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https://www.readbyqxmd.com/read/29453777/intramuscular-allopregnanolone-and-ganaxolone-in-a-mouse-model-of-treatment-resistant-status-epilepticus
#1
Dorota Zolkowska, Chun-Yi Wu, Michael A Rogawski
Allopregnanolone (5α-pregnan-3α-ol-20-one) and its synthetic 3β-methyl analog, ganaxolone, are positive allosteric modulators of synaptic and extrasynaptic γ-aminobutyric acid (GABA) A receptors that exhibit antiseizure activity in diverse animal seizure models, including models of status epilepticus (SE). The 2 neuroactive steroids are being investigated as treatments for SE, including as a treatment for SE induced by chemical threat agents. Intramuscular injection is the preferred route of administration in the prehospital treatment of SE...
February 17, 2018: Epilepsia
https://www.readbyqxmd.com/read/29451785/structure-function-evaluation-of-imidazopyridine-derivatives-selective-for-%C3%AE-subunit-containing-%C3%AE-aminobutyric-acid-type-a-gaba-a-receptors
#2
Kirsten Yakoub, Sascha Jung, Christian Sattler, Helen Damerow, Judith Weber, Annika Kretzschmann, Aylin S Cankaya, Markus Piel, Frank Rösch, Anne S Haugaard, Bente Frølund, Tanja Schirmeister, Hartmut Lüddens
Delta selective compounds 1 and 2 (DS1, compound 22; DS2, compound 16) were introduced as functionally selective modulators of δ-containing GABA receptors type A (GABAAR). In our hands [ 3 H]EBOB binding experiments with recombinant GABA A R using compound 22, showed no proof of δ-selectivity, though a minimally higher preference with respect to potency for α4β3δ and α6β2/3δ receptors. In order to delineate the structural determinant for δ-preference, we synthesized 25 derivatives of DS1 and DS2, and investigated their structure-activity relationship (SAR)...
February 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29447952/insulin-enhances-gaba-a-receptor-mediated-inhibitory-currents-in-rat-central-amygdala-neurons
#3
Sergiy V Korol, Atieh Tafreshiha, Amol K Bhandage, Bryndis Birnir, Zhe Jin
Insulin, a pancreatic hormone, can access the central nervous system, activate insulin receptors distributed in selective brain regions and affect various cellular functions such as neurotransmission. We have previously shown that physiologically relevant concentration of insulin potentiates the GABA A receptor-mediated tonic inhibition and reduces excitability of rat hippocampal CA1 neurons. The central nucleus of the amygdala (CeA) comprises heterogeneous neuronal populations that can respond to hormonal stimulus...
February 12, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29447845/probing-gaba-a-receptors-with-inhibitory-neurosteroids
#4
REVIEW
Sandra Seljeset, Damian P Bright, Philip Thomas, Trevor G Smart
γ-aminobutyric acid type A receptors (GABA A Rs) are important components of the central nervous system and they are functionally tasked with controlling neuronal excitability. These receptors are subject to post-translational modification and also to modulation by endogenous regulators, such as the neurosteroids. These modulators can either potentiate or inhibit GABA A R function. Whilst the former class of neurosteroids are considered to bind to and act from the transmembrane domain of the receptor, the domains that are important for the inhibitory neurosteroids remain less clear...
February 12, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29446159/arginine-vasopressin-differentially-modulates-gabaergic-synaptic-transmission-onto-temperature-sensitive-and-insensitive-neurons-in-the-rat-preoptic-area
#5
Yu Tang, Yan-Ni Sun, Run Xu, Xiao Huang, Shuang Gu, Cheng-Cheng Hong, Mi-Jia Liu, Heng Jiang, Yong-Lu Yang, Jing Shi
The preoptic area (POA) of the hypothalamus, containing temperature-sensitive and -insensitive neurons, plays a key role in specific thermoregulatory responses. Although arginine vasopressin (AVP) has been shown to induce hypothermia by increasing the firing activities of warm-sensitive neurons and decreasing those of cold-sensitive and temperature-insensitive neurons, the effects of AVP on POA GABAergic transmission remain unknown. Herein, inhibitory postsynaptic currents (IPSCs) of temperature-sensitive and temperature-insensitive neurons in POA slices were recorded using whole-cell patch clamp...
February 15, 2018: European Journal of Neuroscience
https://www.readbyqxmd.com/read/29445327/missense-gamma-aminobutyric-acid-receptor-polymorphisms-are-associated-with-reaction-time-motor-time-and-ethanol-effects-in-vivo
#6
Elena García-Martín, María I Ramos, José A Cornejo-García, Segismundo Galván, James R Perkins, Laura Rodríguez-Santos, Hortensia Alonso-Navarro, Félix J Jiménez-Jiménez, José A G Agúndez
Background: The Gamma-aminobutyric acid type A receptor (GABA-A receptor) is affected by ethanol concentrations equivalent to those reached during social drinking. At these concentrations, ethanol usually causes impairment in reaction and motor times in most, but not all, individuals. Objectives: To study the effect of GABA-A receptor variability in motor and reaction times, and the effect of low ethanol doses. Methods: Two hundred and fifty healthy subjects received one single dose of 0.5 g/Kg ethanol per os ...
2018: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29439087/high-constitutive-activity-accounts-for-the-combination-of-enhanced-direct-activation-and-reduced-potentiation-in-mutated-gabaa-receptors
#7
Allison Germann, Daniel Shin, Christina Kuhrau, Alexander Johnson, Alex S Evers, Gustav Akk
GABAA receptors activated by the transmitter GABA are potentiated by several allosterically acting drugs including the intravenous anesthetic propofol. Propofol can also directly activate the receptor, albeit at higher concentrations. Previous functional studies have identified amino acid residues whose substitution reduces potentiation of GABA-activated receptors by propofol while enhancing the ability of propofol to directly activate the receptor. One interpretation of such observations is that the mutation has specific effects on the sites or processes involved in potentiation or activation...
February 8, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29431797/sustained-consumption-of-cocoa-based-dark-chocolate-enhances-seizure-like-events-in-the-mouse-hippocampus
#8
Ana Cicvaric, Tanja Bulat, Daniel Bormann, Jiaye Yang, Bastian Auer, Ivan Milenkovic, Maureen Cabatic, Radoslav Milicevic, Francisco J Monje
While the consumption of caffeine and cocoa has been associated with a variety of health benefits to humans, some authors have proposed that excessive caffeine intake may increase the frequency of epileptic seizures in humans and reduce the efficiency of antiepileptic drugs. Little is known, however, about the proconvulsant potential of the sustained, excessive intake of cocoa on hippocampal neural circuits. Using the mouse as an experimental model, we examined the effects of the chronic consumption of food enriched in cocoa-based dark chocolate on motor and mood-related behaviours as well as on the excitability properties of hippocampal neurons...
February 12, 2018: Food & Function
https://www.readbyqxmd.com/read/29431649/sleep-deprivation-distinctly-alters-glutamate-transporter-1-apposition-and-excitatory-transmission-to-orexin-and-mch-neurons
#9
Chantalle Briggs, Michiru Hirasawa, Kazue Semba
Glutamate transporter 1 (GLT1) is the main astrocytic transporter that shapes glutamatergic transmission in the brain. However, whether this transporter modulates sleep/wake regulatory neurons is unknown. Using quantitative immunohistochemical analysis, we assessed perisomatic GLT1 apposition with sleep/wake neurons in the male rat following 6-h sleep deprivation (SD) or following 6-h undisturbed conditions when animals were mostly asleep (Rest). We found that SD decreased perisomatic GLT1 apposition with wake-promoting orexin (ORX) neurons in the lateral hypothalamus (LH) compared to Rest...
February 5, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29430734/gaba-and-serotonin-expressing-neurons-take-part-in-inhibitory-as-well-as-excitatory-input-pathways-to-the-circadian-clock-of-the-madeira-cockroach-rhyparobia-maderae
#10
Maria Giese, Julia Gestrich, Azar Massah, Jonas Peterle, HongYing Wei, Monika Stengl
In the Madeira cockroach pigment-dispersing factor-immunoreactive (PDF-ir) neurons innervating the circadian clock, the accessory medulla (AME) in the brain's optic lobes, control circadian behavior. Circadian activity rhythms are entrained to daily light-dark cycles only by compound eye photoreceptors terminating in the lamina and medulla. Still, it is unknown which neurons connect the photoreceptors to the clock to allow for light-entrainment. Here, we characterized by multiple-label immunocytochemistry the serotonin (5-HT)-ir anterior fiber fan and GABA-ir pathways connecting the AME- and optic lobe neuropils...
February 11, 2018: European Journal of Neuroscience
https://www.readbyqxmd.com/read/29427106/the-neuropathology-of-spinocerebellar-ataxia-type-3-machado-joseph-disease
#11
Arnulf H Koeppen
Spinocerebellar ataxia type 3 (SCA-3)/Machado-Joseph disease (MJD), the most common autosomal dominant ataxia, affects many regions of the brain and spinal cord. Similar to SCA-1, SCA-2, SCA-6, SCA-7, and SCA-17, the mutation consists of a pathogenic translated cytosine-adenine-guanine (CAG) trinucleotide repeat expansion. Almost invariably, the substantia nigra and the dentate nucleus of the cerebellum bear the brunt of the disease, and these lesions account for the Parkinsonian and ataxic phenotypes. Lesions of motor nuclei in the brain stem cause the complex disturbance of ocular motility and weakness of the tongue...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29419884/balancing-tonic-and-phasic-inhibition-in-hypothalamic-corticotropin-releasing-hormone-neurons
#12
Phillip L W Colmers, Jaideep S Bains
Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are integratory hubs that regulate the endocrine response to stress. GABA inputs provide a basal inhibitory tone that constrains this system and circulating glucocorticoids (CORT) are important feedback controllers of CRH output. Surprisingly little is known about the direct effects of CORT on GABA synapses in PVN. Here we used whole-cell patch clamp recordings from CRH neurons in mouse hypothalamic brain slices to examine the effects of CORT on synaptic and extrasynaptic GABA signalling...
February 8, 2018: Journal of Physiology
https://www.readbyqxmd.com/read/29417477/microrna-34-contributes-to-the-stress-related-behavior-and-affects-5-ht-prefrontal-gaba-amygdalar-system-through-regulation-of-corticotropin-releasing-factor-receptor-1
#13
Diego Andolina, Matteo Di Segni, Alessandra Accoto, Luisa Lo Iacono, Antonella Borreca, Donald Ielpo, Nicola Berretta, Emerald Perlas, Stefano Puglisi-Allegra, Rossella Ventura
Recent studies show that microRNA-34 (miR-34) family is critical in the regulation of stress response also suggesting that it may contribute to the individual responsiveness to stress. We have recently demonstrated that mice carrying a genetic deletion of all miR-34 isoforms (triple knockout, TKO) lack the stress-induced serotonin (5-HT) and GABA release in the medial prefrontal cortex (mpFC) and basolateral amygdala (BLA), respectively. Here, we evaluated if the absence of miR-34 was also able to modify the stress-coping strategy in the forced swimming test...
February 7, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29417470/involvement-of-ventral-periaqueductal-gray-dopaminergic-neurons-in-propofol-anesthesia
#14
Jia Li, Tian Yu, Fu Shi, Yu Zhang, Zikun Duan, Bao Fu, Yi Zhang
It has been reported that central dopaminergic system is implicated in the mechanism underlying general anesthesia. Whether dopamine (DA) neurons in midbrain ventral periaqueductal gray (vPAG) are involved in general anesthesia and how general anesthetics affect these neurons remain sparsely documented. To determine the role of vPAG DA neurons in propofol-induced anesthesia, we performed microinjection of 6-hydroxydopamine (6-OHDA) into vPAG to damage DA neurons and investigated the alteration in somatosensory electroencephalogram (EEG), as well as the induction and recovery time of propofol anesthesia...
February 7, 2018: Neurochemical Research
https://www.readbyqxmd.com/read/29415440/revisiting-the-therapeutic-potential-of-bothrops-jararaca-venom-screening-for-novel-activities-using-connectivity-mapping
#15
Carolina Alves Nicolau, Alyson Prorock, Yongde Bao, Ana Gisele da Costa Neves-Ferreira, Richard Hemmi Valente, Jay William Fox
Snake venoms are sources of molecules with proven and potential therapeutic applications. However, most activities assayed in venoms (or their components) are of hemorrhagic, hypotensive, edematogenic, neurotoxic or myotoxic natures. Thus, other relevant activities might remain unknown. Using functional genomics coupled to the connectivity map (C-map) approach, we undertook a wide range indirect search for biological activities within the venom of the South American pit viper Bothrops jararaca . For that effect, venom was incubated with human breast adenocarcinoma cell line (MCF7) followed by RNA extraction and gene expression analysis...
February 6, 2018: Toxins
https://www.readbyqxmd.com/read/29411793/expeditious-synthesis-of-polyacetylenic-water-hemlock-toxins-and-their-effects-on-the-major-gabaa-receptor-isoform
#16
Martin Berger, Yong Chen, Konstantina Bampali, Margot Ernst, Nuno Maulide
Classical synthetic approaches to highly unsaturated polyene/yne natural products rely on iterative cross-coupling of linear fragments. Herein, we present an expeditious and unified approach to the unsaturated backbone of polyacetylenes via domino cuprate addition/4π-electrocyclic ring opening of a stereodefined cyclobutene intermediate. This sets the stage for a detailed biological assessment of the role of Virol A and Cicutoxin as inhibitors of GABA induced chloride currents, providing further insight into the interaction of these highly potent toxins towards the GABAA receptor, including the structure-activity relationship of the derivatives...
February 7, 2018: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/29411426/integrating-eqtl-data-with-gwas-summary-statistics-in-pathway-based-analysis-with-application-to-schizophrenia
#17
Chong Wu, Wei Pan
Many genetic variants affect complex traits through gene expression, which can be exploited to boost statistical power and enhance interpretation in genome-wide association studies (GWASs) as demonstrated by the transcriptome-wide association study (TWAS) approach. Furthermore, due to polygenic inheritance, a complex trait is often affected by multiple genes with similar functions as annotated in gene pathways. Here, we extend TWAS from gene-based analysis to pathway-based analysis: we integrate public pathway collections, expression quantitative trait locus (eQTL) data and GWAS summary association statistics (or GWAS individual-level data) to identify gene pathways associated with complex traits...
February 7, 2018: Genetic Epidemiology
https://www.readbyqxmd.com/read/29409499/mechanisms-of-multiple-neurotransmitters-in-the-effects-of-lycopene-on-brain-injury-induced-by-hyperlipidemia
#18
Weichun Yang, Ziyi Shen, Sixian Wen, Wei Wang, Minyu Hu
BACKGROUND: Lycopene is a kind of carotenoid, with a strong capacity of antioxidation and regulating the bloodlipid. There has been some evidence that lycopene has protective effects on the central nervous system, but few studies have rigorously explored the role of neurotransmitters in it. Therefore, the present study was designed to investigate the effects of several neurotransmitters as lycopene exerts anti-injury effects induced by hyperlipidemia. METHODS: Eighty adult SD rats, half male and half female, were randomly divided into eight groups on the basis of serum total cholesterol (TC) levels and body weight...
February 7, 2018: Lipids in Health and Disease
https://www.readbyqxmd.com/read/29408355/molecular-cloning-spatiotemporal-and-functional-expression-of-gaba-receptor-subunits-rdl1-and-rdl2-of-the-rice-stem-borer-chilo-suppressalis
#19
Cheng-Wang Sheng, Zhong-Qiang Jia, Yoshihisa Ozoe, Qiu-Tang Huang, Zhao-Jun Han, Chun-Qing Zhao
Insect γ-aminobutyric acid (GABA) receptor (GABAR) is one of the major targets of insecticides. In the present study, cDNAs (CsRDL1A and CsRDL2S) encoding the two isoforms of RDL subunits were cloned from the rice stem borer Chilo suppressalis. Transcripts of both genes demonstrated similar expression patterns in different tissues and developmental stages, although CsRDL2S was ∼2-fold more abundant than CsRDL1A throughout all development stages. To investigate the function of channels formed by CsRDL subunits, both genes were expressed in Xenopus laevis oocytes singly or in combination in different ratios...
February 5, 2018: Insect Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29408282/pharmacological-manipulation-of-gaba-activity-in-nucleus-subpretectalis-interstitio-pretecto-subpretectalis-sp-ips-impairs-figure-ground-discrimination-in-pigeons-running-head-sp-ips-in-figure-ground-segregation
#20
Martin J Acerbo, Olga F Lazareva
Figure-ground segregation is a fundamental visual ability that allows an organism to separate an object from its background. Our earlier research has shown that nucleus rotundus (Rt), a thalamic nucleus processing visual information in pigeons, together with its inhibitory complex, nucleus subpretectalis/interstitio-pretecto-subpretectalis (SP/IPS), are critically involved in figure-ground discrimination (Acerbo et al., 2012; Scully et al., 2014). Here, we further investigated the role of SP/IPS by conducting bilateral microinjections of GABAergic receptor antagonist and agonists (bicuculline and muscimol, respectively) and non-NMDA glutamate receptor antagonist (CNQX) after the pigeons mastered figure-ground discrimination task...
February 2, 2018: Behavioural Brain Research
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