu, Sujuan Fei, Jianfu Zhang
AIMS: We investigated the effects of chemical stimulation of cerebellum fastigial nucleus (FN) on the chronic visceral hypersensitivity (CVH) and its possible mechanism in rats. MAIN METHODS: We stimulated the FN by microinjecting glutamate into the FN, in order to explore whether the cerebellum fastigial nucleus played a role on CVH in rat. The model of CVH was established by colorectal distension (CRD) in neonatal rats. Abdominal withdrawal reflex (AWR) scores, pain threshold, and amplitude of electromyography (EMG) were used to assess the hyperalgesia...
June 15, 2018: Life Sciences
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
#5
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...
July 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
#6
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
#7
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...
July 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
#8
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...
July 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29565038/gabaergic-inhibitory-neurons-as-therapeutic-targets-for-cognitive-impairment-in-schizophrenia
#9
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...
May 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
#10
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
#11
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
#12
C A Wotton, E F Quon, A C Palmer, L K Bekar
Both serotonin (5-HT) and stress exert changes in cortical inhibitory tone to shape the activity of cortical networks. Because astrocytes are also known to affect inhibition through established purinergic pathways, we assessed the role of GABA and purinergic pathways with respect to the effects of rapid corticosterone (CORT) and 5-HT on cortical inhibition. We used a paired-pulse paradigm (P1 and P2) in acutely isolated mouse brain slices to evaluate changes in cortical evoked inhibition. Normally, 5-HT decreases the amplitude of the first pulse P1, whereas it increases the amplitude of P2 (increasing frequency transmission)...
April 2018: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/29532486/glyoxalase-1-glo1-inhibition-or-genetic-overexpression-does-not-alter-ethanol-s-locomotor-effects-implications-for-glo1-as-a-therapeutic-target-in-alcohol-use-disorders
#13
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 (EtOH) drinking. This study assessed whether inhibition of GLO1, or genetic overexpression of Glo1, would also alter the locomotor effects of EtOH, which might explain reduced EtOH consumption following GLO1 inhibition. We used the prototypical GABAA receptor agonist muscimol as a positive control...
May 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
#14
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...
May 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
#15
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...
June 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
#16
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-gaba-a-receptor-isoform
#17
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 20, 2018: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/29376464/the-flavonoid-2-methoxy-6-methylflavone-affords-neuroprotection-following-focal-cerebral-ischaemia
#18
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
#19
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
#20
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
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