DOCSLIB.ORG

Poster Session Iiiwednesday, December 9, 2015

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Poster Session Iiiwednesday, December 9, 2015 Neuropsychopharmacology (2015) 40, S443–S611 & 2015 American College of Neuropsychopharmacology. All rights reserved 0893-133X/15 www.neuropsychopharmacology.org Poster Session III phase of the SDMT was tested using SPM12. To control for Wednesday, December 9, 2015 population stratification, 5 MDS components based on 8M SNP genotypes from a GWAS analysis extracted with EIGENSOFT5.01 were included in the analysis as covariates W1. Rs362691 Polymorphism in RELN Gene Modulates along with age, gender, SNAV, and genotyping batch labels. A the Detrimental Effect of Alzheimer’s Disease Risk region of interest analysis was performed using bilateral Genes on Hippocampal Function hippo-parahippocampal masks from the Anatomical Auto- matic Labeling Atlas. Influence of RELN on association Qiang Chen*, Ena Y. Xiao, Aaron L. Goldman, Rahul between LOAD related AD RPS and hippocampal activation Bharadwaj, Kaitlin Healy, Brad Zoltick, Saumitra Das, was examined separately for five independent Reelin poly- Karen Berman, Daniel R. Weinberger, Venkata S. Mattay morphisms (rs736707, rs362691, rs7341475, rs6943822, and Lieber Institute for Brain Development, Baltimore, rs4298437.) previously implicated in Alzheimer’s disease or Maryland, United States Autism Spectrum Disease using flexible factorial analysis in SPM12. Background: Late Onset Alzheimer’s Disease (LOAD) is one Results: fMRI analysis showed a significant negative of the most common debilitating causes of dementia correlation between LOAD RPS and hippocampal activation worldwide with heritability estimates ranging from 50 – (left: PFWE_corrected ¼ 0.005, MNI coordinates x ¼ -39, y 70%. Genome-wide association studies (GWAS) have ¼ -24, z ¼ -12, right: PFWE_corrected ¼ 0.139, Puncor- identified more than 20 genetic loci in addition to APOEe4 rectedo0.001, MNI coordinates x ¼ 39, y ¼ -18, z ¼ -18) that are associated with increased risk for LOAD. While during the neutral encoding phase of SDMT. There were no most of these genes have weak effects, using a polygenic significant positive correlations. In addition, there was a risk profile score (RPS) approach – a method that allows significant interactive effect (left: PFWE_corrected ¼ 0.076, exploration of the influence of the cumulative effect of risk MNI coordinates x ¼ -30, y ¼ -30, z ¼ -6, right: alleles - we and others have shown the negative influence of PFWE_corrected ¼ 0.368, Puncorrected ¼ 0.002, MNI LOAD risk genes on brain structure (Chauhan et al., 2015) coordinates x ¼ 27, y ¼ -33, z ¼ -9) of rs362691 genotype and function (Xiao et al., 2015 HBM) even in healthy (a G-C missense variant) and LOAD RPS on activation. volunteers. Identifying mechanisms, particularly genetic Furthermore, in the left hippocampus, minor allele C mechanisms that confer resilience to the detrimental effect carriers (N ¼ 56) showed a significant negative relationship of LOAD related risk genes on brain structure and function (r ¼ -0.47, p ¼ 0.0002, post-hoc analysis in R) between RPS could provide a viable avenue to identify novel therapeutic and hippocampal activation, while the major allele G targets for LOAD. To that end, in the current study, we homozygotes (N ¼ 208) showed no such relationship explored the role of polymorphisms in the gene encoding (r ¼ 0.0071, p ¼ 0.9186). None of the other RELN poly- Reelin (RELN), a glycoprotein that has been shown to be morphisms tested showed a significant effect. critical for neuronal development and synaptic plasticity Conclusions: Our results, while showing a cumulative (Kramer et al. 2011), on the detrimental effect of LOAD RPS deleterious effect of several LOAD related risk genes on on hippocampal function. Studies have shown that normal hippocampal function in healthy volunteers, also illustrate RELN levels are necessary to prevent abnormal phosphor- that this relationship is modulated by a missense SNP ylation of tau (Ohkubo et al., 2003) and beta-amyloid- (rs362691) in the RELN gene. In particular, only the minor induced suppression of long term potentiation and NMDA allele C carriers show a significant negative relationship receptors (Durakoglugil et al., 2009). between RPS and hippocampal function suggesting that Methods: BOLD functional MRI images (GE 3 T MRI scanner, homozygosity for the G allele in this polymorphism could TR/TE ¼ 2000/28ms, flip angle ¼ 90 deg, FOV ¼ 64x64, 24 potentially confer a protective effect. axial slices, 170 volumes) were collected for 265 right-handed Keywords: Polygenetic Risk Score, Alzheimer’s Disease, Caucasian healthy volunteers (116 male, 149 female) from fMRI/imaging genetics, Hippocampal Function, Cognitive the age of 18 to 86 years (SD ¼ 14.17) while they performed Resilience a simple declarative memory task (SDMT). Images were Disclosures: Nothing to disclose. motion-corrected, normalized to MNI space, and spatially smoothed (8mm FWHM) using SPM5. Odd’s ratios of 22 independent SNPs, with Po1 Â 10-5 in Hollingworth’s meta- W2. Subtypes of Prefrontal Cortical NMDA Receptors in analysis1 comprising four Alzheimer’s disease GWAS datasets Working Memory and Normal Aging (GERAD1, EADI1, TGEN1, ADNI), spanning the regions of ABCA7, APOC4, APOE, BCAM, BCL3, BIN1, C16orf88, CDK1, Joseph McQuail, B. Sofia Beas, Kyle Kelly, Kailey CEACAM1E, CLPTMI, CLU, CNTN5, CR1, CR2, CUX2, Simpson, C. Jason Frazier, Barry Setlow, Jennifer Bizon* EXOC3L2, IQCK, LRRC68, MS4A4A, MS4A4E, MS4A6A, University of Florida College of Medicine, Gainesville, PICALM, PVR, PVRL2, and TOMM40 genes, were used to Florida, United States calculate the RPS for each individual subject using the approach described by Purcell et al.3. Association between Background: Working memory involves the ability to RPS and hippocampal activation during the neutral encoding briefly maintain context-specific information in mind and ACNP 54th Annual Meeting Abstracts S444 to use this representational knowledge to guide current and mPFC of young rats in Experiment 2 significantly attenu- future action. This form of short-term memory is supported ated working memory performance. In contrast, neither by the prefrontal cortex (PFC) and is believed to rely on NR2B-specific antagonist affected young rats’ working the ability of selectively tuned pyramidal neuron net- memory performance. In Experiment 3, Western blot works to persist in firing even after a to-be-remembered analysis revealed a significant reduction in expression of stimulus is removed from the environment. Ionotropic all NMDA receptor subunits in aged rat mPFC, but only loss glutamate receptors of the NMDA subtype are expressed on of the NR2A subunit strongly predicted working memory pyramidal neurons in the PFC, and altered activity at these decline. Data from Experiments 1-3 suggest that NR2A- receptors has been implicated in working memory deficits containing NMDA receptors in PFC are particularly critical associated with both psychiatric disorders and normal for supporting working memory abilities. The preferred role aging. NMDA receptors are biochemically diverse hetero- of NR2A-containing receptors in working memory may be tetramers comprised of an obligate NR1 subunit and attributable to the fact that these receptors preferentially variable NR2A or NR2B subunits, the latter of which can comprise the synaptic pool of NMDA receptors that enable influence both the channel kinetics and localization of the the persistent firing of pyramidal neurons. In Experiment 4, receptor to synaptic versus extrasynaptic sites. These intra-mPFC microinjection of the well-known NMDA receptor properties conferred by the NR2 subunit suggest receptor co-agonist d-cycloserine, which non-selectively that NMDA receptor subtypes may differentially influence targets both synaptic and extrasynaptic NMDA receptors, normal working memory and the decline of working did not improve working memory in aged rats. In contrast, memory abilities across a variety of pathological conditions. 3-methylpyrazole-5-carboxylic acid, a d-amino acid oxidase The current study was designed to assess the individual inhibitor that more selectively enhances activity at synaptic contribution of PFC NR2A- and NR2B-containing NMDA NMDA receptors by preventing degradation of endogenous receptor subtypes to working memory abilities, and, serine, significantly improved aged rats’ working memory further, to determine which subunit is most relevant to performance. the well-characterized decline of working memory abilities Conclusions: The present experiments specifically implicate in normal aging. NR2A-containing NMDA receptors in normal working Methods: Subjects in all experiments were young (4-6 mo.) memory. The results further suggest that a decline in and aged (22-24 mo.) male F344 rats. In Experiment 1, acute NR2A receptor expression may be a causal factor for slices from young rats were prepared and patch clamp working memory impairments in aging. Our working electrophysiological methods were used to assess the hypothesis is that NR2A-containing NMDA receptors are relative contributions of NR2A- and NR2B-containing particularly important for working memory given that these NMDA receptors to evoked NMDA currents recorded from receptors are preferentially localized to synaptic sites layer II/III PFC pyramidal neurons. In Experiment 2, four whereas NR2B-containing receptors are preferentially loca- cohorts of young rats (n ¼ 6-8 rats/cohort) were surgically lized extrasynaptically. Consistent with this hypothesis, implanted with guide cannulae directed at the medial PFC pharmacological modulation of synaptic
Load more

Recommended publications
  • TABLE 1 Studies of Antagonist Activity in Constitutively Active
    TABLE 1 Studies of antagonist activity in constitutively active receptors systems shown to demonstrate inverse agonism for at least one ligand Targets are natural Gs and constitutively active mutants (CAM) of GPCRs. Of 380 antagonists, 85% of the ligands demonstrate inverse agonism. Receptor Neutral Antagonist Inverse Agonist Reference Human β2-adrenergic Dichloroisoproterenol, pindolol, labetolol, timolol, Chidiac et al., 1996; Azzi et alprenolol, propranolol, ICI 118,551, cyanopindolol al., 2001 Turkey erythrocyte β-adrenergic Propranolol, pindolol Gotze et al., 1994 Human β2-adrenergic (CAM) Propranolol Betaxolol, ICI 118,551, sotalol, timolol Samama et al., 1994; Stevens and Milligan, 1998 Human/guinea pig β1-adrenergic Atenolol, propranolol Mewes et al., 1993 Human β1-adrenergic Carvedilol CGP20712A, metoprolol, bisoprolol Engelhardt et al., 2001 Rat α2D-adrenergic Rauwolscine, yohimbine, WB 4101, idazoxan, Tian et al., 1994 phentolamine, Human α2A-adrenergic Napthazoline, Rauwolscine, idazoxan, altipamezole, levomedetomidine, Jansson et al., 1998; Pauwels MPV-2088 (–)RX811059, RX 831003 et al., 2002 Human α2C-adrenergic RX821002, yohimbine Cayla et al., 1999 Human α2D-adrenergic Prazosin McCune et al., 2000 Rat α2-adrenoceptor MK912 RX821002 Murrin et al., 2000 Porcine α2A adrenoceptor (CAM- Idazoxan Rauwolscine, yohimbine, RX821002, MK912, Wade et al., 2001 T373K) phentolamine Human α2A-adrenoceptor (CAM) Dexefaroxan, (+)RX811059, (–)RX811059, RS15385, yohimbine, Pauwels et al., 2000 atipamezole fluparoxan, WB 4101 Hamster α1B-adrenergic
    [Show full text]
  • From Inverse Agonism to 'Paradoxical Pharmacology' Richard A
    International Congress Series 1249 (2003) 27-37 From inverse agonism to 'Paradoxical Pharmacology' Richard A. Bond*, Kenda L.J. Evans, Zsirzsanna Callaerts-Vegh Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 521 Science and Research Bldg 2, 4800 Caltioun, Houston, TX 77204-5037, USA Received 16 April 2003; accepted 16 April 2003 Abstract The constitutive or spontaneous activity of G protein-coupled receptors (GPCRs) and compounds acting as inverse agonists is a recent but well-established phenomenon. Dozens of receptor subtypes for numerous neurotransmitters and hormones have been shown to posses this property. However, do to the apparently low percentage of receptors in the spontaneously active state, the physiologic relevance of these findings remains questionable. The possibility that the reciprocal nature of the effects of agonists and inverse agonists may extend to cellular signaling is discussed, and that this may account for the beneficial effects of certain p-adrenoceptor inverse agonists in the treatment of heart failure. © 2003 Elsevier Science B.V. All rights reserved. Keywords. Inverse agonism; GPCR; Paradoxical pharmacology 1. Brief history of inverse agonism at G protein-coupled receptors For approximately three-quarters of a century, ligands that interacted with G protein- coupled receptors (GPCRs) were classified either as agonists or antagonists. Receptors were thought to exist in a single quiescent state that could only induce cellular signaling upon agonist binding to the receptor to produce an activated state of the receptor. In this model, antagonists had no cellular signaling ability on their own, but did bind to the receptor and prevented agonists from being able to bind and activate the receptor.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2010/0221245 A1 Kunin (43) Pub
    US 2010O221245A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0221245 A1 Kunin (43) Pub. Date: Sep. 2, 2010 (54) TOPICAL SKIN CARE COMPOSITION Publication Classification (51) Int. Cl. (76) Inventor: Audrey Kunin, Mission Hills, KS A 6LX 39/395 (2006.01) (US) A6II 3L/235 (2006.01) A638/16 (2006.01) Correspondence Address: (52) U.S. Cl. ......................... 424/133.1: 514/533: 514/12 HUSCH BLACKWELL SANDERS LLP (57) ABSTRACT 4801 Main Street, Suite 1000 - KANSAS CITY, MO 64112 (US) The present invention is directed to a topical skin care com position. The composition has the unique ability to treat acne without drying out the user's skin. In particular, the compo (21) Appl. No.: 12/395,251 sition includes a base, an antibacterial agent, at least one anti-inflammatory agent, and at least one antioxidant. The (22) Filed: Feb. 27, 2009 antibacterial agent may be benzoyl peroxide. US 2010/0221 245 A1 Sep. 2, 2010 TOPCAL SKIN CARE COMPOSITION stay of acne treatment since the 1950s. Skin irritation is the most common side effect of benzoyl peroxide and other anti BACKGROUND OF THE INVENTION biotic usage. Some treatments can be severe and can leave the 0001. The present invention generally relates to composi user's skin excessively dry. Excessive use of some acne prod tions and methods for producing topical skin care. Acne Vul ucts may cause redness, dryness of the face, and can actually garis, or acne, is a common skin disease that is prevalent in lead to more acne. Therefore, it would be beneficial to provide teenagers and young adults.
    [Show full text]
  • Development of Pain-Free Methods for Analyzing 231 Multiclass Drugs and Metabolites by LC-MS/MS
    Clinical, Forensic & Toxicology Article “The Big Pain”: Development of Pain-Free Methods for Analyzing 231 Multiclass Drugs and Metabolites by LC-MS/MS By Sharon Lupo As the use of prescription and nonprescription drugs grows, the need for fast, accurate, and comprehensive methods is also rapidly increasing. Historically, drug testing has focused on forensic applications such as cause of death determinations or the detection of drug use in specific populations (military, workplace, probation/parole, sports doping). However, modern drug testing has expanded well into the clinical arena with a growing list of target analytes and testing purposes. Clinicians often request the analysis of large panels of drugs and metabolites that can be used to ensure compliance with prescribed pain medication regimens and to detect abuse or diversion of medications. With prescription drug abuse reaching epidemic levels [1], demand is growing for analytical methods that can ensure accurate results for comprehensive drug lists with reasonable analysis times. LC-MS/MS is an excellent technique for this work because it offers greater sensitivity and specificity than immunoassay and—with a highly selective and retentive Raptor™ Biphenyl column—can provide definitive results for a wide range of compounds. Typically, forensic and pain management drug testing consists of an initial screening analysis, which is qualitative, quick, and requires only minimal sample preparation. Samples that test positive during screening are then subjected to a quantitative confirmatory analysis. Whereas screening assays may cover a broad list of compounds and are generally less sensitive and specific, confirmation testing provides fast, targeted analysis using chromatographic conditions that are optimized for specific panels.
    [Show full text]
  • Ciproxifan, a Histamine H3 Receptor Antagonist, Reversibly Inhibits Monoamine Oxidase a and B Received: 05 September 2016 S
    www.nature.com/scientificreports OPEN Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B Received: 05 September 2016 S. Hagenow1, A. Stasiak2, R. R. Ramsay3 & H. Stark1 Accepted: 07 December 2016 Ciproxifan is a well-investigated histamine H receptor (H3R) inverse agonist/antagonist, showing Published: 13 January 2017 3 an exclusively high species-specific affinity at rodent compared to human H3R. It is well studied as reference compound for H3R in rodent models for neurological diseases connected with neurotransmitter dysregulation, e.g. attention deficit hyperactivity disorder or Alzheimer’s disease. In a screening for potential monoamine oxidase A and B inhibition ciproxifan showed efficacy on both enzyme isoforms. Further characterization of ciproxifan revealed IC50 values in a micromolar concentration range for human and rat monoamine oxidases with slight preference for monoamine oxidase B in both species. The inhibition by ciproxifan was reversible for both human isoforms. Regarding inhibitory potency of ciproxifan on rat brain MAO, these findings should be considered, when using high doses in rat models for neurological diseases. As the H3R and monoamine oxidases are all capable of affecting neurotransmitter modulation in brain, we consider dual targeting ligands as interesting approach for treatment of neurological disorders. Since ciproxifan shows only moderate activity at human targets, further investigations in animals are not of primary interest. On the other hand, it may serve as starting point for the development of dual targeting ligands. Ciproxifan (cyclopropyl 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl methanone) is a well characterized species-specific histamine 3H receptor (H3R) inverse agonist/antagonist (Fig.
    [Show full text]
  • 7 X 11.5 Three Lines.P65
    Cambridge University Press 978-0-521-71413-6 - Antipsychotics and Mood Stabilizers: Stahl’s Essential Psychopharmacology, Third Edition Stephen M. Stahl Index More information Index Page numbers followed by ‘f ’ indicate figures; page numbers followed by ‘t ’ indicate tables. 3PPP, 134f agitation, benzodiazepines for, 188 AAADC (aromatic amino acid decarboxylase), and receptor conformation, 132f 97, 98f agranulocytosis, clozapine and, 164 ABT089, 203 akathisia acetylcholine (ACh), from aripiprazole, 175 in arousal pathways, 150, 152f nigrostriatal pathway dopamine deficiencies and blocked dopamine receptors, 93f and, 31 overactivity, 95 alanine-serine-cysteine transporter (ASC-T), reciprocal relationship with dopamine, 92f glial, 34 acetylcholine-linked mechanisms, 202 alogia, 5, 6t ACP 103, 200 alpha 1 adrenergic receptors ACP-104, 129, 134f atypical antipsychotic agents and, 139f ACR16, 134f and sedation, 151f adipose tissue, insulin resistance in, 141, alpha-1 receptor, antagonism, 94f 144f alpha-2 adrenergic receptors, atypical adolescence antipsychotic agents and, 139f aggressiveness in, 179 alpha 2 antagonists, 168 removal of synaptic connections, 68 alpha-4 beta-2 nicotinic acetylcholine receptor, risperidone for treating psychotic disorders, 203 166 alpha-7-nicotinic cholinergic agonists, affective blunting, 5 202 affective flattening, as SSRI side effect, 110 alpha amino-3-hydroxy-5-methyl-4- affective symptoms isoxazolepropionic acid (AMPA) dorsal vs. ventral regulation, 76f receptors, 40, 40f, 66f mesolimbic dopamine pathway role
    [Show full text]
  • Pharmacokinetic Drug–Drug Interactions Among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients
    International Journal of Molecular Sciences Review Pharmacokinetic Drug–Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients Marta Kara´zniewicz-Łada 1 , Anna K. Główka 2 , Aniceta A. Mikulska 1 and Franciszek K. Główka 1,* 1 Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 60-781 Pozna´n,Poland; [email protected] (M.K.-Ł.); [email protected] (A.A.M.) 2 Department of Bromatology, Poznan University of Medical Sciences, 60-354 Pozna´n,Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-(0)61-854-64-37 Abstract: Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, rang- ing from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug–drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carba- Citation: Kara´zniewicz-Łada,M.; mazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration Główka, A.K.; Mikulska, A.A.; of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and Główka, F.K.
    [Show full text]
  • (19) United States (12) Patent Application Publication (10) Pub
    US 20130289061A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0289061 A1 Bhide et al. (43) Pub. Date: Oct. 31, 2013 (54) METHODS AND COMPOSITIONS TO Publication Classi?cation PREVENT ADDICTION (51) Int. Cl. (71) Applicant: The General Hospital Corporation, A61K 31/485 (2006-01) Boston’ MA (Us) A61K 31/4458 (2006.01) (52) U.S. Cl. (72) Inventors: Pradeep G. Bhide; Peabody, MA (US); CPC """"" " A61K31/485 (201301); ‘4161223011? Jmm‘“ Zhu’ Ansm’ MA. (Us); USPC ......... .. 514/282; 514/317; 514/654; 514/618; Thomas J. Spencer; Carhsle; MA (US); 514/279 Joseph Biederman; Brookline; MA (Us) (57) ABSTRACT Disclosed herein is a method of reducing or preventing the development of aversion to a CNS stimulant in a subject (21) App1_ NO_; 13/924,815 comprising; administering a therapeutic amount of the neu rological stimulant and administering an antagonist of the kappa opioid receptor; to thereby reduce or prevent the devel - . opment of aversion to the CNS stimulant in the subject. Also (22) Flled' Jun‘ 24’ 2013 disclosed is a method of reducing or preventing the develop ment of addiction to a CNS stimulant in a subj ect; comprising; _ _ administering the CNS stimulant and administering a mu Related U‘s‘ Apphcatlon Data opioid receptor antagonist to thereby reduce or prevent the (63) Continuation of application NO 13/389,959, ?led on development of addiction to the CNS stimulant in the subject. Apt 27’ 2012’ ?led as application NO_ PCT/US2010/ Also disclosed are pharmaceutical compositions comprising 045486 on Aug' 13 2010' a central nervous system stimulant and an opioid receptor ’ antagonist.
    [Show full text]
  • Chapter 25 Mechanisms of Action of Antiepileptic Drugs
    Chapter 25 Mechanisms of action of antiepileptic drugs GRAEME J. SILLS Department of Molecular and Clinical Pharmacology, University of Liverpool _________________________________________________________________________ Introduction The serendipitous discovery of the anticonvulsant properties of phenobarbital in 1912 marked the foundation of the modern pharmacotherapy of epilepsy. The subsequent 70 years saw the introduction of phenytoin, ethosuximide, carbamazepine, sodium valproate and a range of benzodiazepines. Collectively, these compounds have come to be regarded as the ‘established’ antiepileptic drugs (AEDs). A concerted period of development of drugs for epilepsy throughout the 1980s and 1990s has resulted (to date) in 16 new agents being licensed as add-on treatment for difficult-to-control adult and/or paediatric epilepsy, with some becoming available as monotherapy for newly diagnosed patients. Together, these have become known as the ‘modern’ AEDs. Throughout this period of unprecedented drug development, there have also been considerable advances in our understanding of how antiepileptic agents exert their effects at the cellular level. AEDs are neither preventive nor curative and are employed solely as a means of controlling symptoms (i.e. suppression of seizures). Recurrent seizure activity is the manifestation of an intermittent and excessive hyperexcitability of the nervous system and, while the pharmacological minutiae of currently marketed AEDs remain to be completely unravelled, these agents essentially redress the balance between neuronal excitation and inhibition. Three major classes of mechanism are recognised: modulation of voltage-gated ion channels; enhancement of gamma-aminobutyric acid (GABA)-mediated inhibitory neurotransmission; and attenuation of glutamate-mediated excitatory neurotransmission. The principal pharmacological targets of currently available AEDs are highlighted in Table 1 and discussed further below.
    [Show full text]
  • Brain Imaging
    Publications · Brochures Brain Imaging A Technologist’s Guide Produced with the kind Support of Editors Fragoso Costa, Pedro (Oldenburg) Santos, Andrea (Lisbon) Vidovič, Borut (Munich) Contributors Arbizu Lostao, Javier Pagani, Marco Barthel, Henryk Payoux, Pierre Boehm, Torsten Pepe, Giovanna Calapaquí-Terán, Adriana Peștean, Claudiu Delgado-Bolton, Roberto Sabri, Osama Garibotto, Valentina Sočan, Aljaž Grmek, Marko Sousa, Eva Hackett, Elizabeth Testanera, Giorgio Hoffmann, Karl Titus Tiepolt, Solveig Law, Ian van de Giessen, Elsmarieke Lucena, Filipa Vaz, Tânia Morbelli, Silvia Werner, Peter Contents Foreword 4 Introduction 5 Andrea Santos, Pedro Fragoso Costa Chapter 1 Anatomy, Physiology and Pathology 6 Elsmarieke van de Giessen, Silvia Morbelli and Pierre Payoux Chapter 2 Tracers for Brain Imaging 12 Aljaz Socan Chapter 3 SPECT and SPECT/CT in Oncological Brain Imaging (*) 26 Elizabeth C. Hackett Chapter 4 Imaging in Oncological Brain Diseases: PET/CT 33 EANM Giorgio Testanera and Giovanna Pepe Chapter 5 Imaging in Neurological and Vascular Brain Diseases (SPECT and SPECT/CT) 54 Filipa Lucena, Eva Sousa and Tânia F. Vaz Chapter 6 Imaging in Neurological and Vascular Brain Diseases (PET/CT) 72 Ian Law, Valentina Garibotto and Marco Pagani Chapter 7 PET/CT in Radiotherapy Planning of Brain Tumours 92 Roberto Delgado-Bolton, Adriana K. Calapaquí-Terán and Javier Arbizu Chapter 8 PET/MRI for Brain Imaging 100 Peter Werner, Torsten Boehm, Solveig Tiepolt, Henryk Barthel, Karl T. Hoffmann and Osama Sabri Chapter 9 Brain Death 110 Marko Grmek Chapter 10 Health Care in Patients with Neurological Disorders 116 Claudiu Peștean Imprint 126 n accordance with the Austrian Eco-Label for printed matters.
    [Show full text]
  • 5-HT2A/2C Receptor Modulation of Absence Seizures and Characterization of the GHB-Model
    5-HT2A/2C receptor modulation of absence seizures and characterization of the GHB-model A thesis submitted to Cardiff University for the degree of Doctor of Philosophy by Marcello Venzi (MSc) School of Biosciences, Cardiff University, October 2014 Chapter 1 Declaration and Statements This work has not been submitted in substance for any other degree or award at this or any other university or place of learning, nor is being submitted concurrently in candidature for any degree or other award. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of PhD . Signed ………………………………………… (candidate) Date ………………………… STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. The views expressed are my own. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter- library loan, and for the title and summary to be made available to outside organisations. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 4: PREVIOUSLY APPROVED BAR ON ACCESS I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter- library loans after expiry of a bar on access previously approved by the Academic Standards & Quality Committee. Signed ………………………………………… (candidate) Date ………………………… II Chapter 1 Summary Absence seizures (ASs) are non-convulsive epileptic events which are common in pediatric and juvenile epilepsies. They consist of EEG generalized spike-and-wave-discharges (SWDs) accompanied by an impairment of consciousness and are expressed within the thalamocortical network.
    [Show full text]
  • Compositions and Methods for Selective Delivery of Oligonucleotide Molecules to Specific Neuron Types
    (19) TZZ ¥Z_T (11) EP 2 380 595 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 26.10.2011 Bulletin 2011/43 A61K 47/48 (2006.01) C12N 15/11 (2006.01) A61P 25/00 (2006.01) A61K 49/00 (2006.01) (2006.01) (21) Application number: 10382087.4 A61K 51/00 (22) Date of filing: 19.04.2010 (84) Designated Contracting States: • Alvarado Urbina, Gabriel AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Nepean Ontario K2G 4Z1 (CA) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL • Bortolozzi Biassoni, Analia Alejandra PT RO SE SI SK SM TR E-08036, Barcelona (ES) Designated Extension States: • Artigas Perez, Francesc AL BA ME RS E-08036, Barcelona (ES) • Vila Bover, Miquel (71) Applicant: Nlife Therapeutics S.L. 15006 La Coruna (ES) E-08035, Barcelona (ES) (72) Inventors: (74) Representative: ABG Patentes, S.L. • Montefeltro, Andrés Pablo Avenida de Burgos 16D E-08014, Barcelon (ES) Edificio Euromor 28036 Madrid (ES) (54) Compositions and methods for selective delivery of oligonucleotide molecules to specific neuron types (57) The invention provides a conjugate comprising nucleuc acid toi cell of interests and thus, for the treat- (i) a nucleic acid which is complementary to a target nu- ment of diseases which require a down-regulation of the cleic acid sequence and which expression prevents or protein encoded by the target nucleic acid as well as for reduces expression of the target nucleic acid and (ii) a the delivery of contrast agents to the cells for diagnostic selectivity agent which is capable of binding with high purposes.
    [Show full text]