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Gaba a inhibitor

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https://www.readbyqxmd.com/read/28808187/g-aminobutyric-acid-promotes-methionine-choline-deficient-diet-induced-nonalcoholic-steatohepatitis
#1
Yoon Seok Roh, Ara Cho, Zixiong Zhou, Hyuneui Jeong, Jeong-Eun Park, Youn-Soo Cha, Suk-Heung Oh, Chae-Woong Lim, Bumseok Kim
Nonalcoholic steatohepatitis (NASH) is one of the most common liver diseases and a major cause of liver fibrosis worldwide. G-Aminobutyric acid (GABA) is one of the most abundant inhibitory neurotransmitters in the central nervous system. Recently, it has been reported that GABAergic signaling pathways are found in various non-neuronal tissues including the immune system and play a functional role. In the present study, we investigated whether administration of GABA has effects on NASH through its immunomodulatory effects...
October 17, 2016: Journal of Biomedical Research
https://www.readbyqxmd.com/read/28807873/neurophysiologically-informed-markers-of-individual-variability-and-pharmacological-manipulation-of-human-cortical-gamma
#2
A D Shaw, R J Moran, S D Muthukumaraswamy, J Brealy, D E Linden, K J Friston, K D Singh
The ability to quantify synaptic function at the level of cortical microcircuits from non-invasive data would be enormously useful in the study of neuronal processing in humans and the pathophysiology that attends many neuropsychiatric disorders. Here, we provide proof of principle that one can estimate inter-and intra-laminar interactions among specific neuronal populations using induced gamma responses in the visual cortex of human subjects - using dynamic causal modelling based upon the canonical microcircuit (CMC; a simplistic model of a cortical column)...
August 11, 2017: NeuroImage
https://www.readbyqxmd.com/read/28807671/selective-inhibition-of-extra-synaptic-%C3%AE-5-gabaa-receptors-by-s44819-a-new-therapeutic-agent
#3
Lori-An Etherington, Balázs Mihalik, Adrienn Pálvölgyi, István Ling, Katalin Pallagi, Szabolcs Kertész, Péter Varga, Ben G Gunn, Adam R Brown, Matthew R Livesey, Olivia Monteiro, Delia Belelli, József Barkóczy, Michael Spedding, István Gacsályi, Ferenc A Antoni, Jeremy J Lambert
In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibition and are important therapeutic targets. GABAARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20-30 GABAAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties. We report the discovery of S44819, a novel tricyclic oxazolo-2,3-benzodiazepine-derivative, that selectively inhibits α5-subunit-containing GABAARs (α5-GABAARs)...
August 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28793908/transcriptomic-analysis-comparing-mouse-strains-with-extreme-total-lung-capacities-identifies-novel-candidate-genes-for-pulmonary-function
#4
Leema George, Ankita Mitra, Tania A Thimraj, Martin Irmler, Sangeetha Vishweswaraiah, Lars Lunding, Dorothea Hühn, Alicia Madurga, Johannes Beckers, Heinz Fehrenbach, Swapna Upadhyay, Holger Schulz, George D Leikauf, Koustav Ganguly
BACKGROUND: Failure to attain peak lung function by early adulthood is a risk factor for chronic lung diseases. Previously, we reported that C3H/HeJ mice have about twice total lung capacity (TLC) compared to JF1/MsJ mice. We identified seven lung function quantitative trait loci (QTL: Lfnq1-Lfnq7) in backcross/intercross mice derived from these inbred strains. We further demonstrated, superoxide dismutase 3, extracellular (Sod3), Kit oncogene (Kit) and secreted phosphoprotein 1 (Spp1) located on these Lfnqs as lung function determinants...
August 9, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28782641/nitric-oxide-cgmp-signaling-via-guanylyl-cyclase-isoform-1-modulates-glutamate-and-gaba-release-in-somatosensory-cortex-of-mice
#5
Qi Wang, Evanthia Mergia, Doris Koesling, Thomas Mittmann
In hippocampus, two guanylyl cyclases (NO-GC1 and NO-GC2) are involved in the transduction of the effects of nitric oxide (NO) on synaptic transmission. However, the respective roles of the NO-GC isoforms on synaptic transmission are less clear in other regions of the brain. In the present study, we used knock-out mice deficient for the NO-GC1 isoform (NO-GC1 KO) to analyze its role in the glutamatergic and GABAergic neurotransmission at pyramidal neurons in layers II/III of somatosensory cortex. NO-GC1 KO slices revealed reduced frequencies of miniature excitatory- and inhibitory-postsynaptic currents, increased paired-pulse ratios and decreased input-output curves of evoked signals, which indicated the reduction of glutamate and GABA release in NO-GC1 KO mice...
August 4, 2017: Neuroscience
https://www.readbyqxmd.com/read/28775328/inhibition-of-glutamate-decarboxylase-gad-by-ethyl-ketopentenoate-ekp-induces-treatment-resistant-epileptic-seizures-in-zebrafish
#6
Yifan Zhang, Michiel Vanmeert, Aleksandra Siekierska, Annelii Ny, Jubi John, Geert Callewaert, Eveline Lescrinier, Wim Dehaen, Peter A M de Witte, Rafal M Kaminski
Epilepsy is a chronic brain disorder characterized by recurrent seizures due to abnormal, excessive and synchronous neuronal activities in the brain. It affects approximately 65 million people worldwide, one third of which are still estimated to suffer from refractory seizures. Glutamic acid decarboxylase (GAD) that converts glutamate into GABA is a key enzyme in the dynamic regulation of neural network excitability. Importantly, clinical evidence shows that lowered GAD activity is associated with several forms of epilepsy which are often treatment resistant...
August 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28741622/in-vivo-detection-of-cpp-115-target-engagement-in-human-brain
#7
Andrew P Prescot, Steven R Miller, Gary Ingenito, Rebekah S Huber, Douglas G Kondo, Perry F Renshaw
CPP-115, a next-generation γ-amino butyric acid (GABA)-aminotransferase (AT) inhibitor, shows comparable pharmacokinetics, improved safety and tolerability, and a more favorable toxicity profile when compared to vigabatrin. The pharmacodynamic characteristics of CPP-115 remain to be evaluated. The present study employed state-of-the-art proton magnetic resonance spectroscopy techniques to measure changes in brain GABA+ (the composite resonance of GABA, homocarnosine, and macromolecules) concentrations in healthy subjects receiving oral daily doses of CPP-115 or placebo...
July 25, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28735749/initiation-of-behavioral-response-to-antidepressants-by-cholecystokinin-neurons-of-the-dentate-gyrus
#8
Lucian Medrihan, Yotam Sagi, Zintis Inde, Oleh Krupa, Chelsea Daniels, Adrien Peyrache, Paul Greengard
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressant drugs, but the cellular and molecular mechanisms by which their therapeutic action is initiated are poorly understood. Here we show that serotonin 5-HT1B receptors in cholecystokinin (CCK) inhibitory interneurons of the mammalian dentate gyrus (DG) initiate the therapeutic response to antidepressants. In these neurons, 5-HT1B receptors are expressed presynaptically, and their activation inhibits GABA release. Inhibition of GABA release from CCK neurons disinhibits parvalbumin (PV) interneurons and, as a consequence, reduces the neuronal activity of the granule cells...
August 2, 2017: Neuron
https://www.readbyqxmd.com/read/28734674/retinal-exposure-to-high-glucose-condition-modifies-the-gabaergic-system-regulation-by-nitric-oxide
#9
R Carpi-Santos, R S Maggesissi, M P von Seehausen, K C Calaza
Diabetic retinopathy is a severe retinal complication that diabetic patients are susceptible to present. Although this disease is currently characterized as a microvascular disease, there is growing evidence that neural changes occur and maybe precede vascular impairments. Using chicken retina, an avascular tissue with no direct contact with blood vessels and neural retina, this study aimed to evaluate the influence of acute exposure to high glucose concentration in the retinal GABAergic system, and the role of nitric oxide (NO) in this modulation...
September 2017: Experimental Eye Research
https://www.readbyqxmd.com/read/28711518/antagonism-of-the-5-ht6-receptor-preclinical-rationale-for-the-treatment-of-alzheimer-s-disease
#10
REVIEW
Inge E M de Jong, Arne Mørk
Antagonism of the 5-HT6 receptor is a promising approach for the symptomatic treatment of Alzheimer's disease (AD). There is compelling preclinical evidence for the procognitive potential of 5-HT6 receptor antagonists and several compounds are in clinical development, as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). This manuscript summarizes the scientific rationale for the use of 5-HT6 receptor antagonists as AD treatment, with some focus on the selective and high-affinity 5-HT6 receptor antagonist idalopirdine (Lu AE58054)...
July 12, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28676760/combined-oral-administration-of-gaba-and-dpp-4-inhibitor-prevents-beta-cell-damage-and-promotes-beta-cell-regeneration-in-mice
#11
Wenjuan Liu, Dong Ok Son, Harry K Lau, Yinghui Zhou, Gerald J Prud'homme, Tianru Jin, Qinghua Wang
γ-aminobutyric acid (GABA) or glucagon-like peptide-1 based drugs, such as sitagliptin (a dipeptidyl peptidase-4 inhibitor), were shown to induce beta cell regenerative effects in various diabetic mouse models. We propose that their combined administration can bring forth an additive therapeutic effect. We tested this hypothesis in a multiple low-dose streptozotocin (STZ)-induced beta cell injury mouse model (MDSD). Male C57BL/6J mice were assigned randomly into four groups: non-treatment diabetic control, GABA, sitagliptin, or GABA plus sitagliptin...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28658981/pharmacotherapy-of-alcoholism-an-update-on-approved-and-off-label-medications
#12
Michael Soyka, Christian A Müller
Only a few medications are available for the treatment of alcohol use disorders (AUDs). Areas covered: This paper discusses approved AUD medications, including the opioid antagonists naltrexone and nalmefene (the latter is licensed for reduction of alcohol consumption only), the putative glutamate receptor antagonist acamprosate and the aldehyde dehydrogenase inhibitor disulfiram. It also covers off-label medications of interest, including topiramate, gabapentin, ondansetron, varenicline, baclofen, sodium oxybate and antidepressants...
July 24, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28555334/prenatal-nicotine-exposure-induces-hpa-axis-hypersensitivity-in-offspring-rats-via-the-intrauterine-programming-of-up-regulation-of-hippocampal-gad67
#13
Xia He, Juan Lu, Wanting Dong, Zhexiao Jiao, Chong Zhang, Ying Yu, Zhaohui Zhang, Hui Wang, Dan Xu
The intrauterine programming of hypothalamic-pituitary-adrenal (HPA) axis hypersensitivity is associated with chronic adult diseases. Our previous studies demonstrated the HPA-axis hypersensitivity in offspring rats induced by prenatal nicotine exposure. The goal of the present study is to further investigate the intrauterine programming mechanism. Pregnant Wistar rats were subcutaneously administered with 2.0 mg/kg day of nicotine from gestational day (GD) 9-20. A group of the pregnant rats was euthanized at GD20, and the fetal rats were extracted...
May 29, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28524180/aberrant-epigenetic-regulation-of-gabrp-associates-with-aggressive-phenotype-of-ovarian-cancer
#14
Hye Youn Sung, San-Duk Yang, Woong Ju, Jung-Hyuck Ahn
Metastasis is a major cause of therapeutic failure in ovarian cancer. To elucidate molecular mechanisms of ovarian cancer metastasis, we previously established a metastatic xenograft mouse model using human ovarian carcinoma SK-OV-3 cells. Using gene expression profiling, we found that γ-aminobutyric acid (GABA)A receptor π subunit (GABRP) expression was upregulated (>4-fold) in metastatic tissues from our xenograft mice compared with SK-OV-3 cells. Importantly, GABRP knockdown diminished the migration and invasion of SK-OV-3 cells, and reduced extracellular signal-regulated kinase (ERK) activation while overexpression of GABRP exhibited significantly increased cell migration, invasion and ERK activation...
May 19, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28514338/-a-comparative-chemoreactome-analysis-of-mexidol
#15
I Yu Torshin, O A Gromova, I S Sardaryan, L E Fedotova
AIM: To compare mexidol with control molecules (choline alfoscerate, piracetam, glycine, semax) using chemoreactome analysis. MATERIAL AND METHODS: The chemical structure of mexidol was compared to molecule metabolites extracted from the Human Metabolome Database (HMDB) and a drug database. More than 40 000 of metabolites from HMDB were used as a model of human metabolome. RESULTS AND CONCLUSION: The chemoreactome analysis showed that mexidol may be (1) an agonist of acetylcholine and GABA-A receptors; (2) an anti-inflammatory agent, the effects of which are carried out by inhibiting the synthesis of pro-inflammatory prostaglandins; (3) a neurotrophic agent with neuroprotective properties; (4) a coagulation inhibitor; (5) a diabetes medication and (6) a hypolipidemic agent...
2017: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
https://www.readbyqxmd.com/read/28499915/early-life-stress-and-later-peer-distress-on-depressive-behavior-in-adolescent-female-rats-effects-of-a-novel-intervention-on-gaba-and-d2-receptors
#16
Jodi L Lukkes, Shirisha Meda, Britta S Thompson, Nadja Freund, Susan L Andersen
Early life adversity (ELA) increases the risk of depression during adolescence that may result from a decline in parvalbumin (PVB) secondary to increased neuroinflammation. In this study, we investigated depressive-like behavior following exposure to two different types of stressors that are relevant for their developmental period: 1) chronic ELA (maternal separation; MS) and 2) an acute emotional stressor during adolescence (witnessing their peers receive multiple shocks; WIT), and their interaction. We also determined whether reducing inflammation by cyclooxygenase-2 (COX-2) inhibition would prevent the onset of depressive-like behavior...
July 14, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28485599/enantioselective-three-step-synthesis-of-homo-%C3%AE-proline-a-donor-acceptor-cyclopropane-as-key-intermediate
#17
Ludwig K A Pilsl, Thomas Ertl, Oliver Reiser
An enantioselective three-step synthesis of the GABA uptake inhibitor (S)-(+)-homo-β-proline was developed. The basis for the synthesis was the enantioselective Cu(I)-catalyzed cyclopropanation of N-Boc-pyrrole, a substrate that persistently has proved to be challenging in such transformations. The cyclopropanation can be performed on a 150 mmol scale, and the two subsequent steps (i.e., hydrogenation and in situ cyclopropane-opening/double-deprotection) toward the target molecule proceed smoothly in quantitative yield without loss of enantiopurity...
May 9, 2017: Organic Letters
https://www.readbyqxmd.com/read/28456011/neurosteroid-biosynthesis-downregulation-and-changes-in-gabaa-receptor-subunit-composition-a-biomarker-axis-in-stress-induced-cognitive-and-emotional-impairment
#18
REVIEW
Andrea Locci, Graziano Pinna
By rapidly modulating neuronal excitability, neurosteroids regulate physiological processes, such as responses to stress and development. Excessive stress affects their biosynthesis and causes an imbalance in cognition and emotions. The progesterone derivative, allopregnanolone (Allo) enhances extrasynaptic and postsynaptic inhibition by directly binding at GABAA receptors, and thus, positively and allosterically modulates the function of GABA. Allo levels are decreased in stress-induced psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), and elevating Allo levels may be a valid therapeutic approach to counteract behavioural dysfunction...
April 29, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28443033/high-gama-aminobutyric-acid-contents-involved-in-abamectin-resistance-and-predation-an-interesting-phenomenon-in-spider-mites
#19
Zhifeng Xu, Yanchao Liu, Peng Wei, Kaiyang Feng, Jinzhi Niu, Guangmao Shen, Wencai Lu, Wei Xiao, Jinjun Wang, Guy J Smagghe, Qiang Xu, Lin He
Abamectin has been widely used as an insecticide/acaricide for more than 30 years because of its superior bioactivity. Recently, an interesting phenomenon was identified in the carmine spider mite, Tetranychus cinnabarinus, an important pest in agriculture. The gamma aminobutyric acid (GABA) contents in a laboratory abamectin resistant strain of T. cinnabarinus (AbR) were significantly increased. Decreases in activity and mRNA expression of GABA transaminase (GABA-T) were responsible for GABA accumulation in AbR mites...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28440808/automated-and-manual-patch-clamp-data-of-human-induced-pluripotent-stem-cell-derived-dopaminergic-neurons
#20
Denise Franz, Hervør Lykke Olsen, Oliver Klink, Jan Gimsa
Human induced pluripotent stem cells can be differentiated into dopaminergic neurons (Dopa.4U). Dopa.4U neurons expressed voltage-gated NaV and KV channels and showed neuron-like spontaneous electrical activity. In automated patch clamp measurements with suspended Dopa.4U neurons, delayed rectifier K(+) current (delayed KV) and rapidly inactivating A-type K(+) current (fast KV) were identified. Examination of the fast KV current with inhibitors yielded IC50 values of 0.4 mM (4-aminopyridine) and 0.1 mM (tetraethylammonium)...
April 25, 2017: Scientific Data
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