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Gaba a inhibitor

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https://www.readbyqxmd.com/read/28225041/pvn-blockade-of-p44-42-mapk-pathway-attenuates-salt-induced-hypertension-through-modulating-neurotransmitters-and-attenuating-oxidative-stress
#1
Hong-Li Gao, Xiao-Jing Yu, Kai-Li Liu, Xiao-Lian Shi, Jie Qi, Yan-Mei Chen, Yan Zhang, Juan Bai, Qiu-Yue Yi, Zhi-Peng Feng, Wen-Sheng Chen, Wei Cui, Jin-Jun Liu, Guo-Qing Zhu, Yu-Ming Kang
The imbalance of neurotransmitters and excessive oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether blockade of p44/42 MAPK pathway in the hypothalamic paraventricular nucleus (PVN) ameliorates the development of hypertension through modulating neurotransmitters and attenuating oxidative stress. Dahl salt-sensitive (S) rats received a high-salt diet (HS, 8% NaCl) or a normal-salt diet (NS, 0.3% NaCl) for 6 weeks and were treated with bilateral PVN infusion of PD-98059 (0...
February 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28192175/increased-anxiety-like-phenotype-in-female-guinea-pigs-following-reduced-neurosteroid-exposure-in-utero
#2
Angela L Cumberland, Hannah K Palliser, Gabrielle K Crombie, David W Walker, Jonathan J Hirst
Neurosteroids are essential for aiding proper fetal neurodevelopment. Pregnancy compromises such as preterm birth, prenatal stress and intrauterine growth restriction are associated with an increased risk of developing behavioural and mood disorders, particularly during adolescence. These pathologies involve the premature loss or alteration of trophic steroid hormones reaching the fetus leading to impaired neurodevelopment. While the specific programming mechanisms are yet to be fully elucidated, in adult life, dysfunctions of allopregnanolone action are prevalent in individuals with depression, post-traumatic stress disorder and anxiety disorders...
February 9, 2017: International Journal of Developmental Neuroscience
https://www.readbyqxmd.com/read/28176016/choline-induces-opposite-changes-in-pyramidal-neuron-excitability-and-synaptic-transmission-through-a-nicotinic-receptor-independent-process-in-hippocampal-slices
#3
E Albiñana, J G Luengo, A M Baraibar, M D Muñoz, L Gandía, J M Solís, J M Hernández-Guijo
Choline is present at cholinergic synapses as a product of acetylcholine degradation. In addition, it is considered a selective agonist for α5 and α7 nicotinic acetylcholine receptors (nAChRs). In this study, we determined how choline affects action potentials and excitatory synaptic transmission using extracellular and intracellular recording techniques in CA1 area of hippocampal slices obtained from both mice and rats. Choline caused a reversible depression of evoked field excitatory postsynaptic potentials (fEPSPs) in a concentration-dependent manner that was not affected by α7 nAChR antagonists...
February 8, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28153485/loop-f-of-the-%C3%AE-subunit-determines-the-pharmacologic-profile-of-novel-competitive-inhibitors-of-gabaa-receptors
#4
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/28137424/pr-independent-neurosteroid-regulation-of-%C3%AE-2-gaba-a-receptors-mrna-in-the-hippocampus-subfields
#5
Doodipala Samba Reddy, Omkaram Gangisetty, Xin Wu
Progesterone (P) binding to the intracellular progesterone receptors (PRs) plays a key role in epilepsy via modulation of GABA-A receptor plasticity in the brain. This is thought to occur via conversion of P to neurosteroids such as allopregnanolone, an allosteric modulator of GABA-A receptors. In the female brain, the composition of GABA-A receptors is not static and undergoes dynamic spatial changes in response to fluctuations in P and neurosteroid levels. Synaptic α2-containing GABA-A receptors contribute to phasic neuronal excitability and seizure susceptibility...
January 27, 2017: Brain Research
https://www.readbyqxmd.com/read/28129110/correcting-mir92a-vgat-mediated-gabaergic-dysfunctions-rescues-human-tau-induced-anxiety-in-mice
#6
Xiaoguang Li, Zhihao Wang, Lu Tan, Yali Wang, Chengbiao Lu, Rongxiang Chen, Shujuan Zhang, Yuan Gao, Yanchao Liu, Yaling Yin, Xinghua Liu, Enjie Liu, Ying Yang, Yu Hu, Zhipeng Xu, Fuqiang Xu, Jie Wang, Gong-Ping Liu, Jian-Zhi Wang
Patients with Alzheimer's disease (AD) commonly show anxiety behaviors, but the molecular mechanisms are not clear and no efficient intervention exists. Here, we found that overexpression of human wild-type, full-length tau (termed htau) in hippocampus significantly decreased the extracellular γ-aminobutyric acid (GABA) level with inhibition of γ oscillation and the evoked inhibitory postsynaptic potential (eIPSP). With tau accumulation, the mice show age-dependent anxiety behaviors. Among the factors responsible for GABA synthesis, release, uptake, and transport, we found that accumulation of htau selectively suppressed expression of the intracellular vesicular GABA transporter (vGAT)...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28126740/unique-substrate-specificity-of-ornithine-aminotransferase-from-toxoplasma-gondii
#7
Alessandra Astegno, Elena Maresi, Mariarita Bertoldi, Valentina La Verde, Alessandro Paiardini, Paola Dominici
Toxoplasma gondii is a protozoan parasite of medical and veterinary relevance responsible for toxoplasmosis in humans. As an efficacious vaccine remains a challenge, chemotherapy is still the most effective way to combat the disease. In search for novel druggable targets, herein we performed a thorough characterization of the putative pyridoxal 5'-phosphate (PLP)-dependent enzyme ornithine aminotransferase from T. gondii ME49 (TgOAT). We overexpressed the protein in E. coli and analyzed its molecular and kinetic properties by UV-visible absorbance, fluorescence, and CD spectroscopy, in addition to kinetic studies of both the steady state and pre-steady state...
January 26, 2017: Biochemical Journal
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
#8
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
#9
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/28074534/depolarizing-gaba-contributes-to-glutamatergic-network-rewiring-in-epilepsy
#10
Nazim Kourdougli, Christophe Pellegrino, Juho-Matti Renko, Stanislav Khirug, Geneviève Chazal, Tiina-Kaisa Kukko-Lukjanov, Sari E Lauri, Jean-Luc Gaiarsa, Liang Zhou, Angélique Peret, Eero Castrén, Raimo Kalevi Tuominen, Valérie Crépel, Claudio Rivera
OBJECTIVE: Rewiring of excitatory glutamatergic neuronal circuits is a major abnormality in epilepsy. Besides the rewiring of excitatory circuit, an abnormal depolarizing GABAergic drive has been hypothesized to participate in the epileptogenic processes. However, a remaining clinically relevant question is whether early post Status Epilepticus (SE) evoked chloride dysregulation is important for the remodeling of aberrant glutamatergic neuronal circuit. METHODS: Osmotic mini-pumps were used to infuse intracerebrally a specific inhibitor of depolarizing GABAergic transmission as well as a functionally blocking antibody towards the pan-neurotrophin receptor p75 (p75(NTR) )...
January 11, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28072455/src-and-phospho-fak-kinases-are-activated-by-allopregnanolone-promoting-schwann-cells-motility-morphology-and-myelination
#11
Simona Melfi, Maria Magdalena Montt Guevara, Veronica Bonalume, Massimiliano Ruscica, Alessandra Colciago, Tommaso Simoncini, Valerio Magnaghi
Schwann cells' (SCs) development and maturation require coordinate and complementary interaction among several signals and intracellular pathways. Among factors controlling these processes, the signalling intermediates Src tyrosine kinase and focal adhesion kinase (FAK) are relevant for SCs' fate, participating in regulation of SC adhesion, motility and migration. Recently, the progesterone metabolite allopregnanolone (ALLO) was proved to be synthesized by SCs, whereas it acts autocrinally on SC motility and proliferation, which are crucial processes for nerve development, maturation and regeneration...
January 10, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28071826/gat-1-mediated-gaba-uptake-in-rat-oligodendrocytes
#12
Giorgia Fattorini, Marcello Melone, María Victoria Sánchez-Gómez, Rogelio O Arellano, Silvia Bassi, Carlos Matute, Fiorenzo Conti
Stimulated by the results of a recent paper on the effects of tiagabine, a selective inhibitor of the main GABA transporter GAT-1, on oligodendrogenesis, we verified the possibility that GAT-1 may be expressed in oligodendrocytes using immunocytochemical methods and functional assays. Light microscopic analysis of the subcortical white matter of all animals revealed the presence of numerous GAT-1+ cells of different size (from 3 to 29 µm) and morphology. An electron microscope analysis revealed that, besides fibrous astrocytes and interstitial neurons, GAT-1 immunoreactivity was present in immature and mature oligodendrocytes...
March 2017: Glia
https://www.readbyqxmd.com/read/28066142/participation-of-central-gabaa-receptors-in-the-trigeminal-processing-of-mechanical-allodynia-in-rats
#13
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/28057537/the-chloride-co-transporters-nkcc1-and-kcc2-in-experimental-autoimmune-encephalomyelitis-eae
#14
Muhammad Saad Yousuf, Kasia Zubkow, Gustavo Tenorio, Bradley Kerr
Patients with multiple sclerosis (MS) often complain of neuropathic pain. According to the Gate Control Theory of Pain, spinal networks of GABAergic inhibitory interneurons are important in modulating nociceptive inputs from the periphery. Na+-K+-2Cl- co-transporter 1 (NKCC1) and K+-Cl- co-transporter 2 (KCC2) generally dictate the tone of GABA/glycine inhibition by regulating intracellular chloride concentrations. In this study, we investigated the role of NKCC1 and KCC2 in neuropathic pain observed in the animal model, experimental autoimmune encephalomyelitis (EAE), a commonly used model to study the pathophysiology of MS...
March 6, 2017: Neuroscience
https://www.readbyqxmd.com/read/28057450/antiepileptic-drugs-prevent-seizures-in-hyperbaric-oxygen-a-novel-model-of-epileptiform-activity
#15
Ivan T Demchenko, Sergei Yu Zhilyaev, Alexander N Moskvin, Alexander I Krivchenko, Claude A Piantadosi, Barry W Allen
Breathing oxygen at sufficiently elevated pressures can trigger epileptiform seizures. Therefore, we tested the hypothesis that pre-treatment with FDA-approved antiepileptic drugs could prevent seizure onset in hyperoxia at 5 atmospheres absolute. We selected drugs from two putative functional categories, Na(+)-channel antagonists and GABA enhancers, each administered intraperitoneally at four doses in separate groups of C57BL/6 mice. The drugs varied in efficacy at the doses used. Of the five tested Na(+)-channel antagonists, carbamazepine and lamotrigine more than tripled seizure latency compared to values seen in vehicle controls...
January 2, 2017: Brain Research
https://www.readbyqxmd.com/read/28053242/nitric-oxide-promotes-gaba-release-by-activating-a-voltage-independent-ca2-influx-pathway-in-retinal-amacrine-cells
#16
John Wesley Maddox, Evanna L Gleason
Retinal amacrine cells express nitric oxide synthase and produce nitric oxide (NO), making NO available to regulate the function of amacrine cells. Here, we test the hypothesis that NO can alter the GABAergic synaptic output of amacrine cells. We investigate this using whole-cell voltage clamp recordings and Ca(2+) imaging of cultured chick retinal amacrine cells. When recording from amacrine cells receiving synaptic input from other amacrine cells, we find that NO increases GABAergic spontaneous postsynaptic current (sPSC) frequency...
January 4, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28019695/determination-of-enantiomeric-excess-of-nipecotic-acid-as-1-7-nitrobenzo-c-1-2-5-oxadiazol-4-yl-derivatives
#17
Simone K Schmidt, Georg Höfner, Klaus T Wanner
For the enantiopure synthesis of novel chiral GABA uptake inhibitors, nipecotic acid (1) is an important key precursor. To characterize accurately the pharmacological activity of these interesting target compounds, the determination of the correct enantiomeric purity of nipecotic acid as the starting material is indispensable. In this report, a sensitive high-performance liquid chromatography (HPLC) based method for the separation and quantitation of both enantiomers of nipecotic acid as 1-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl) derivatives (5) on a Chiralpak ID-3 column (Daicel, Illkirch, France) was established...
December 26, 2016: Chirality
https://www.readbyqxmd.com/read/27994987/preventative-and-therapeutic-effects-of-a-gaba-transporter-1-inhibitor-administered-systemically-in-a-mouse-model-of-paclitaxel-induced-neuropathic-pain
#18
Willias Masocha, Subramanian S Parvathy
BACKGROUND: There is a dearth of drugs to manage a dose-limiting painful peripheral neuropathy induced by paclitaxel in some patients during the treatment of cancer. Gamma-aminobutyric acid transporter-1 (GAT-1) whose expression is increased in the brain and spinal cord during paclitaxel-induced neuropathic pain (PINP) might be a potential therapeutic target for managing PINP. Thus, our aim was to evaluate if systemic administration of a GAT-1 inhibitor ameliorates PINP. METHODS: The reaction latency to thermal stimuli (hot plate test; at 55 °C) and cold stimuli (cold plate test; at 4 °C) of female BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel, its vehicle, and/or a selective GAT-1 inhibitor NO-711...
2016: PeerJ
https://www.readbyqxmd.com/read/27956036/effects-of-new-fluorinated-analogues-of-gaba-pregabalin-bioisosters-on-the-ambient-level-and-exocytotic-release-of-3-h-gaba-from-rat-brain-nerve-terminals
#19
T Borisova, N Pozdnyakova, E Shaitanova, I Gerus, M Dudarenko, G Haufe, V Kukhar
Recently, we have shown that new fluorinated analogues of γ-aminobutyric acid (GABA), bioisosters of pregabalin (β-i-Bu-GABA), i.e. β-polyfluoroalkyl-GABAs (FGABAs), with substituents: β-CF3-β-OH (1), β-CF3 (2); β-CF2CF2H (3), are able to increase the initial rate of [(3)H]GABA uptake by isolated rat brain nerve terminals (synaptosomes), and this effect is higher than that of pregabalin. So, synthesized FGABAs are structural but not functional analogues of GABA. Herein, we assessed the effects of synthesized FGABAs (100μM) on the ambient level and exocytotic release of [(3)H]GABA in nerve terminals and compared with those of pregabalin (100μM)...
January 15, 2017: Bioorganic & Medicinal Chemistry
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
#20
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
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