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Gabaa inhibitor

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https://www.readbyqxmd.com/read/28273868/pharmacological-potential-and-synthetic-approaches-of-imidazo-4-5-b-pyridine-and-imidazo-4-5-c-pyridine-derivatives
#1
REVIEW
Malwina Krause, Henryk Foks, Katarzyna Gobis
The structural resemblance between the fused imidazopyridine heterocyclic ring system and purines has prompted biological investigations to assess their potential therapeutic significance. They are known to play a crucial role in numerous disease conditions. The discovery of their first bioactivity as GABAA receptor positive allosteric modulators divulged their medicinal potential. Proton pump inhibitors, aromatase inhibitors, and NSAIDs were also found in this chemical group. Imidazopyridines have the ability to influence many cellular pathways necessary for the proper functioning of cancerous cells, pathogens, components of the immune system, enzymes involved in carbohydrate metabolism, etc...
March 4, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28214522/prelimbic-cortex-extracellular-signal-regulated-kinase-1-2-activation-is-required-for-memory-retrieval-of-long-term-inhibitory-avoidance
#2
Fei Luo, Jian Zheng, Xuan Sun, Wei-Ke Deng, Bao Ming Li, Fang Liu
Neural mechanism underlying memory retrieval has been extensively studied in the hippocampus and amygdala. However, little is known about the role of medial prefrontal cortex in long-term memory retrieval. We evaluate this issue in one-trial step-through inhibitory avoidance (IA) paradigm. Our results showed that, 1) inactivation of mPFC by local infusion of GABAA-receptor agonist muscimol caused severe deficits in retrieval of 1-day and 7-day but had no effects on 2-h inhibitory avoidance memory; 2) the protein level of phosphorylated-ERK1/2 in mPFC were significantly increased following retrieval of 1-day and 7-day IA memory, so did the numbers of phosphorylated-ERK (pERK) and phosphorylated-CREB (pCREB) labeled neurons; 3) intra-mPFC infusion of ERK kinase inhibitor PD98095 significantly reduced phosphorylated ERK1/2 levels and phosphorylated-ERK1/2 and phosphorylated-CREB labeled cells, and severely impaired retrieval of 7-day IA memory when the drugs were administrated 30min prior to test...
April 15, 2017: Brain Research
https://www.readbyqxmd.com/read/28153485/loop-f-of-the-%C3%AE-subunit-determines-the-pharmacologic-profile-of-novel-competitive-inhibitors-of-gabaa-receptors
#3
Balázs Mihalik, Adrienn Pálvölgyi, Ferenc Bogár, Katalin Megyeri, István Ling, József Barkóczy, Ferenc Bartha, Tamás A Martinek, István Gacsályi, Ferenc A Antoni
The neurotransmitter γ-amino butyric acid (GABA) has a fundamental role in CNS function and ionotropic (GABAA) receptors that mediate many of the actions of GABA are important therapeutic targets. This study reports the mechanism of action of novel GABAA antagonists based on a tricyclic oxazolo-2,3-benzodiazepine scaffold. These compounds are orthosteric antagonists of GABA on heteropentameric GABAA receptors of αxβ2γ2 configuration expressed in HEK293 cells. In silico modelling predicted that the test compounds docked in the GABA binding-pocket and would interact with amino-acid residues in the α- and β-subunit interface that are known to be important for the binding of GABA...
January 31, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28129443/anxiolytic-effects-of-hippocampal-neurosteroids-in-normal-and-neuropathic-rats-with-spared-nerve-injury
#4
Meng Zhang, Jia Liu, Meng-Meng Zhou, Honghai Wu, Yanning Hou, Yun-Feng Li, Yuxin Yin, Lemin Zheng, Jie Cai, Fei-Fei Liao, Feng-Yu Liu, Ming Yi, You Wan
Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of GABAA receptors, which play a vital role in modulating hippocampal functions. Chronic pain is accompanied by increased neurosteroid production in the spinal cord and thalamus. We hypothesize that hippocampal neurosteroids participate in pain or pain-associated emotions, which we tested with high-performance liquid chromatography/tandem mass spectrometry and pharmacological behavioral tests...
January 27, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28109985/the-synthetic-neuroactive-steroid-sge-516-reduces-status-epilepticus-and-neuronal-cell-death-in-a-rat-model-of-soman-intoxication
#5
Alison L Althaus, Hilary S McCarren, Aymen Alqazzaz, Cecelia Jackson, John H McDonough, Carl D Smith, Ethan Hoffman, Rebecca S Hammond, Albert J Robichaud, James J Doherty
Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase that pose a serious threat to public health because of their use as chemical weapons. Exposure to high doses of OPNAs can dramatically potentiate cholinergic synaptic activity and cause status epilepticus (SE). Current standard of care for OPNA exposure involves treatment with cholinergic antagonists, oxime cholinesterase reactivators, and benzodiazepines. However, data from pre-clinical models suggest that OPNA-induced SE rapidly becomes refractory to benzodiazepines...
January 18, 2017: Epilepsy & Behavior: E&B
https://www.readbyqxmd.com/read/28109911/rho-kinase-inhibitor-prevents-acute-injury-against-transient-focal-cerebral-ischemia-by-enhancing-the-expression-and-function-of-gaba-receptors-in-rats
#6
Lin Huang, Qin Li, Ruiting Wen, Zhiying Yu, Na Li, Liping Ma, Wanyu Feng
Studies have shown hydroxyfasudil-mediated inhibition of Rho-kinase (ROCK) has efficacy in rodent models of focal ischemia and in in vitro systems that recapitulate stroke conditions. However, the mechanisms underlying the neuroprotective effects of the ROCK inhibitor on stroke are not well understood. In this study, we examined the role of γ-aminobutyric acid (GABA) interneurons in the effects of hydroxyfasudil on transient middle cerebral artery occlusion (tMCAO) induced acute ischemia-reperfusion injury to explore the mechanisms...
January 18, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28105535/the-neuropeptide-orexin-a-inhibits-the-gabaa-receptor-by-pkc-and-ca-2-camkii-dependent-phosphorylation-of-its-%C3%AE-1-subunit
#7
Divya Sachidanandan, Haritha P Reddy, Anitha Mani, Geoffrey J Hyde, Amal Kanti Bera
Orexin-A and orexin-B (Ox-A, Ox-B) are neuropeptides produced by a small number of neurons that originate in the hypothalamus and project widely in the brain. Only discovered in 1998, the orexins are already known to regulate several behaviours. Most prominently, they help to stabilise the waking state, a role with demonstrated significance in the clinical management of narcolepsy and insomnia. Orexins bind to G-protein-coupled receptors (predominantly postsynaptic) of two subtypes, OX1R and OX2R. The primary effect of Ox-OXR binding is a direct depolarising influence mediated by cell membrane cation channels, but a wide variety of secondary effects, both pre- and postsynaptic, are also emerging...
January 19, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28069825/intravenous-anesthetic-propofol-binds-to-5-lipoxygenase-and-attenuates-leukotriene-b4-production
#8
Toshiaki Okuno, Sophia Koutsogiannaki, Mai Ohba, Matthew Chamberlain, Weiming Bu, Fu-Yan Lin, Roderic G Eckenhoff, Takehiko Yokomizo, Koichi Yuki
Propofol is an intravenous anesthetic that produces its anesthetic effect, largely via the GABAA receptor in the CNS, and also reduces the N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophil respiratory burst. Because fMLP-stimulated neutrophils produce leukotriene (LT)B4, we examined the effect of propofol on LTB4 production in vivo and in vitro Cecal ligation and puncture surgery was performed in mice, with or without exposure to propofol. Propofol attenuated the production of 5-lipoxygenase (5-LOX)-related arachidonic acid (AA) derivatives in the peritoneal fluid...
January 9, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28066142/participation-of-central-gabaa-receptors-in-the-trigeminal-processing-of-mechanical-allodynia-in-rats
#9
Min Ji Kim, Young Hong Park, Kui Ye Yang, Jin Sook Ju, Yong Chul Bae, Seong Kyu Han, Dong Kuk Ahn
Here we investigated the central processing mechanisms of mechanical allodynia and found a direct excitatory link with low-threshold input to nociceptive neurons. Experiments were performed on male Sprague-Dawley rats weighing 230-280 g. Subcutaneous injection of interleukin 1 beta (IL-1β) (1 ng/10 µL) was used to produce mechanical allodynia and thermal hyperalgesia. Intracisternal administration of bicuculline, a gamma aminobutyric acid A (GABAA) receptor antagonist, produced mechanical allodynia in the orofacial area under normal conditions...
January 2017: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/27987210/anti-anhedonic-effect-of-selective-serotonin-reuptake-inhibitors-with-affinity-for-sigma-1-receptors-in-picrotoxin-treated-mice
#10
S Hasebe, Y Ago, Y Watabe, S Oka, N Hiramatsu, T Tanaka, C Umehara, H Hashimoto, K Takuma, T Matsuda
BACKGROUND AND PURPOSE: Prefrontal dopamine release by the combined activation of 5-HT1A and sigma-1 (σ1 ) receptors is enhanced by the GABAA receptor antagonist picrotoxin in mice. Here, we examined whether this neurochemical event was accompanied by behavioural changes. EXPERIMENTAL APPROACH: Male mice were treated with picrotoxin to decrease GABAA receptor function. Their anhedonic behaviour was measured using the female encounter test. The expression of c-Fos was determined immunohistochemically...
February 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27940054/betaine-attenuates-memory-impairment-after-water-immersion-restraint-stress-and-is-regulated-by-the-gabaergic-neuronal-system-in-the-hippocampus
#11
Kazuo Kunisawa, Kiwamu Kido, Natsuki Nakashima, Takuya Matsukura, Toshitaka Nabeshima, Masayuki Hiramatsu
GABA mediated neuronal system regulates hippocampus-dependent memory and stress responses by controlling plasticity and neuronal excitability. Here, we demonstrate that betaine ameliorates water-immersion restraint stress (WIRS)-induced memory impairments. This improvement was inhibited by a betaine/GABA transporter-1 (GABA transporter-2: GAT2) inhibitor, NNC 05-2090. In this study, we investigated whether memory amelioration by betaine was mediated by the GABAergic neuronal system. Adult male mice were co-administered betaine and GABA receptor antagonists after WIRS...
December 7, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27933876/inhibition-of-human-monoamine-oxidase-biological-and-molecular-modeling-studies-on-selected-natural-flavonoids
#12
Simone Carradori, Maria Concetta Gidaro, Anél Petzer, Giosuè Costa, Paolo Guglielmi, Paola Chimenti, Stefano Alcaro, Jacobus P Petzer
Naturally occurring flavonoids display a plethora of different biological activities, but emerging evidence suggests that this class of compounds may also act as antidepressant agents endowed with multiple mechanisms of action in the central nervous system, increasing central neurotransmission, limiting the reabsorption of bioamines by synaptosomes, and modulating the neuroendocrine and GABAA systems. Due to their presence in foods, food-derived products, and nutraceuticals, we established their role and structure-activity relationships as reversible and competitive human monoamine oxidase (MAO) inhibitors...
November 30, 2016: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/27826117/neonatal-inhibition-of-na-k-2cl-cotransporter-prevents-ketamine-induced-spatial-learning-and-memory-impairments
#13
Ryan A Stevens, Brandon D Butler, Saurabh S Kokane, Andrew W Womack, Qing Lin
Prolonged ketamine exposure in neonates at anesthetic doses is known to cause long-term impairments of learning and memory. A current theoretical mechanism explains this phenomenon as being neuro-excitotoxicity mediated by compensatory upregulation of N-methyl-d-aspartate receptors (NMDARs), which then initiates widespread neuroapoptosis. Additionally, the excitatory behavior of GABAergic synaptic transmission mediated by GABAA receptors (GABAARs), occurring during the early neuronal development period, is proposed as contributing to the susceptibility of neonatal neurons to ketamine-induced injury...
November 5, 2016: Neurotoxicology and Teratology
https://www.readbyqxmd.com/read/27816307/mtor-inhibition-mitigates-molecular-and-biochemical-alterations-of-vigabatrin-induced-visual-field-toxicity-in-mice
#14
Kara R Vogel, Garrett R Ainslie, Michelle A Schmidt, Jonathan P Wisor, K Michael Gibson
BACKGROUND: Gamma-vinyl-γ-aminobutyric acid (GABA) (vigabatrin) is an antiepileptic drug and irreversible GABA transaminase inhibitor associated with visual field impairment, which limits its clinical utility. We sought to relate altered visual evoked potentials associated with vigabatrin intake to transcriptional changes in the mechanistic target of rapamycin (mTOR) pathway and GABA receptors to expose further mechanisms of vigabatrin-induced visual field loss. METHODS: Vigabatrin was administered to mice via an osmotic pump for two weeks to increase GABA levels...
January 2017: Pediatric Neurology
https://www.readbyqxmd.com/read/27799911/huperzine-a-provides-robust-and-sustained-protection-against-induced-seizures-in-scn1a-mutant-mice
#15
Jennifer C Wong, Stacey B B Dutton, Stephen D Collins, Steven Schachter, Andrew Escayg
De novo loss-of-function mutations in the voltage-gated sodium channel (VGSC) SCN1A (encoding Nav1.1) are the main cause of Dravet syndrome (DS), a catastrophic early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), refractory afebrile epilepsy, cognitive and behavioral deficits, and a 15-20% mortality rate. SCN1A mutations also lead to genetic epilepsy with febrile seizures plus (GEFS+), which is an inherited disorder characterized by early-life FSs and the development of a range of adult epilepsy subtypes...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27757785/2-3-o-substituted-atp-derivatives-as-potent-antagonists-of-purinergic-p2x3-receptors-and-potential-analgesic-agents
#16
Diego Dal Ben, Anna Marchenkova, Ajiroghene Thomas, Catia Lambertucci, Andrea Spinaci, Gabriella Marucci, Andrea Nistri, Rosaria Volpini
Blocking membrane currents evoked by the activation of purinergic P2X3 receptors localized on nociceptive neurons represents a promising strategy for the development of agents useful for the treatment of chronic pain conditions. Among compounds endowed with such antagonistic action, 2',3'-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP) is an ATP analogue, whose inhibitory activity on P2X receptors has been previously reported. Based on the results of molecular modelling studies performed with homology models of the P2X3 receptor, novel adenosine nucleotide analogues bearing cycloalkyl or arylalkyl substituents replacing the trinitrophenyl moiety of TNP-ATP were designed and synthesized...
March 2017: Purinergic Signalling
https://www.readbyqxmd.com/read/27735054/2-deoxy-d-glucose-enhances-tonic-inhibition-through-the-neurosteroid-mediated-activation-of-extrasynaptic-gabaa-receptors
#17
Nicola Forte, Lucian Medrihan, Beatrice Cappetti, Pietro Baldelli, Fabio Benfenati
OBJECTIVE: The inhibition of glycolysis exerts potent antiseizure effects, as demonstrated by the efficacy of ketogenic and low-glucose/nonketogenic diets in the treatment of drug-resistant epilepsy. ATP-sensitive potassium (KATP ) channels have been initially identified as the main determinant of the reduction of neuronal hyperexcitability. However, a plethora of other mechanisms have been proposed. Herein, we report the ability of 2-deoxy-d-glucose (2-DG), a glucose analog that inhibits glycolytic enzymes, of potentiating γ-aminobutyric acid (GABA)ergic tonic inhibition via neurosteroid-mediated activation of extrasynaptic GABAA receptors...
December 2016: Epilepsia
https://www.readbyqxmd.com/read/27663259/increasing-spinal-5-ht2a-receptor-responsiveness-mediates-anti-allodynic-effect-and-potentiates-fluoxetine-efficacy-in-neuropathic-rats-evidence-for-gaba-release
#18
Amandine Dupuis, Anne-Sophie Wattiez, Jérémy Pinguet, Damien Richard, Frédéric Libert, Maryse Chalus, Youssef Aissouni, Benoit Sion, Denis Ardid, Philippe Marin, Alain Eschalier, Christine Courteix
Antidepressants are one of the first line treatments for neuropathic pain but their use is limited by the incidence and severity of side effects of tricyclics and the weak effectiveness of selective serotonin reuptake inhibitors (SSRIs). Serotonin type 2A (5-HT2A) receptors interact with PDZ proteins that regulate their functionality and SSRI efficacy to alleviate pain. We investigated whether an interfering peptide (TAT-2ASCV) disrupting the interaction between 5-HT2A receptors and associated PDZ proteins would improve the treatment of traumatic neuropathic allodynia...
September 20, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27659492/cb1-receptor-activation-in-the-rat-paraventricular-nucleus-induces-bi-directional-cardiovascular-effects-via-modification-of-glutamatergic-and-gabaergic-neurotransmission
#19
Emilia Grzęda, Eberhard Schlicker, Marek Toczek, Iwona Zalewska, Marta Baranowska-Kuczko, Barbara Malinowska
We have shown previously that the cannabinoid receptor agonist CP55940 microinjected into the paraventricular nucleus of the hypothalamus (PVN) of urethane-anaesthetized rats induces depressor and pressor cardiovascular effects in the absence and presence of the CB1 antagonist AM251, respectively. The aim of our study was to examine whether the hypotension and/or hypertension induced by CP55940 given into the PVN results from its influence on glutamatergic and GABAergic neurotransmission. CP55940 was microinjected into the PVN of urethane-anaesthetized rats twice (S1 and S2, 20 min apart)...
January 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/27615800/akting-up-in-the-gaba-hypothesis-of-schizophrenia-akt1-deficiency-modulates-gabaergic-functions-and-hippocampus-dependent-functions
#20
Chia-Yuan Chang, Yi-Wen Chen, Tsu-Wei Wang, Wen-Sung Lai
Accumulating evidence implies that both AKT1 and GABAA receptor (GABAAR) subunit genes are involved in schizophrenia pathogenesis. Activated Akt promotes GABAergic neuron differentiation and increases GABAAR expression on the plasma membrane. To elucidate the role of Akt1 in modulating GABAergic functions and schizophrenia-related cognitive deficits, a set of 6 in vitro and in vivo experiments was conducted. First, an Akt1/2 inhibitor was applied to evaluate its effect on GABAergic neuron-like cell formation from P19 cells...
September 12, 2016: Scientific Reports
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