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Gaba a inhibitor

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https://www.readbyqxmd.com/read/28074534/depolarizing-gaba-contributes-to-glutamatergic-network-rewiring-in-epilepsy
#1
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
#2
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
#3
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...
January 10, 2017: Glia
https://www.readbyqxmd.com/read/28066142/participation-of-central-gabaa-receptors-in-the-trigeminal-processing-of-mechanical-allodynia-in-rats
#4
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
#5
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...
January 3, 2017: Neuroscience
https://www.readbyqxmd.com/read/28057450/antiepileptic-drugs-prevent-seizures-in-hyperbaric-oxygen-a-novel-model-of-epileptiform-activity
#6
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
#7
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
#8
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
#9
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
#10
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
#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/27923157/adjuvant-neuronal-nitric-oxide-synthase-inhibition-for-combined-treatment-of-epilepsy-and-comorbid-depression
#12
Tanveer Singh, Rajesh Kumar Goel
BACKGROUND: Elevated nitric oxide (NO) levels in the brain have been apparently associated with depression in kindled animals. Owing to the major role of neuronal nitric oxide synthase (nNOS) in brain and ineffectiveness of antiepileptic drugs (AEDs) in restoring nitrosative stress, the present study was envisaged to evaluate the adjuvant nNOS inhibitor, 7-nitroindazole (7-NI) with valproic acid for combined treatment of epilepsy and associated depression. METHODS: Pentylenetetrazole kindled animals associated with depression were treated with vehicle, valproate (300mg/kg/day ip), valproate with 7-NI (10mg/kg; 20mg/kg; 40mg/kg)/day ip and 7-NI (40mg/kg/day ip) for 15days...
February 2017: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/27919211/development-of-mlr-and-svm-aided-qsar-models-to-identify-common-sar-of-gaba-uptake-herbal-inhibitors-used-in-the-treatment-of-schizophrenia
#13
Sahila Mohammed Marunnan, Babitha Pallikkara Pulikka, Anitha Jabamalairaj, Srinivas Bandaru, Mukesh Yadav, Anuraj Nayarisseri, Victor Arokia Doss
Deficits in GABAnergic system is implicated in the pathophysiology of schizophrenia. Available antipsychotics that target GABA receptor form a desirable therapeutic strategy in the treatment regimen of schizophrenia but, unfortunately, suffers serious setback due to their prolonged side effects. The present investigation focuses on developing QSAR models from the biological activity of herbal compounds and their derivatives that promise to be alternative candidates to GABA uptake inhibitors. Three sets of compounds were undertaken in the study to develop the QSAR models...
5, 2016: Current Neuropharmacology
https://www.readbyqxmd.com/read/27903293/personalized-medicine-approach-confirms-a-milder-case-of-abat-deficiency
#14
A Besse, A K Petersen, J V Hunter, V Appadurai, S R Lalani, P E Bonnen
ABAT deficiency (OMIM 613163) is a rare inborn error of metabolism caused by recessive variants in the gene 4-aminobutyric acid transaminase (ABAT), which is responsible for both the catalysis of GABA and maintenance of nucleoside pools in the mitochondria. To date, only a few patients have been reported worldwide. Their clinical presentation has been remarkably consistent with primary features of severe psychomotor retardation, encephalopathy, hypotonia, and infantile-onset refractory epilepsy. We report a new case of ABAT deficiency that marks an important departure from previous clinical findings...
December 1, 2016: Molecular Brain
https://www.readbyqxmd.com/read/27891231/a-pharmacokinetic-evaluation-and-metabolite-identification-of-the-ghb-receptor-antagonist-ncs-382-in-mouse-informs-novel-therapeutic-strategies-for-the-treatment-of-ghb-intoxication
#15
Garrett R Ainslie, K Michael Gibson, Kara R Vogel
Gamma-aminobutyric acid (GABA) is an endogenous inhibitory neurotransmitter and precursor of gamma-hydroxybutyric acid (GHB). NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzo-cyclohept-6-ylideneacetic acid), a known GHB receptor antagonist, has shown significant efficacy in a murine model of succinic semialdehyde dehydrogenase deficiency (SSADHD), a heritable neurological disorder featuring chronic elevation of GHB that blocks the final step of GABA degradation. NCS-382 exposures and elimination pathways remain unknown; therefore, the goal of the present work was to obtain in vivo pharmacokinetic data in a murine model and to identify the NCS-382 metabolites formed by mouse and human...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/27890827/adolescent-gbr12909-exposure-induces-oxidative-stress-disrupts-parvalbumin-positive-interneurons-and-leads-to-hyperactivity-and-impulsivity-in-adult-mice
#16
Asma Khan, Loek A W de Jong, Mary E Kamenski, Kerin K Higa, Jacinta D Lucero, Jared W Young, M Margarita Behrens, Susan B Powell
The adolescent period in mammals is a critical period of brain maturation and thus represents a time of susceptibility to environmental insult, e.g. psychosocial stress and/or drugs of abuse, which may cause lasting impairments in brain function and behavior and even precipitate symptoms in at-risk individuals. One likely effect of these environmental insults is to increase oxidative stress in the developing adolescent brain. Indeed, there is increasing evidence that redox dysregulation plays an important role in the development of schizophrenia and other neuropsychiatric disorders and that GABA interneurons are particularly susceptible to alterations in oxidative stress...
November 24, 2016: Neuroscience
https://www.readbyqxmd.com/read/27851770/direct-stimulation-of-islet-insulin-secretion-by-glycolytic-and-mitochondrial-metabolites-in-kcl-depolarized-islets
#17
Javier Pizarro-Delgado, Jude T Deeney, Barbara E Corkey, Jorge Tamarit-Rodriguez
We have previously demonstrated that islet depolarization with 70 mM KCl opens Cx36 hemichannels and allows diffusion of small metabolites and cofactors through the β-cell plasma membrane. We have investigated in this islet "permeabilized" model whether glycolytic and citric acid cycle intermediates stimulate insulin secretion and how it correlates with ATP production (islet content plus extracellular nucleotide accumulation). Glycolytic intermediates (10 mM) stimulated insulin secretion and ATP production similarly...
2016: PloS One
https://www.readbyqxmd.com/read/27843587/life-threatening-colitis-and-complete-response-with-ipilimumab-in-a-patient-with-metastatic-braf-mutant-melanoma-and-rheumatoid-arthritis
#18
Francisco Aya, Lydia Gaba, Ivan Victoria, Aranzazu Fernandez-Martinez, Virginia Ruiz-Esquide, Estela Pineda, Monica Tosca, Margarita Viladot, Veronica Pereira, Josep Malvehy, Aleix Prat, Ana Arance
Immune checkpoint inhibitors, such as ipilimumab (an anti-CTLA4 antibody), have become a commonly used therapy in cancer. To date, safety data of patients with underlying autoimmune disease is limited. We present a case of a patient with rheumatoid arthritis who was diagnosed of a BRAF-mutant metastatic melanoma. The patient was treated with ipilimumab and presented with high-grade colitis requiring immunosuppressors. Despite of the immune-related adverse event, no exacerbation of the rheumatoid arthritis was observed and the patient achieved a complete response...
2016: ESMO Open
https://www.readbyqxmd.com/read/27834131/recent-highlights-on-molecular-hybrids-potentially-useful-in-central-nervous-system-disorders
#19
Mariana Matias, Samuel Silvestre, Amílcar Falcão, Gilberto Alves
Molecular hybridization is a recent strategy based in the covalent fusion of two or more existing pharmacophores to create a single molecule with multiple mechanisms of action, which represents an encouraging approach in the development of new drugs with potential therapeutic application in several pathologies. This review provides a comprehensive perspective of the most relevant advances in the development of hybrid molecules acting in the central nervous system. For instance, several opioid hybrids based on endogenous opioid peptides, such as enkephalins, deltorphin and endomorphin, have been developed and γ-aminobutyric acid (GABA) agonists have also been designed for neuropathic pain control...
November 11, 2016: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/27827370/ethanol-sensitive-pacemaker-neurons-in-the-mouse-external-globus-pallidus
#20
Karina P Abrahao, Jessica H Chancey, C Savio Chan, David M Lovinger
Although ethanol is one of the most widely used drugs, we still lack a full understanding of which neuronal subtypes are affected by this drug. Pacemaker neurons exert powerful control over brain circuit function, but little is known about ethanol effects on these types of neurons. Neurons in the external globus pallidus (GPe) generate pacemaker activity that controls basal ganglia, circuitry associated with habitual and compulsive drug use. We performed patch-clamp recordings from GPe neurons and found that bath application of ethanol dose-dependently decreased the firing rate of low-frequency GPe neurons, but did not alter the firing of high-frequency neurons...
December 14, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
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