DOCSLIB.ORG

CHARACTERIZING the MELATONERGIC SYSTEM AFTER BRAIN INJURY by Nicole Danielle Osier Bachelor of Science (B.S.) in Nutritional

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
CHARACTERIZING the MELATONERGIC SYSTEM AFTER BRAIN INJURY by Nicole Danielle Osier Bachelor of Science (B.S.) in Nutritional CHARACTERIZING THE MELATONERGIC SYSTEM AFTER BRAIN INJURY by Nicole Danielle Osier Bachelor of Science (B.S.) in Nutritional Science, Michigan State University, 2008 Bachelor of Science in Nursing (B.S.N.), Michigan State University, 2008 Submitted to the Graduate Faculty of School of Nursing in partial fulfillment of the requirements for the degree of Doctor of Philosophy (PhD) in Nursing University of Pittsburgh 2016 UNIVERSITY OF PITTSBURGH SCHOOL OF NURSING This dissertation was presented by Nicole Danielle Osier It was defended on July 12, 2016 and approved by C. Edward Dixon, PhD, Professor, School of Medicine Yvette Conley, PhD, Professor, School of Nursing Dianxu Ren, MD, PhD, Associate Professor, School of Nursing Ava Puccio, PhD, Assistant Professor, School of Medicine Dissertation Advisor: Sheila Alexander, PhD, Associate Professor, School of Nursing ii Copyright © by Nicole Danielle Osier 2016 iii CHARACTERIZING THE MELATONERGIC SYSTEM AFTER BRAIN INJURY Nicole Danielle Osier, PhD, BSN, BS, RN University of Pittsburgh, 2016 Traumatic brain injury (TBI) affects individuals of all ages, races, and geographies and is often associated with expensive clinical management. Melatonin (MEL) has been trialed as a TBI therapeutic with mixed results, due in part to a lack of understanding of the mechanism. This study characterizes endogenous changes in melatonergic receptors (MT1 and MT2) after experimental TBI induced using pneumatic CCI (2.8 mm depth) in young adult Sprague Dawley rats. Half the rats were exposed to sham surgery to control for the effects of anesthesia and craniectomy. In total, 25 rats were enrolled in the study, with 6-7 rats per group. Test animals were sacrificed at 2 post- surgery time points, either 6 hours (hr) or 24 hr post-surgery. Following sacrifice, the test animal’s brain was harvested, dissected, and flash frozen until analysis. Whole cell lysates were prepared, aliquoted, and used for western blot analysis, probing for cytochrome C (to validate injury severity), MT1, MT2, and beta actin (to control for protein loading). ImageJ and Image Lab software were used to quantify protein data; SPSS software was used to run t-tests to compare group means on a single variable and correlation testing was used to explore the relationship between outcomes of interest. Melatonin receptors were down-regulated in a brain region- and time point- dependent manner. MT1 was downregulated in the frontal cortex at 24 hr and in the hippocampus at both 6 hr and 24 hr post-TBI. Similarly, MT2 was downregulated in the frontal cortex at 24 hr and in the hippocampus at both 6 and 24 hr post-TBI. This is the first study to report downregulation of MT1 and MT2 after neurotrauma; receptor downregulation may affect the efficacy of MEL therapy. Additional research to characterize these changes after TBI are necessary iv including efforts to establish the time course and regional patterns, replication in more diverse samples, as well as inclusion of additional cellular, histological, and behavioral endpoints. TBI in rats modeled using CCI results in acute downregulation of MEL-specific receptors (subtypes MT1 and MT2); replication of these findings is necessary as are evaluations of the implications of lower receptor levels. v TABLE OF CONTENTS PREFACE ................................................................................................................................. XIX 1.0 INTRODUCTION TO THE STUDY AS ORIGINALLY PLANNED ................. 23 1.1 PURPOSE AND SPECIFIC AIMS .................................................................. 27 1.2 BACKGROUND AND SIGNIFICANCE ........................................................ 28 Rationale for studying traumatic brain injury ........................................... 31 Rationale for using a pre-clinical (animal) model of brain injury ............ 32 Rationale for using a molecular genetic approach ..................................... 33 Rationale for examining the melatonergic system ...................................... 34 Rationale for examining apoptosis as a cellular level outcome ................. 35 Rationale for functional outcomes: learning, memory, and motor ........... 36 Conceptual framework.................................................................................. 37 Innovation....................................................................................................... 40 Summary ........................................................................................................ 41 1.3 PRELIMINARY STUDIES .............................................................................. 42 Establishing the apoptotic consequences of the model ............................... 44 Evaluating endogenous levels of MT1 in the model ................................... 45 Establishing behavioral consequences of the model ................................... 46 Effects of exogenous MEL on behavior after CCI ...................................... 49 vi 1.4 RESEARCH DESIGN AND METHODS ........................................................ 51 Animal subjects .............................................................................................. 51 Overview of study design .............................................................................. 52 Sample............................................................................................................. 54 Injury induction ............................................................................................. 56 1.4.4.1 Controlled cortical impact model (CCI) ........................................... 56 1.4.4.2 Specific injury parameters ................................................................. 58 Melatonin therapy ......................................................................................... 58 Measurement of apoptotic proteins ............................................................. 59 Measurement of functional deficits .............................................................. 60 1.4.7.1 Morris water maze (MWM) ............................................................... 60 1.4.7.2 Beam balance task ............................................................................... 65 1.4.7.3 Novel object recognition ..................................................................... 66 Analysis ........................................................................................................... 67 1.4.8.1 Sample size justification ..................................................................... 67 1.4.8.2 Preliminary data analysis ................................................................... 67 1.4.8.3 Aim 1 analysis ...................................................................................... 68 1.4.8.4 Aim 2 analysis ...................................................................................... 68 1.4.8.5 Expected findings and interpretation ................................................ 70 1.5 LIMITATIONS AND PROPOSED ALTERNATIVES ................................. 70 1.6 HAZARDOUS MATERIALS AND PROCEDURES .................................... 72 1.7 RESEARCH SUBJECT RISKS, BENEFITS, AND PROTECTIONS ........ 72 Potential risks and protection against risks ................................................ 73 vii Potential benefits............................................................................................ 74 Data safety and monitoring plan .................................................................. 74 2.0 SUMMARY OF DISSERTATION STUDY ............................................................ 75 2.1 PROPOSAL CHANGES ................................................................................... 78 Animals that were lost or excluded from the pilot sample ........................ 79 Concerns raised during analysis of full 8-group pilot sample ................... 80 Comparison of vehicle-treated animals to establish injury effect ............. 82 2.1.3.1 Beam balance task ............................................................................... 83 2.1.3.2 Novel object recognition (NOR) ......................................................... 84 2.1.3.3 Morris water maze (MWM) ............................................................... 86 Possible sources of error and other issues ................................................... 89 Alternative CCI model trialed ...................................................................... 91 Delayed breeding of knockout mice ............................................................. 92 Changes made to study plan ......................................................................... 93 2.1.7.1 Refinement of variables ...................................................................... 94 2.1.7.2 Replacement of animal model ............................................................ 94 2.1.7.3 Modification of brain injury model ................................................... 95 2.1.7.4 Revised sample and groups ................................................................ 95 2.1.7.5 Revised specific aims ........................................................................... 96 2.1.7.6 Revised methods .................................................................................. 96 2.1.7.7 Revised analysis ................................................................................... 97 Summary of study after modifications ........................................................ 97 Discussion
Load more

Recommended publications
  • Homology Models of Melatonin Receptors: Challenges and Recent Advances
    Int. J. Mol. Sci. 2013, 14, 8093-8121; doi:10.3390/ijms14048093 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review Homology Models of Melatonin Receptors: Challenges and Recent Advances Daniele Pala 1, Alessio Lodola 1, Annalida Bedini 2, Gilberto Spadoni 2 and Silvia Rivara 1,* 1 Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy; E-Mails: [email protected] (D.P.); [email protected] (A.L.) 2 Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino “Carlo Bo”, Piazza Rinascimento 6, I-61029 Urbino, Italy; E-Mails: [email protected] (A.B.); [email protected] (G.S.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +39-0521-905-061; Fax: +39-0521-905-006. Received: 7 March 2013; in revised form: 28 March 2013 / Accepted: 28 March 2013 / Published: 12 April 2013 Abstract: Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT1 and MT2. So far, a number of different MT1 and MT2 receptor homology models, built either from the prototypic structure of rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been proposed. These receptor models differ in the binding modes hypothesized for melatonin and melatonergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. The receptor models will be described, and they will be discussed in light of the available information from mutagenesis experiments and ligand-based pharmacophore models.
    [Show full text]
  • ANTIDEPRESSANTS in USE in CLINICAL PRACTICE Mark Agius1 & Hannah Bonnici2 1Clare College, University of Cambridge, Cambridge, UK 2Hospital Pharmacy St
    Psychiatria Danubina, 2017; Vol. 29, Suppl. 3, pp 667-671 Conference paper © Medicinska naklada - Zagreb, Croatia ANTIDEPRESSANTS IN USE IN CLINICAL PRACTICE Mark Agius1 & Hannah Bonnici2 1Clare College, University of Cambridge, Cambridge, UK 2Hospital Pharmacy St. James Hospital Malta, Malta SUMMARY The object of this paper, rather than producing new information, is to produce a useful vademecum for doctors prescribing antidepressants, with the information useful for their being prescribed. Antidepressants need to be seen as part of a package of treatment for the patient with depression which also includes psychological treatments and social interventions. Here the main Antidepressant groups, including the Selective Serotonin uptake inhibiters, the tricyclics and other classes are described, together with their mode of action, side effects, dosages. Usually antidepressants should be prescribed for six months to treat a patient with depression. The efficacy of anti-depressants is similar between classes, despite their different mechanisms of action. The choice is therefore based on the side-effects to be avoided. There is no one ideal drug capable of exerting its therapeutic effects without any adverse effects. Increasing knowledge of what exactly causes depression will enable researchers not only to create more effective antidepressants rationally but also to understand the limitations of existing drugs. Key words: antidepressants – depression - psychological therapies - social therapies * * * * * Introduction Monoamine oxidase (MAO) inhibitors í Non-selective Monoamine Oxidase Inhibitors Depression may be defined as a mood disorder that í Selective Monoamine Oxidase Type A inhibitors negatively and persistently affects the way a person feels, thinks and acts. Common signs include low mood, Atypical Anti-Depressants and other classes changes in appetite and sleep patterns and loss of inte- rest in activities that were once enjoyable.
    [Show full text]
  • Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-Glcnacylation, Acetyl-Coa and Melatonergic Pathway in Regulat
    International Journal of Molecular Sciences Review Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types—Tumour Microenvironment and Metabolism George Anderson Clinical Research Communications (CRC) Scotland & London, Eccleston Square, London SW1V 6UT, UK; [email protected] Abstract: This article reviews the dynamic interactions of the tumour microenvironment, highlight- ing the roles of acetyl-CoA and melatonergic pathway regulation in determining the interactions between oxidative phosphorylation (OXPHOS) and glycolysis across the array of cells forming the tumour microenvironment. Many of the factors associated with tumour progression and immune resistance, such as yin yang (YY)1 and glycogen synthase kinase (GSK)3β, regulate acetyl-CoA and the melatonergic pathway, thereby having significant impacts on the dynamic interactions of the different types of cells present in the tumour microenvironment. The association of the aryl hydrocarbon receptor (AhR) with immune suppression in the tumour microenvironment may be mediated by the AhR-induced cytochrome P450 (CYP)1b1-driven ‘backward’ conversion of mela- tonin to its immediate precursor N-acetylserotonin (NAS). NAS within tumours and released from tumour microenvironment cells activates the brain-derived neurotrophic factor (BDNF) receptor, TrkB, thereby increasing the survival and proliferation of cancer stem-like cells. Acetyl-CoA is a cru- Citation:
    [Show full text]
  • Novel Melatonin MT1 Receptor Agonists As Antidepressants
    Novel melatonin MT1 receptor agonists as antidepressants: In vivo electrophysiological and behavioural characterization Ada R. Posner Degree of Master of Science Neurobiological Psychiatry Unit Department of Psychiatry Faculty of Medicine McGill University Montreal, Quebec, Canada April, 2015 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Master of Science in Psychiatry Copyright Ada R. Posner, 2015 Table of Contents Table of Contents ................................................................................................ 2 Abstract ............................................................................................................... 3 Résumé ............................................................................................................... 5 Acknowledgements ............................................................................................. 7 Preface & Contribution of Authors ...................................................................... 8 Abbreviations ...................................................................................................... 9 Introduction ....................................................................................................... 14 Melatonin ...................................................................................................... 14 Sites and mechanisms of melatonin action: receptors ................................. 17 Localization and distribution of melatonin receptors in the brain
    [Show full text]
  • Α2 Adrenergic Receptor Trafficking As a Therapeutic Target in Antidepressant Drug Action
    CHAPTER NINE α2 Adrenergic Receptor Trafficking as a Therapeutic Target in Antidepressant Drug Action Christopher Cottingham*,1, Craig J. Ferryman*, Qin Wang†,1 *Department of Biology and Chemistry, Morehead State University, Morehead, Kentucky, USA †Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA 1Corresponding authors: e-mail address: [email protected]; [email protected] Contents 1. Introduction 207 2. Physiological Basis for Studying α2AAR Trafficking in Depression 209 3. Arrestin-Biased Regulation of the α2AAR by the TCA Drug Class 211 4. Therapeutic Implications 216 References 219 Abstract Antidepressant drugs remain poorly understood, especially with respect to pharmaco- logical mechanisms of action. This lack of knowledge results from the extreme complex- ity inherent to psychopharmacology, as well as to a corresponding lack of knowledge regarding depressive disorder pathophysiology. While the final analysis is likely to be multifactorial and heterogeneous, compelling evidence exists for upregulation of brain α2 adrenergic receptors (ARs) in depressed patients. This evidence has sparked a line of research into actions of a particular antidepressant drug class, the tricyclic antidepres- sants (TCAs), as direct ligands at α2AARs. Our findings, as outlined herein, demonstrate that TCAs function as arrestin-biased ligands at α2AARs. Importantly, TCA-induced α2AAR/arrestin recruitment leads to receptor endocytosis and downregulation of α2AAR expression with prolonged exposure. These findings represent a novel mecha- nism linking α2AR trafficking with antidepressant pharmacology. 1. INTRODUCTION Psychopharmacology is an exceedingly intricate discipline, aiming as it does to modulate human emotion, behavior, and other complex cognitive processes. Although our understanding of brain–behavior relationships has # Progress in Molecular Biology and Translational Science, Volume 132 2015 Elsevier Inc.
    [Show full text]
  • Serotonin 2C Receptor Antagonists Induce Fast-Onset Antidepressant Effects
    Molecular Psychiatry (2013), 1–9 & 2013 Macmillan Publishers Limited All rights reserved 1359-4184/13 www.nature.com/mp ORIGINAL ARTICLE Serotonin 2C receptor antagonists induce fast-onset antidepressant effects MD Opal1,2, SC Klenotich1,2, M Morais3,4, J Bessa3,4, J Winkle2, D Doukas2,LJKay1,5,6, N Sousa3,4 and SM Dulawa1,2 Current antidepressants must be administered for several weeks to produce therapeutic effects. We show that selective serotonin 2C (5-HT2C) antagonists exert antidepressant actions with a faster-onset (5 days) than that of current antidepressants (14 days) in mice. Subchronic (5 days) treatment with 5-HT2C antagonists induced antidepressant behavioral effects in the chronic forced swim test (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy paradigm. This treatment regimen also induced classical markers of antidepressant action: activation of cAMP response element-binding protein (CREB) and induction of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). None of these effects were induced by subchronic treatment with citalopram, a prototypical selective serotonin reuptake inhibitor (SSRI). Local infusion of 5-HT2C antagonists into the ventral tegmental area was sufficient to induce BDNF in the mPFC, and dopamine D1 receptor antagonist treatment blocked the antidepressant behavioral effects of 5-HT2C antagonists. 5-HT2C antagonists also activated mammalian target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the mPFC, effects recently linked to rapid antidepressant action. Furthermore, 5-HT2C antagonists reversed CMS-induced atrophy of mPFC pyramidal neurons. Subchronic SSRI treatment, which does not induce antidepressant behavioral effects, also activated mTOR and eEF2 and reversed CMS-induced neuronal atrophy, indicating that these effects are not sufficient for antidepressant onset.
    [Show full text]
  • Cyclohexanesulfonyl Derivatives As Glyt1
    (19) TZZ_¥_T (11) EP 1 893 566 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07C 317/30 (2006.01) C07D 213/82 (2006.01) 13.02.2013 Bulletin 2013/07 C07D 239/28 (2006.01) C07D 249/04 (2006.01) C07C 233/70 (2006.01) A61K 31/166 (2006.01) (2006.01) (2006.01) (21) Application number: 06744089.1 A61K 31/44 A61K 31/4412 A61K 31/4192 (2006.01) A61P 25/18 (2006.01) C07C 233/76 (2006.01) C07D 231/12 (2006.01) (22) Date of filing: 05.06.2006 C07D 231/18 (2006.01) C07D 307/68 (2006.01) C07D 333/38 (2006.01) C07D 471/04 (2006.01) C07D 495/04 (2006.01) C07D 295/135 (2006.01) C07D 285/125 (2006.01) C07D 295/108 (2006.01) (86) International application number: PCT/GB2006/002035 (87) International publication number: WO 2006/131711 (14.12.2006 Gazette 2006/50) (54) CYCLOHEXANESULFONYL DERIVATIVES AS GLYT1 INHIBITORS TO TREAT SCHIZOPHRENIA CYCLOHEXANSULFONYLDERIVATE ALS GLYT1-HEMMER ZUR BEHANDLUNG VON SCHIZOPHRENIE DERIVES DE CYCLOHEXANESULFONYLE EN TANT QU INHIBITEURS DE GLYT1 POUR TRAITER LA SCHIZOPHRENIE (84) Designated Contracting States: • CASTRO PINEIRO, Jose, Luis AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Merck & Co., Inc. HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI Harlow Essex CM20 2QR (GB) SK TR • LEWIS, Richard, Thomas Designated Extension States: Merck & Co., Inc. HR Harlow Essex CM20 2QR (GB) • NAYLOR, Elizabeth, Mary (30) Priority: 06.06.2005 GB 0511452 Merck & Co., Inc.
    [Show full text]
  • Status of Neuropharmacology Research in India
    Published Online on 2 April 2018 Proc Indian Natn Sci Acad 84 No. 1 March 2018 pp. 15-31 Printed in India. DOI: 10.16943/ptinsa/2018/49309 Review Article Status of Neuropharmacology Research in India YOGENDRA K GUPTA*, JATINDER KATYAL and SANGEETHA GUPTA Neuropharmacology Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110 029, India (Received on 13 September 2017; Accepted on 11 December 2017) Neurological and neuropsychiatric problems have been recognized as formidable issue worldwide in developed as well as developing countries due to a sizable mortality and debilitating sequelae. A lot of impetus on research in this area over the past two decades has led to a better understanding of these diseases and made available tools in the form of experimental model systems, mechanistic pathways and genetic connections to provide the researchers with an enabling environment for drug discovery, better value from existing drugs and circumventing toxic effects. In India, the past decade has witnessed a broadening of research base of neuropharmacology research and a close look reveals that Indian research is very much contemporary. A kaleidoscopic view of neuropharmacology research in India in over the past five years is presented in this article. Keywords: Neuropharmacology; Research; Neurological Disorders; Neuropsychiatric Disorders; Epilepsy; Stroke; Parkinson’s Disease; Alzheimer’s Disease; Pain Introduction is constituted by cerebrovascular diseases which are responsible for 85% of the deaths, 12% by Alzheimer Neuropharmacology is a branch of pharmacology, and other dementias and 8% each by epilepsy and which evolved with only four drugs prior 1900s namely migraine. The lower middle income countries account morphine and aspirin for pain, nitrous oxide as 16.8% of the total deaths as compared to 13.2% in anesthetic agent for surgery and caffeine for high income countries (WHO 2006).
    [Show full text]
  • Improving Antidepressant Drugs: Update on Recently Patented
    Improving antidepressant drugs: update on recently patented compounds ABSTRACT Background: According to the World Health Organization, depression is a common condition that affects about 121 million people worldwide. Although the pathophysiological origin of this condition is still unknown, most of the known antidepressants enhance the extracellular availability of brain monoamines (serotonin and/or noradrenaline). Objective/Method: We have searched for the potential drugs and targets being addressed in the most recent patents. Hence, we have explored the Patent Database of the European Patent Office using the esp@cenet searching engine for the period 2005-2008, looking for “antidepressants”. In addition, a search in the Medtrack database yielded information on pharmaceutical companies developing compounds as antidepressants, market size and their market prospects. Conclusions: We have found that, in general, the preferred targets to develop antidepressants continue to be those aiming the serotoninergic system and, in a less extend, the noradrenergic one; but, more particularly, those that aim multiple targets are preferred due to problems concerning the efficacy of highly selective drugs. Additionally, a small number of new systems are being targeted, such as the melatonergic. However, when looking at the pharma-market and the antidepressants in the pipeline a new trend is observed developing dual-action drugs that could be used in depression and schizophrenia therapy. KEYWORDS Antidepressants, SSRI, SNRI, α2-adrenoceptor antagonist, 5-HT antagonist, fluoxetine, mirtazapine, schizophrenia, glycinergic system, melatonin, multi-target drugs. 1. INTRODUCTION According to the World Health Organization, depression is a common condition that affects about 121 million people worldwide.1 Moreover, neuropsychiatric disorders are the second largest cause of disease burden in the world after cardiovascular diseases, and the number of people affected with these disorders is likely to increase further as the population ages.
    [Show full text]
  • Synthesis, 142 Termination of Action, 142–143 See Also Serotonin
    Cambridge University Press 978-1-107-02598-1 — Stahl's Essential Psychopharmacology 4th Edition Index More Information Index 5HT (5-hydroxytryptamine) acetaminophen, 340 alpha 1 adrenergic antagonists synthesis, 142 acetylation of histones, 24 atypical antipsychotics, 173 termination of action, 142–143 acetylcholine, 5 alpha 2 antagonists, 317–322 See also serotonin. as brain’s own nicotine, 543 alpha 2 delta ligands 5HT1A receptor partial agonists basis for cholinesterase treatment as anxiolytics, 403–405 atypical antipsychotics, 156–159 of dementia, 522–528 alpha 2A adrenergic agonists vilazodone, 300–302 cholinergic pathways, 524 ADHD treatment, 495–499 5HT1B/D receptors cholinergic receptors, 523–528 alpha-melanocyte stimulating effects of atypical antipsychotics, precursors, 524 hormone (alpha-MSH), 565 159–160 acetylcholine transporters, 523 alprazolam, 5, 49 terminal autoreceptors, 159–160 acetylcholine vesicular transporter, 29 Alzheimer’s dementia, 504 5HT2A receptor antagonists, 318 acetylcholinesterase, 46, 522–525 and psychosis, 79 atypical antipsychotic actions, Adapin, 342 Alzheimer’s disease 142–156 adenosine antagonist acetylcholine as target for current effects on dopamine D2 receptors, caffeine, 469 symptomatic treatment, 522–527 151–156 adiponectin, 565 aggressive and hostile symptoms, 85 effects on extrapyramidal adolescents amyloid as target of disease- symptoms, 150 bipolar disorder, 386 modifying treatment, 520–523 effects on prolactin levels, mania, 386 amyloid cascade hypothesis, 150–151 mood stabilizer selection,
    [Show full text]
  • Agomelatine, the First Melatonergic Antidepressant: Discovery, Characterization and Development
    Nature Reviews Drug Discovery | AOP, published online 25 June 2010; doi:10.1038/nrd3140 REVIEWS CASE HISTORY Agomelatine, the first melatonergic antidepressant: discovery, characterization and development Christian de Bodinat*, Béatrice Guardiola-Lemaitre‡, Elisabeth Mocaër*, Pierre Renard§, Carmen Muñoz|| and Mark J. Millan¶ Abstract | Current management of major depression, a common and debilitating disorder with a high social and personal cost, is far from satisfactory. All available antidepressants act through monoaminergic mechanisms, so there is considerable interest in novel non-monoaminergic approaches for potentially improved treatment. One such strategy involves targeting melatonergic receptors, as melatonin has a key role in synchronizing circadian rhythms, which are known to be perturbed in depressed states. This article describes the discovery and development of agomelatine, which possesses both melatonergic agonist and complementary 5-hydroxytryptamine 2C (5-HT2C) antagonist properties. Following comprehensive pharmacological evaluation and extensive clinical trials, agomelatine (Valdoxan/Thymanax; Servier) was granted marketing authorization in 2009 for the treatment of major depression in Europe, thereby becoming the first approved antidepressant to incorporate a non-monoaminergic mechanism of action. Depression is a complex, heterogeneous and incapacitating soon became apparent1–3,7. In their wake, the 1980s and disorder that is associated with a heavy burden to the 1990s witnessed the introduction of more specific patients and their families, and to society. Although inhibitors of serotonin (also known as 5-hydroxytrypt- *Institut de Recherches currently available antidepressants have genuine value in amine; 5-HT) and/or noradrenaline reuptake. Selective Internationales Servier, 6 Place des Pléiades, 92415 the treatment of this disorder, they take several weeks to serotonin reuptake inhibitors (SSRIs), noradrenaline Courbevoie, Cedex, France.
    [Show full text]
  • Circadian and Homeostatic Sleep-Wake Regulation in Women
    Circadian and Homeostatic Sleep-Wake Regulation in Women: Effects of Age and Major Depressive Disorder Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Sylvia Frey aus Gontenschwil (AG) Zürich, 2012 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Dissertationsleiter: Prof. Dr. Christian Cajochen Fakultätsverantwortlicher: Prof. Dr. Heinrich Reichert Korreferent: Prof. Dr. Robert Thurnheer Basel, den 21.6.2011 Prof. Dr. Martin Spiess Dekan 3 !∀ # ∀ ∃ % &∀∀∀ % ∀ ∋( ) ∗ ∀ # ∗ +, ∀ # ∀ % ∗ −. ! ∀ # % 9% & ∗ .0 .0 12234 : 0 % 9% ∗ ; ∗ .∀ % % < ∗ 9 9 ∀ % ) 9% = / 0.0 12234 %0563778 Contents Summary 1 1 Introduction 5 2 Consequences of the timing of menarche on female adolescent sleep phase preference 29 3 Challenging the sleep homeostat in young depressed and healthy older women: sleep in depression is not premature aging 43 4 Young women with major depression live on higher homeostatic sleep pressure than healthy controls 69 5 Concluding and prospective remarks 97 Bibliography 103 Curriculum Vitae 127 Publications 129 Acknowledgments 133 i Summary Everyday life of all organisms is governed by rhythmic physiological changes throughout the 24-h day. The most obvious circadian rhythm is the sleep-wake cycle. During a human lifespan the sleep-wake cycle undergoes a number of specific changes, which involve sleep duration, sleep architecture, electrophysiological characteristics, and sleep timing. Age, gender and developmental stage during childhood and adolescence have strong influences on sleep. Abnormalities in sleep-wake cycle regulation are often sequelae of different disorders and may often be the cause of specific diseases. Two groups where marked alterations in sleep-wake cycles occur include adolescents and people with psychiatric disorders.
    [Show full text]