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Gaba a inhibitor

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https://www.readbyqxmd.com/read/29148909/inhibition-of-gaba-transporters-fails-to-afford-significant-protection-following-focal-cerebral-ischemia
#1
Maria Ek Lie, Emma K Gowing, Rasmus P Clausen, Petrine Wellendorph, Andrew N Clarkson
Brain ischemia triggers excitotoxicity and cell death, yet no neuroprotective drugs have made it to the clinic. While enhancing GABAergic signaling to counterbalance excitotoxicity has shown promise in animal models, clinical studies have failed. Blockade of GABA transporters (GATs) offers an indirect approach to increase GABA inhibition to lower the excitation threshold of neurons. Among the GATs, GAT1 is known to promote neuroprotection, while the protective role of the extrasynaptic transporters GAT3 and BGT1 is elusive...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/29146941/developmental-excitatory-to-inhibitory-gaba-polarity-switch-is-disrupted-in-22q11-2-deletion-syndrome-a-potential-target-for-clinical-therapeutics
#2
Hayder Amin, Federica Marinaro, Davide De Pietri Tonelli, Luca Berdondini
Individuals with 22q11.2 microdeletion syndrome (22q11.2 DS) show cognitive and behavioral dysfunctions, developmental delays in childhood and risk of developing schizophrenia and autism. Despite extensive previous studies in adult animal models, a possible embryonic root of this syndrome has not been determined. Here, in neurons from a 22q11.2 DS mouse model (Lgdel (+/-)), we found embryonic-premature alterations in the neuronal chloride cotransporters indicated by dysregulated NKCC1 and KCC2 protein expression levels...
November 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29131576/pharmacological-characterization-of-3h-atpca-as-a-substrate-for-studying-the-functional-role-of-the-betaine-gaba-transporter-1-and-the-creatine-transporter
#3
Anas Al-Khawaja, Anne S Haugaard, Ales Marek, Rebekka Löffler, Louise Thiesen, Monica Santiveri, Maria Damgaard, Christoffer Bundgaard, Bente Frølund, Petrine Wellendorph
The betaine/γ-aminobutyric acid (GABA) transporter 1 (BGT1) is one of the four GABA transporters (GATs) involved in the termination of GABAergic neurotransmission. Although suggested to be implicated in seizure management, the exact functional importance of BGT1 in the brain is still elusive. This is partly owing to the lack of potent and selective pharmacological tool compounds that can be used to probe its function. We previously reported the identification of 2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid (ATPCA), a selective substrate for BGT1 over GAT1/GAT3, but also an agonist for GABAA receptors...
November 13, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29127598/gaba-uptake-inhibition-reduces-in-vivo-extraction-fraction-in-the-ventral-tegmental-area-of-long-evans-rats-measured-by-quantitative-microdialysis-under-transient-conditions
#4
Shannon L Zandy, Rueben A Gonzales
Inhibitory signaling in the ventral tegmental area (VTA) is involved in the mechanism of action for many drugs of abuse. Although drugs of abuse have been shown to alter extracellular γ-aminobutyric acid (GABA) concentration in the VTA, knowledge on how uptake mechanisms are regulated in vivo is limited. Quantitative (no-net-flux) microdialysis is commonly used to examine the extracellular concentration and clearance of monoamine neurotransmitters, however it is unclear whether this method is sensitive to changes in clearance for amino acid neurotransmitters such as GABA...
November 10, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/29123263/nuclear-igf-1r-predicts-chemotherapy-and-targeted-therapy-resistance-in-metastatic-colorectal-cancer
#5
Jordi Codony-Servat, Miriam Cuatrecasas, Elena Asensio, Carla Montironi, Anna Martínez-Cardús, Mercedes Marín-Aguilera, Carlos Horndler, Eva Martínez-Balibrea, Michele Rubini, Pedro Jares, Oscar Reig, Iván Victoria, Lydia Gaba, Marta Martín-Richard, Vicente Alonso, Pilar Escudero, Carlos Fernández-Martos, Jaime Feliu, Jose Carlos Méndez, Miguel Méndez, Javier Gallego, Antonieta Salud, Federico Rojo, Antoni Castells, Aleix Prat, Rafael Rosell, Xabier García-Albéniz, Jordi Camps, Joan Maurel
BACKGROUND: Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. METHODS: We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients...
November 9, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29093445/blood-meal-acquisition-enhances-arbovirus-replication-in-mosquitoes-through-activation-of-the-gabaergic-system
#6
Yibin Zhu, Rudian Zhang, Bei Zhang, Tongyan Zhao, Penghua Wang, Guodong Liang, Gong Cheng
Mosquitoes are hematophagous insects that carry-on and transmit many human viruses. However, little information is available regarding the common mechanisms underlying the infection of mosquitoes by these viruses. In this study, we reveal that the hematophagous nature of mosquitoes contributes to arboviral infection after a blood meal, which suppresses antiviral innate immunity by activating the GABAergic pathway. dsRNA-mediated interruption of the GABA signaling and blockage of the GABAA receptor by the specific inhibitors both significantly impaired arbovirus replication...
November 2, 2017: Nature Communications
https://www.readbyqxmd.com/read/29089046/the-novel-isoxazoline-ectoparasiticide-lotilaner-credelio%C3%A2-a-non-competitive-antagonist-specific-to-invertebrates-%C3%AE-aminobutyric-acid-gated-chloride-channels-gabacls
#7
Lucien Rufener, Vanessa Danelli, Daniel Bertrand, Heinz Sager
BACKGROUND: The isoxazolines are a novel class of parasiticides that are potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and, to a lesser extent, of inhibitory glutamate-gated chloride channels (GluCls). Lotilaner (Credelio™), a novel representative of this chemical class, is currently evaluated for its excellent ectoparasiticide properties. METHODS: In this study, we investigated the molecular mode of action and pharmacology of lotilaner...
November 1, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/29054135/alterations-in-the-timing-of-huperzine-a-cerebral-pharmacodynamics-in-the-acute-traumatic-brain-injury-setting
#8
Ugur Damar, Roman Gersner, Joshua T Johstone, Kush Kapur, Stephen D Collins, Steven Schachter, Alexander Rotenberg
Traumatic brain injury (TBI) may affect the pharmacodynamics of centrally acting drugs. Paired-pulse transcranial magnetic stimulation (ppTMS) is a safe and noninvasive measure of cortical GABA-mediated cortical inhibition. Huperzine A (HupA) is a naturally-occurring acetylcholinesterase inhibitor with newly discovered potent GABA-mediated antiepileptic capacity, which is reliably detected by ppTMS. To test whether TBI alters cerebral HupA pharmacodynamics, we exposed rats to fluid percussion injury (FPI), and tested whether ppTMS metrics of cortical inhibition differ in magnitude and temporal pattern in injured rats...
October 20, 2017: Journal of Neurotrauma
https://www.readbyqxmd.com/read/29054014/sex-differences-in-behavioral-and-neurochemical-effects-of-gonadectomy-and-aromatase-inhibition-in-rats
#9
N Kokras, N Pastromas, D Papasava, C de Bournonville, C A Cornil, C Dalla
Aromatase inhibitors, which are widely used for the treatment of estrogen-dependent cancers, have been associated with psychiatric side effects ranging from mania to depression. In the present study, we investigated sex differences in the behavioral and neurochemical effects of aromatase inhibition on male and female, sham-operated or gonadectomized adult rats. Three weeks after surgery, rats received chronic treatment with the aromatase inhibitor letrozole or vehicle and were then subjected to the open field test, which assesses general activity...
October 10, 2017: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/29053192/dissociation-of-nnos-from-psd-95-promotes-functional-recovery-after-cerebral-ischaemia-in-mice-through-reducing-excessive-tonic-gaba-release-from-reactive-astrocytes
#10
Yu-Hui Lin, Hai-Ying Liang, Ke Xu, Huan-Yu Ni, Jian Dong, Hui Xiao, Lei Chang, Hai-Yin Wu, Fei Li, Dong-Ya Zhu, Chun-Xia Luo
Mechanisms underlying functional recovery after stroke are little known, and effective drug intervention during the delayed stage is desirable. One potential drug target, the protein-protein interaction between neuronal nitric oxide synthase (nNOS) and postsynaptic density protein 95 (PSD-95), is critical to acute ischaemic damage and neurogenesis. We show that nNOS-PSD-95 dissociation induced by microinjection of a recombinant fusion protein Tat-nNOS-N1-133 or systemic administration of a small molecule ZL006 from days 4 to 10 after photothrombotic ischaemia in mice reduced excessive tonic inhibition in the peri-infarct cortex and ameliorated motor functional outcome...
October 20, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/29051727/syvn1-an-erad-e3-ubiquitin-ligase-is-involved-in-gabaa%C3%AE-1-degradation-associated-with-methamphetamine-induced-conditioned-place-preference
#11
Dong-Liang Jiao, Yan Chen, Yao Liu, Yun-Yue Ju, Jian-Dong Long, Jiang Du, Chang-Xi Yu, Yu-Jun Wang, Min Zhao, Jing-Gen Liu
Abuse of methamphetamine (METH), a powerful addictive amphetamine-type stimulants (ATS), is becoming a global public health problem. The gamma-aminobutyric acid (GABA)ergic system plays a critical role in METH use disorders. By using rat METH conditioned place preference (CPP) model, we previously demonstrated that METH-associated rewarding memory formation was associated with the reduction of GABAAα1 expression in the dorsal straitum (Dstr), however, the underlying mechanism was unclear. In the present study, we found that METH-induced CPP formation was accompanied by a significant increase in the expression of Synovial apoptosis inhibitor 1 (SYVN1), an endoplasmic reticulum (ER)-associated degradation (ERAD) E3 ubiquitin ligase, in the Dstr...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29048739/pharmacotherapy-for-social-anxiety-disorder-sand
#12
REVIEW
Taryn Williams, Coenraad J Hattingh, Catherine M Kariuki, Sean A Tromp, Anton J van Balkom, Jonathan C Ipser, Dan J Stein
BACKGROUND: Recognition is growing that social anxiety disorder (SAnD) is a chronic and disabling disorder, and data from early trials demonstrate that medication may be effective in its treatment. This systematic review is an update of an earlier review of pharmacotherapy of SAnD. OBJECTIVES: To assess the effects of pharmacotherapy for social anxiety disorder in adults and identify which factors (methodological or clinical) predict response to treatment. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR-Studies and CCMDCTR-References) to 17 August 2015...
October 19, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/29046924/liquid-chromatography-mass-spectrometry-with-triazole-bonded-stationary-phase-for-n-methyl-d-aspartate-receptor-related-amino-acids-development-and-application-in-microdialysis-studies
#13
Tatsuya Sakamoto, Riho Onuma, Shoko Furukawa, Akane Hayasaka, Mayu Onozato, Hiromi Nakazawa, Hideaki Iizuka, Hideaki Ichiba, Takeshi Fukushima
We aimed to monitor changes in the levels of amino acid neurotransmitters or neuromodulators simultaneously at the synaptic clefts of experimental animals. We developed a method for the simultaneous determination of the levels of amino acids, such as D-Ser, Gly, and L-Glu, which were involved in neurotransmission via the N-methyl-D-aspartate (NMDA) receptor, and other protein-constituted amino acids in a rat brain microdialysis (MD) sample. We used a liquid chromatography-mass spectrometry (LC-MS)/MS device equipped with a triazole-bonded column...
October 18, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/29035834/synergistic-effect-of-mild-hypothermia-and-the-notch-inhibitor-dapt-against-post-stroke-seizures
#14
Guo-Shuai Yang, Xiao-Yan Zhou, Xue-Fang An, Xuan-Jun Liu, Yan-Jun Zhang, Dan Yu
Seizure is a serious complication of stroke, indicating poor prognosis. Notch signaling is associated with neuronal activity. Inhibition of Notch signaling suppresses seizure activity induced by kainic acid. The present study investigated the effect of the Notch inhibitor, DAPT, alone or in combination with mild hypothermia, on post-stroke seizures. A global cerebral ischemia (GCI) model was performed in Sprague Dawley (SD) male rats. Seizure activity was evaluated by the frequency of seizure attacks, seizure severity scores, and seizure discharges...
October 13, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29023733/tonic-inhibition-of-brown-adipose-tissue-sympathetic-nerve-activity-via-muscarinic-acetylcholine-receptors-in-the-rostral-raphe-pallidus
#15
Ellen Paula Santos da Conceição, Christopher J Madden, Shaun F Morrison
We sought to determine if body temperature and energy expenditure are influenced by a cholinergic input to neurons in the rostral raphe pallidus (rRPa), the site of sympathetic premotor neurons controlling brown adipose tissue (BAT) thermogenesis. Nanoinjections of the muscarinic acetylcholine receptor (mAChR) receptor agonist, oxotremorine, or the cholinesterase inhibitor, neostigmine (NEOS), in the rRPa of anaesthetized rats decreased cold-evoked BAT sympathetic nerve activity (SNA, nadirs: -72%, and -95%), BAT temperature (TBAT, -0...
October 10, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28991462/structure-activity-relationship-pharmacological-characterization-and-molecular-modeling-of-noncompetitive-inhibitors-of-the-betaine-%C3%AE-aminobutyric-acid-transporter-1-bgt1
#16
Lars Jørgensen, Anas Al-Khawaja, Stefanie Kickinger, Stine B Vogensen, Jonas Skovgaard-Petersen, Emil Rosenthal, Nrupa Borkar, Rebekka Löffler, Karsten K Madsen, Hans Bräuner-Osborne, Arne Schousboe, Gerhard F Ecker, Petrine Wellendorph, Rasmus P Clausen
N-(1-Benzyl-4-piperidinyl)-2,4-dichlorobenzamide 5 (BPDBA) is a noncompetitive inhibitor of the betaine/GABA transporter 1 (BGT1). We here report the synthesis and structure-activity relationship of 71 analogues. We identify 26m as a more soluble 2,4-Cl substituted 3-pyridine analogue with retained BGT1 activity and an improved off-target profile compared to 5. We performed radioligand-based uptake studies at chimeric constructs between BGT1 and GAT3, experiments with site-directed mutated transporters, and computational docking in a BGT1 homology model based on the newly determined X-ray crystal structure of the human serotonin transporter (hSERT)...
October 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28928441/effects-of-anti-epileptic-drugs-on-spreading-depolarization-induced-epileptiform-activity-in-mouse-hippocampal-slices
#17
Ching-Huei Lin, Shih-Pin Hsu, Ting-Chun Cheng, Chin-Wei Huang, Yao-Chang Chiang, I-Han Hsiao, Ming-Hsueh Lee, Mei-Lin Shen, Dong Chuan Wu, Ning Zhou
Epilepsy and spreading depolarization (SD) are both episodic brain disorders and often exist together in the same individual. In CA1 pyramidal neurons of mouse hippocampal slices, induction of SD evoked epileptiform activities, including the ictal-like bursts, which occurred during the repolarizing phase of SD, and the subsequent generation of paroxysmal depolarization shifts (PDSs), which are characterized by mild depolarization plateau with overriding spikes. The duration of the ictal-like activity was correlated with both the recovery time and the depolarization potential of SD, whereas the parameters of PDSs were not significantly correlated with the parameters of SD...
September 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28900387/social-isolation-in-early-versus-late-adolescent-mice-is-associated-with-persistent-behavioral-deficits-that-can-be-improved-by-neurosteroid-based-treatment
#18
Andrea Locci, Philippe Geoffroy, Michel Miesch, Ayikoe-Guy Mensah-Nyagan, Graziano Pinna
Early trauma and stress exposure during a critical period of life may increase the risk of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) in adulthood. The first-choice treatment for MDD and PTSD are selective serotonin reuptake inhibitor (SSRI) antidepressants. Unfortunately, half of MDD and PTSD patients show resistance to the therapeutic effects of these drugs and more efficient treatments are essential. Both MDD and PTSD patients present reduced levels of allopregnanolone (Allo), a potent endogenous positive allosteric modulator of GABA action at GABAA receptors which are normalized by SSRIs in treatment responders...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28885452/microrna-mediated-downregulation-of-potassium-chloride-cotransporter-and-vesicular-%C3%AE-aminobutyric-acid-transporter-expression-in-spinal-cord-contributes-to-neonatal-cystitis-induced-visceral-pain-in-rats
#19
Jian Zhang, James Yu, Pradeep Kannampalli, Linghui Nie, Hui Meng, Bidyut K Medda, Reza Shaker, Jyoti N Sengupta, Banani Banerjee
Loss of GABAergic inhibition in pain pathways has been considered to be a key component in the development of chronic pain. In the present study, we intended to examine whether miR-92b-mediated posttranscriptional dysregulation of spinal potassium chloride cotransporter (KCC2) and vesicular γ-aminobutyric acid transporter (VGAT) plays a major role in the development and maintenance of long-term visceral hyperalgesia in neonatal zymosan-treated rats. Neonatal cystitis was induced by transurethral zymosan administration from postnatal (P) days 14 to 16 (protocol 1)...
December 2017: Pain
https://www.readbyqxmd.com/read/28881432/protein-4-1r-is-involved-in-the-transport-of-5-aminolevulinic-acid-by-interaction-with-gats-in-mef-cells
#20
Shuwei Ning, Qiaozhen Kang, Dandan Fan, Jingjing Liu, Chaoyue Xue, Xiaolin Zhang, Cong Ding, Jianying Zhang, Qian Peng, Zhenyu Ji
5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT) has been successfully used in the treatment of cancers. However, the mechanism of 5-ALA transportation into cancer cells is still not fully elucidated. Previous studies have confirmed that the efficiency of 5-ALA-PDT could be affected by the membrane skeleton protein 4.1R. In this study, we investigated the role of 4.1R in the transport of 5-ALA into cells. Wild-type (4.1R(+/+) ) and 4.1R gene knockout (4.1R(-/-) ) mouse embryonic fibroblast (MEF) cells were incubated with 1 mm 5-ALA and different concentrations of specific inhibitors of GABA transporters GAT (1-3)...
September 7, 2017: Photochemistry and Photobiology
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