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Gaba a inhibitor

Alexandra R Sowa, Allen F Brooks, Xia Shao, Bradford D Henderson, Phillip S Sherman, Janna Arteaga, Jenelle Stauff, Adam C Lee, Robert A Koeppe, Peter J H Scott, Michael R Kilbourn
In vivo PET imaging of the γ-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radioligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure-activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril® ) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter...
May 15, 2018: ACS Chemical Neuroscience
Lisbeth Kristensson, Anders Lundin, David Gustafsson, Jan Fryklund, Tomas Fex, Delsing Louise, Erik Ryberg
Plasminogen binding inhibitors (PBIs) reduce the risk of bleeding in hemorrhagic conditions. However, generic PBIs are also associated with an increased risk of seizures, an adverse effect linked to unwanted activities towards inhibitory neuronal receptors. Development of novel PBIs serve to remove compounds with such properties, but progress is limited by a lack of higher throughput methods with human translatability. Herein we apply human induced pluripotent stem cell (hiPSC) derived neurons in combination with dynamic mass redistribution (DMR) technology to demonstrate robust and reproducible modulation of both GABAA and glycine receptors...
May 11, 2018: Neuroscience Letters
Antonia Serrano, Francisco J Pavon, Matthew W Buczynski, Joel Schlosburg, Luis A Natividad, Ilham Y Polis, David G Stouffer, Eric P Zorrilla, Marisa Roberto, Benjamin F Cravatt, Rémi Martin-Fardon, Fernando Rodriguez de Fonseca, Loren H Parsons
Negative emotional states that are associated with excessive alcohol intake, particularly anxiety-like states, have been linked to opponent processes in the central nucleus of the amygdala (CeA), affecting stress-related transmitters and monoamines. This study extends these observations to include endocannabinoid signaling in alcohol-dependent animals. Rats and mice were exposed to chronic intermittent alcohol with vapor inhalation or liquid diet to induce dependence. In vivo microdialysis was used to estimate interstitial concentrations of endocannabinoids [N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG)] and amino acids (glutamate and GABA) in rat CeA...
April 5, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Gustavo Roberto Villas Boas, Ana Paula Stefanello da Silveira, Brunna Charlla Feitosa Farinelli, Claudia Andréa Lima Cardoso, Emely Arce, Silvia Aparecida Oesterreich
OBJECTIVES: Campomanesia pubescens (DC) O.BERG (Myrtaceae) fruits contain high levels of flavonoids and are widely consumed by the South American population. In the central nervous system (CNS), some flavonoids act as modulators of GABA-A receptors and monoamine oxidase inhibitors, resulting in anxiolytic antidepressants effects, respectively. The objective of the present study was to evaluate the anxiolytic and antidepressant effects of ethanolic extract of C. pubescens fruits (EEFCP) in rats...
May 1, 2018: Nutritional Neuroscience
Qinhu Wang, Daipeng Chen, Mengchun Wu, Jindong Zhu, Cong Jiang, Jin-Rong Xu, Huiquan Liu
Trichothecene mycotoxins, such as deoxynivalenol (DON) produced by the fungal pathogen, Fusarium graminearum , are not only important for plant infection but are also harmful to human and animal health. Trichothecene targets the ribosomal protein Rpl3 that is conserved in eukaryotes. Hence, a self-defense mechanism must exist in DON-producing fungi. It is reported that TRI (trichothecene biosynthesis) 101 and TRI12 are two genes responsible for self-defense against trichothecene toxins in Fusarium . In this study, however, we found that simultaneous disruption of TRI101 and TRI12 has no obvious influence on DON resistance upon exogenous DON treatment in F...
2018: Frontiers in Plant Science
Ling-Ling Zhen, Bei Miao, Ying-Ying Chen, Zhen Su, Man-Qiu Xu, Sujuan Fei, Jianfu Zhang
AIMS: We investigated the effects of chemical stimulation of cerebellum fastigial nucleus (FN) on the chronic visceral hypersensitivity (CVH) and its possible mechanism in rats. MAIN METHODS: We stimulated the FN by microinjecting glutamate into the FN, in order to explore whether the cerebellum fastigial nucleus played a role on CVH in rat. The model of CVH was established by colorectal distension (CRD) in neonatal rats. Abdominal withdrawal reflex (AWR) scores, pain threshold, and amplitude of electromyography (EMG) were used to assess the hyperalgesia...
April 25, 2018: Life Sciences
Bulut Hamali, Sandra Pichler, Elisabeth Wischnitzki, Klaus Schicker, Melanie Burger, Marion Holy, Kathrin Jaentsch, Martina Molin, Eva Maria Sehr, Oliver Kudlacek, Michael Freissmuth
The parasitic liver fluke Fasciola hepatica infests mainly ruminants, but it can also cause fasciolosis in people, who ingest the metacercariae encysted on plants. The drug of choice to treat fasciolosis is triclabendazole (TBZ), which has been on the market for several decades. This is also true for the other available drugs. Accordingly, drug-resistant flukes have been emerging at an increasing rate making it desirable to identify alternative drug targets. Here, we focused on the fact that adult F. hepatica persists in the hostile environment of the bile ducts of infected organisms...
April 27, 2018: PLoS Neglected Tropical Diseases
Ning Li, Jiale Liu, Mengyang Wang, Zepeng Yu, Kuo Zhu, Jiaqi Gao, Chunmei Wang, Jinghui Sun, Jianguang Chen, He Li
Schisandrin B (SchB) is an active lignan component from Schisandra chinensis Turcz. Baill that has been long used as Traditional Chinese Medical Herb in the prescriptions for "tranquilizing the mind and overcoming anxiety". Given that SchB is one of the most abundant ingredients of Schisandra chinensis Baill, we examined the sedative and hypnotic effects of SchB and explored the underlying mechanism. The results showed that SchB can significantly decrease mouse locomotor activities and improved sleeping quality index, including increased number of sleeping mice treated with the subthreshold dose of pentobarbital sodium, increased sleep time, shortened sleep latency and prolonged sleep duration...
April 17, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Marwa Y Sallam, Sahar M El-Gowilly, Abdel-Galil A Abdel-Galil, Mahmoud M El-Mas
We have previously shown that cyclosporine (CSA) counteracts cardiovascular manifestations induced by endotoxemia (lipopolysaccharide, LPS) such as hypotension and cardiac autonomic dysfunction in conscious rats. In this study we investigated whether the facilitation of central γ-amino butyric acid (GABA) neurotransmission blunts these favorable influences of CSA. The LPS-CSA interaction was determined in the absence and presence of drugs that activate GABAA or GABAB receptors or elevate synaptic GABA levels in the central nervous system...
April 18, 2018: Fundamental & Clinical Pharmacology
Nirja Chaudhari, Mitali Dawalbhakta, Laxmipriya Nampoothiri
BACKGROUND: GnRH is the master molecule of reproduction that is influenced by several intrinsic and extrinsic factors such as neurotransmitters and neuropeptides. Any alteration in these regulatory loops may result in reproductive-endocrine dysfunction such as the polycystic ovarian syndrome (PCOS). Although low dopaminergic tone has been associated with PCOS, the role of neurotransmitters in PCOS remains unknown. The present study was therefore aimed at understanding the status of GnRH regulatory neurotransmitters to decipher the neuroendocrine pathology in PCOS...
April 11, 2018: Reproductive Biology and Endocrinology: RB&E
Gabriele Ruffolo, Carlo Di Bonaventura, Pierangelo Cifelli, Cristina Roseti, Jinane Fattouch, Alessandra Morano, Cristina Limatola, Eleonora Aronica, Eleonora Palma, Anna Teresa Giallonardo
Epilepsy is one of the most common chronic neurological diseases, and its pharmacological treatment holds great importance for both physicians and national authorities, especially considering the high proportion of drug-resistant patients (about 30%). Lacosamide (LCM) is an effective and well-tolerated new-generation antiepileptic drug (AED), currently licensed as add-on therapy for partial-onset seizures. However, LCM mechanism of action is still a matter of debate, although its effect on the voltage sensitive sodium channels is by far the most recognized...
April 2, 2018: Neurobiology of Disease
Sebahattin Karabulut, Ruslan Bayramov, Keziban Korkmaz Bayramov, Ahmet K Filiz, Ahmet S Taskiran, Ercan Ozdemir
Absence epilepsy is a generalized nonconvulsive type of epilepsy that is characterized by spike-wave discharges (SWD) with a frequency of 2.5-4 Hz in the EEG. The activation of the GABAergic system in central nervous system suppresses convulsive seizures but exacerbates absence seizures. Endogenous neuroactive steroids such as 3α-hydroxy-5α-pregnan-20-one (3α,5α-THPROG; allopregnanolone) and 3α,21-dihydroxy-5α-pregnan-20-one (3α,5α-THDOC, allotetrahydrodeoxycorticosteron) are GABA-A receptor-positive allosteric modulators...
March 2018: General Physiology and Biophysics
Ming-Xia Song, Zhen-Yuan Wang, Shi-Hui He, Sheng-Wang Yu, Shi-Long Chen, Dong-Fu Guo, Wen-Hao Zhao, Xian-Qing Deng
In this study, a novel series of 4-(2-(alkylthio)benzo[ d ]oxazol-5-yl)-2,4-dihydro-3 H -1,2,4-triazol-3-ones ( 4a - m ) was designed and synthesized. The anticonvulsant activities of these compounds were evaluated by using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. The neurotoxicity of these compounds was evaluated using the rotarod neurotoxicity test. The majority of compounds showed anti-MES activities at 100 or 300 mg/kg. Compound 4g was considered to be the most promising, based on its potency against MES- and PTZ-induced seizures with ED50 values of 23...
March 25, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Richard B Silverman
When the brain concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) diminishes below a threshold level, the excess neuronal excitation can lead to convulsions. This imbalance in neurotransmission can be corrected by inhibition of the enzyme γ-aminobutyric acid aminotransferase (GABA-AT), which catalyzes the conversion of GABA to the excitatory neurotransmitter l-glutamic acid. It also has been found that raising GABA levels can antagonize the rapid elevation and release of dopamine in the nucleus accumbens, which is responsible for the reward response in addiction...
March 23, 2018: Chemical Reviews
Meng-Yi Xu, Albert H C Wong
Schizophrenia is considered primarily as a cognitive disorder. However, functional outcomes in schizophrenia are limited by the lack of effective pharmacological and psychosocial interventions for cognitive impairment. GABA (gamma-aminobutyric acid) interneurons are the main inhibitory neurons in the central nervous system (CNS), and they play a critical role in a variety of pathophysiological processes including modulation of cortical and hippocampal neural circuitry and activity, cognitive function-related neural oscillations (eg, gamma oscillations) and information integration and processing...
March 22, 2018: Acta Pharmacologica Sinica
Alan L Pehrson, Christian S Pedersen, Kirstine Sloth Tølbøl, Connie Sanchez
Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine's effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected vortioxetine's cognitive effects to those on GABA and glutamate neurotransmission...
2018: Frontiers in Pharmacology
C A Wotton, E F Quon, A C Palmer, L K Bekar
Both serotonin (5-HT) and stress exert changes in cortical inhibitory tone to shape the activity of cortical networks. Because astrocytes are also known to affect inhibition through established purinergic pathways, we assessed the role of GABA and purinergic pathways with respect to the effects of rapid corticosterone (CORT) and 5-HT on cortical inhibition. We used a paired-pulse paradigm (P1 and P2) in acutely isolated mouse brain slices to evaluate changes in cortical evoked inhibition. Normally, 5-HT decreases the amplitude of the first pulse P1, whereas it increases the amplitude of P2 (increasing frequency transmission)...
April 2018: Journal of Neuroendocrinology
Alexander J Riordan, Ari W Schaler, Jenny Fried, Tracie A Paine, Janice E Thornton
The cognitive symptoms of schizophrenia are poorly understood and difficult to treat. Estrogens may mitigate these symptoms via unknown mechanisms. To examine these mechanisms, we tested whether increasing estradiol (E) or decreasing luteinizing hormone (LH) could mitigate short-term episodic memory loss in a phencyclidine (PCP) model of schizophrenia. We then assessed whether changes in cortical or hippocampal GABA may underlie these effects. Female rats were ovariectomized and injected subchronically with PCP...
May 2018: Psychoneuroendocrinology
John Peyton Bohnsack, Benjamin A Hughes, Todd K O'Buckley, Kamyra Edokpolor, Joyce Besheer, A Leslie Morrow
Alcohol use disorders are chronic debilitating diseases characterized by severe withdrawal symptoms that contribute to morbidity and relapse. GABAA receptor (GABAA R) adaptations have long been implicated in the chronic effects of alcohol and contribute to many withdrawal symptoms associated with alcohol dependence. In rodents, GABAA R hypofunction results from decreases in Gabra1 expression, although the underlying mechanism controlling Gabra1 expression after chronic ethanol exposure is still unknown. We found that chronic ethanol exposure using either ethanol gavage or two-bottle choice voluntary access paradigms decreased Gabra1 expression and increased Hdac2 and Hdac3 expression...
June 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Kyle J Brymer, Erin Y Fenton, Lisa E Kalynchuk, Hector J Caruncho
Depression is a serious psychiatric disorder frequently comorbid with autoimmune disorders. Previous work in our lab has demonstrated that repeated corticosterone (CORT) injections in rats reliably increase depressive-like behavior, impair hippocampal-dependent memory, reduce the number and complexity of adult-generated neurons in the dentate gyrus, decrease hippocampal reelin expression, and alter markers of GABAergic function. We hypothesized that peripheral injections of the TNF-α inhibitor etanercept could exert antidepressant effects through a restoration of many of these neurobiological changes...
2018: Frontiers in Pharmacology
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