DOCSLIB.ORG

The Role of Calcium and Mitochondria in the Etiology and Treatment of Three Different Disease Paradigms

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of Calcium and Mitochondria in the Etiology and Treatment of Three Different Disease Paradigms Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Sciences The Role of Calcium and Mitochondria in the Etiology and Treatment of Three Different Disease Paradigms Submitted by: Christine Brink In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences Examination Committee Major Advisor: David Giovannucci, Ph.D. Academic Linda Dokas, Ph.D. Advisory Committee: Joseph Margiotta, Ph.D. Andrew Beavis, Ph.D. Ana Marie Oyarce, Ph.D. L. John Greenfield, M.D., Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: December 7, 2007 The Role of Calcium and Mitochondria in the Etiology and Treatment of Three Different Disease Paradigms Christine A. Brink University of Toledo, Health Science Campus 2007 Acknowledgements First, I would like to thank my advisor, Dr. David Giovannucci, for his encouragement and support throughout my graduate training. His advice and understanding have been essential to my success over the past 5 years. I will always be grateful for the education he has provided to me, and the compassion he has shown toward me. Next, I would like to thank Jenny Giovannucci for her illustrations and encouragement. I would also like to thank Rebecca Pierson for providing the primary cortical neuronal cultures, and countless words of advice. Additionally, I would like to thank Christian Peters for his counsel and assistance throughout our training. In addition, I would like to thank my committee members, Dr. Greenfield, Dr. Dokas, Dr. Margiotta, Dr. Beavis, and Dr. Oyarce, for their contributions and guidance. Lastly, I would like to express my unending gratitude toward my family. My husband’s patience and encouragement have been indispensable during this time. Also, the love and support of my parents were critical in preparing me to take on this incredible and fascinating journey. i Abbreviations Used IP3 1,4,5,triphosphate GABA γ-aminobutyric acid Allo Allopregnanolone AD Alzheimer’s disease Aβ Amyloid-β APP Amyloid precursor protein ALS Amyotrophic lateral sclerosis Ca2+ Calcium CRAC Calcium release activated channel CCE Capacitative calcium entry FCCP Carbonylcyanide-4-(trifluoromethoxy)-phenylhydrazone CAI Carboxyamidotriazole Icrac Current from CRAC channel CIF Cytochrome c efflux inducing factor DMEM Delbeco’s Modified Eagle Medium EC50 Effective concentration at 50% ER Endoplasmic reticulum EDTA Ethylenediamine-tetraacetic acid disodium salt EGTA Ethleneglycol-O, O’ bis(2aminoethyl)N,N,N’,N’-tetraacetic acid GFAP Glial fibrillary acidic protein HVA High voltage activated ii HN Hypothalamic neurohypophysis HPA Hypothalamic pituitary axis ISS Intercellular saline solution LDP Long term depression LTP Long term potentiation LVA Low voltage activated HEDTA N-(2-hydroxyethlenediamine-N, N’, N’-triacetic acid trisodium salt PIP2 Phosphatidylinositol biphosphate PLC Phospholipase C PSS Physiological saline solution PKC Protein kinase C SR Sarcoplasmic reticulum SERCA Sarcoplasmic/endoplasmic reticulum calcium ATPase SCID Severe combined immunodeficency syndrome SNARES Soluble N-ethylmalemide sensitive factor protein receptor SOC Store operated channel TMRM Tetramethyl-rhodamine methyl ester perchlorate TRP Transient receptor protein VGCC Voltage gated calcium channel iii Table of Contents Preliminaries Page Acknowledgments i Abbreviations Page ii Table of Contents iv Chapters Page I Introduction 1 II Methods 6 III Background and Literature Review 15 IV Results 39 V Results 56 VI Results 78 VII Conclusions 103 Bibliography 106 Abstract 139 iv Chapter I: Introduction Calcium (Ca2+) is an important cellular messenger involved in a variety of critical messaging pathways. From cell proliferation to apoptosis, Ca2+ is involved in multiple facets of cell health. Even in the most primitive prokaryotes maintaining the Ca2+ gradient is important, and cytosolic free Ca2+ concentrations are controlled (Case, 2007) . In eukaryotes, Ca2+’s importance is demonstrated early in development, as it controls fertilization and cellular differentiation (Lory et al., 2006). After development, Ca2+ plays a critical role through its control of gene transcription, and is responsible for a myriad of messages including: control of movement, synaptic plasticity, wound healing, insulin secretion and a host of other important functions (Berridge et al., 1998). Consequently, to control all these signaling pathways, Ca2+ uses a diverse range of signaling mechanisms to convey the proper signal for the desired outcome. To achieve specificity of the signals, cells have devised a multitude of means to separate the messages. This is accomplished by a variety of types, locations, amplitudes, kinetics and specific sources of Ca2+ signals. For example, Ca2+ can enter the cytosol through the plasma membrane from a variety of types of Ca2+ channels or transporters, or Ca2+ can be released from internal stores through the action of second messengers like inositol 1,4,5-triphosphate (IP3) on the intracellular release channel, the IP3 Receptor (Broad et al., 1999). Localization of Ca2+ signals is often manifested as microdomains classified by the types of channels involved. Specific examples of these are: sparklets from voltage-operated channels, sparks from ryanodine receptors, blinks which are 1 decreases in ER Ca2+ due to release, and puffs which are responsible for Ca2+ waves induced by IP3 receptors (Berridge, 2006). In addition, there are two types of Ca2+ waves, intracellular and intercellular, and each of these wave types is responsible for different signals (Bootman et al., 2001). There are also a multitude of types of Ca2+ channels that help with specificity of the Ca2+ message. These include: voltage-gated channels (L-type, T-type, R-type, N- type), pumps and exchangers, Ca2+ ATPases, receptor operated channels, second messenger operated channels, and channels on mitochondria and internal stores. Additionally, each of these sources of Ca2+ signaling may be linked to specific physiological outcomes. However, because Ca2+ signaling is so critical and utilizes such diverse pathways, disturbing the critical balance of Ca2+ levels can be devastating to cell health and physiological cell function. Correspondingly, many diseases involve an interruption or unbalance in a Ca2+-signaling pathway. For example, Alzheimer’s Disease (AD), cancer, diabetes, and Parkinson’s disease, have all been linked to a possible deregulation of Ca2+; and in some cases altering the Ca2+ signaling has been considered a possible treatment mechanism. Ca2+ is known to be involved in regulation of the cell cycle. For example, Kao et al (1990) demonstrated that chelating cytosolic Ca2+ blocked the transition from metaphase to anaphase in three different cell types, showing that altering physiological Ca2+ can alter the cell-cycle. Additionally, Guderman and Roelle (2006) found evidence suggesting that disruption of Ca2+ signaling was a key event in the abnormal growth of some small cell lung cancers. Furthermore, 2 many neurodegenerative disorders have focused on Ca2+ dysregulation having a role in the death of neurons. Ca2+ is a major player in the pathways of apoptosis, having a role in both the intrinsic and extrinsic pathways of apoptosis, including those induced by ROS, UV-fragmentation of DNA, and cytotoxic drugs (Hajnoczky et al., 2003). Apoptosis is suspected to play a role in neuronal death in diseases such as AD. Additionally, there are multiple diseases and disorders that involve defects of specific Ca2+ channels. For example, genetic defects in voltage gated Ca2+ channels can result in disorders involving the musculature, neurological, cardiac and vision systems. However, in order to exploit Ca2+ signaling pathways for treatment, a better understanding of the pathways must be established. One important element in understanding Ca2+ signaling is the role of mitochondria. The ability of mitochondria to uptake Ca2+ was first discovered in the 1960’s (Babcock et al., 1997). Mitochondria sequester Ca2+ through the mitochondrial uniporter, a highly selective pore on the mitochondria that utilizes the membrane potential of mitochondria to drive the uptake of positively charged Ca2+ ions (Kirichok et al., 2004). The mitochondrial membrane potential is established through the electron gradient created by the proton-motive force, a mechanism in which positively charged hydrogen ions are moved from inside the inner mitochondrial membrane to outside the membrane. Thus, this process creates a negative charge on the inside of the mitochondrial membrane, which is the driving force for influx of positively charged Ca2+ ions. Therefore, the 3 mitochondrial membrane potential is essential for the maintenance of Ca2+ signaling in mitochondria. Furthermore, mitochondria are intimately involved in shaping many Ca2+ signals (Duchen, 2000; Rizzuto et al., 2000). However, the role of mitochondria in Ca2+ signaling pathways was not fully appreciated until the discovery of Ca2+ microdomains, discussed previously. For example, the role of mitochondria in capacitative Ca2+ entry has recently been identified. When Ca2+ is released from internal stores, store operated channels (SOC) on the plasma membrane are activated, causing them to open and influx more Ca2+. High levels of Ca2+ around the SOC can deactivate the channels, causing them to close. Mitochondria, however, can take up the excess Ca2+ around the SOC keeping the levels low enough for the channel to remain open, allowing
Load more

Recommended publications
  • Determining the Role of Gabaergic Signaling in The
    DETERMINING THE ROLE OF GABAERGIC SIGNALING IN THE CRANIOFACIAL DEVELOPMENT OF LARVAL ZEBRAFISH by LINDSEY L. BEEBE (Under the Direction of James D. Lauderdale) ABSTRACT Although best known as an inhibitory neurotransmitter, intriguing evidence has implicated GABA as a key signaling molecule in craniofacial development in mammals. Glutamate is converted to GABA by an enzyme called glutamic acid decarboxylase (GAD), which exists in two isoforms, GAD67 and GAD65. The GAD1 and GAD2 genes encode these isoforms, respectively. A decrease in GAD activity in the human brain is often associated with epilepsy, schizophrenia and related neurological disorders. In mice and humans, mutations in gad1, but not gad2, result in defects in palate development, and mutations in the Gabrb3 gene, which encodes the β3 subunit of the GABAA receptor, exhibit a comparable phenotype to gad1 mutations. These results suggest that GABA signaling, through the GABAA receptor, can play an important and conserved role in craniofacial development. However, the mechanism of this process is not known and cannot be easily investigated in a mammalian system. In this work, translation-blocking morpholinos against the GAD genes were used to alter expression within the larval zebrafish. While gad2 morphants looked phenotypically normal, gad1 morphant animals exhibited altered cranial structures at 1 and 7 dpf. Yet, both gad1 and gad2 morphants exhibited spontaneous seizure-like neural activity. Through the use of photoactivatable caged-morpholinos, the craniofacial deformities could be bypassed when photolysis was carried out at 24 hpf. Electrophysiological recordings showed that while dark-raised CyHQ-gad1 morphant animals looked phenotypically comparable to wild-type animals, they exhibited abnormal, seizure-like neural activity.
    [Show full text]
  • Herbal Contraindications & Drug Interactions
    Herbal Contraindications & Drug Interactions plus Herbal Adjuncts with Medicines FOURTH EDITION, 2010 © by Francis Brinker, N.D. References 1. Sherman JA (comp.). The Complete Botanical Prescriber, 2nd ed. National College of Naturopathic Medicine, Portland, Ore., 1979 2. Brinker F. The Toxicology of Botanical Medicines, 3rd ed. Eclectic Medical Pub., Sandy, Ore., 2000 3. Brinker F. “Botanical Medicine Research Summaries,” from Eclectic Dispensatory of Botanical Therapeutics, vol. II. Eclectic Medical Pub., Sandy, Ore., 1995 4. Wichtl M (ed.). Herbal Drugs and Phytopharmaceuticals. CRC Press, Boca Raton, 1994 5. Felter HW, Lloyd JU. King’s American Dispensatory [1898]. Eclectic Medical Pub., Sandy, Ore., 1993 6. De Smet PAGM et al. (eds.). Adverse Effects of Herb Drugs 2. Springer-Verlag, Berlin, 1993 7. Lust J. The Herb Book. Bantam Books, New York, 1974 8. Boyd JR (ed.-in-chief). Facts and Comparisons. J.B. Lippincott Co., St. Louis, Miss., 1985 9. Ruddiman EA. Incompatibilities in Prescriptions. John Wiley & Sons, Inc., New York, 1925 10. Lewis WH, Elvin-Lewis MPF. Medical Botany. John Wiley & Sons, New York, 1977 11. Gibelli C. The hemostatic action of Equisetum. Arch. intern. pharmacodynamie, 41:419-429, 1931 (Chem. Abs. 26:6019) 12. Gutierrez RMP, Laguna GY, Walkowski, A. diuretic activity of Mexican Equisetum. J. Ethnopharm., 14:269- 272, 1985 13. Lepor H. Nonoperative management of benign prostatic hyperplasia. J. Urol., 141:1283-1289, 1989 14. Albert-Puleo M. Fennel and anise as estrogenic agents. J. Ethnopharm., 2:337-344, 1980 15. Albert-Puleo M. Mythobotany, pharmacology, and chemistry of thujone-containing plants and derivatives. Econ. Bot., 32:65-74, 1978 16.
    [Show full text]
  • Front Matter
    zpt0040800SPC1.qxd 3/11/08 10:55 AM Page 1 Volume 325 ■ Number 1 ■ April 2008 ■ ISSN 0022-3565 The Journal of PHARMACOLOGY And Experimental Therapeutics A Adaptations (Network Architecture) Can Create Unpredicted Therapeutic Actions Drug Predicted Effect Unexpected Effect B Complexity Creates Unpredicted Targets Predicted Effect Drug Target Unpredicted Target A Publication of the American Society for Pharmacology and Experimental Therapeutics Edited for the Society by Rick G. Schnellmann The Journal of PHARMACOLOGY And Experimental Therapeutics A Publication of the American Society for Pharmacology and Experimental Therapeutics April 2008 Vol. 325, No. 1 Contents PERSPECTIVES IN PHARMACOLOGY Exploiting Complexity and the Robustness of Network Marc K. Hellerstein 1 Architecture for Drug Discovery BEHAVIORAL PHARMACOLOGY Early Postnatal Stress Alters Place Conditioning to Both ␮- and Clifford C. Michaels and Stephen G. Holtzman 313 ␬-Opioid Agonists CARDIOVASCULAR □ ␤ S Design of Mutant 2 Subunits as Decoy Molecules to Reduce the Sabine Te´le´maque, Swapnil Sonkusare, 37 ,Expression of Functional Ca2؉ Channels in Cardiac Cells Terrie Grain, Sung W. Rhee, Joseph R. Stimers Nancy J. Rusch, and James D. Marsh Sphingosine 1-Phosphate Inhibits Nitric Oxide Production Takuji Machida, Yukihiro Hamaya, 200 Induced by Interleukin-1␤ in Rat Vascular Smooth Muscle Cells Sachiko Izumi, Yumika Hamaya, Kenji Iizuka, Yasuyuki Igarashi, Masaru Minami, Roberto Levi, and Masahiko Hirafuji Andrographolide Up-Regulates Cellular-Reduced Glutathione Anthony Y. H. Woo, Mary M. Y. Waye, 226 Level and Protects Cardiomyocytes against Stephen K. W. Tsui, Sandy T. W. Yeung, and Hypoxia/Reoxygenation Injury Christopher H. K. Cheng Orally Available Levosimendan Dose-Related Positive Inotropic Satoshi Masutani, Heng-Jie Cheng, 236 and Lusitropic Effect in Conscious Chronically Instrumented Minja Hyttila¨-Hopponen, Jouko Levijoki, Normal and Heart Failure Dogs Aira Heikkila¨, Arja Vuorela, William C.
    [Show full text]
  • Neurotransmitters-Drugs Andbrain Function.Pdf
    Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Edited by R. A. Webster Department of Pharmacology, University College London, UK JOHN WILEY & SONS, LTD Chichester Á New York Á Weinheim Á Brisbane Á Singapore Á Toronto Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Copyright # 2001 by John Wiley & Sons Ltd. Bans Lane, Chichester, West Sussex PO19 1UD, UK National 01243 779777 International ++44) 1243 779777 e-mail +for orders and customer service enquiries): [email protected] Visit our Home Page on: http://www.wiley.co.uk or http://www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1P0LP,UK, without the permission in writing of the publisher. Other Wiley Editorial Oces John Wiley & Sons, Inc., 605 Third Avenue, New York, NY 10158-0012, USA WILEY-VCH Verlag GmbH, Pappelallee 3, D-69469 Weinheim, Germany John Wiley & Sons Australia, Ltd.
    [Show full text]
  • GABA Receptors
    D Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews Review No.7 / 1-2011 GABA receptors Wolfgang Froestl , CNS & Chemistry Expert, AC Immune SA, PSE Building B - EPFL, CH-1015 Lausanne, Phone: +41 21 693 91 43, FAX: +41 21 693 91 20, E-mail: [email protected] GABA Activation of the GABA A receptor leads to an influx of chloride GABA ( -aminobutyric acid; Figure 1) is the most important and ions and to a hyperpolarization of the membrane. 16 subunits with γ most abundant inhibitory neurotransmitter in the mammalian molecular weights between 50 and 65 kD have been identified brain 1,2 , where it was first discovered in 1950 3-5 . It is a small achiral so far, 6 subunits, 3 subunits, 3 subunits, and the , , α β γ δ ε θ molecule with molecular weight of 103 g/mol and high water solu - and subunits 8,9 . π bility. At 25°C one gram of water can dissolve 1.3 grams of GABA. 2 Such a hydrophilic molecule (log P = -2.13, PSA = 63.3 Å ) cannot In the meantime all GABA A receptor binding sites have been eluci - cross the blood brain barrier. It is produced in the brain by decarb- dated in great detail. The GABA site is located at the interface oxylation of L-glutamic acid by the enzyme glutamic acid decarb- between and subunits. Benzodiazepines interact with subunit α β oxylase (GAD, EC 4.1.1.15). It is a neutral amino acid with pK = combinations ( ) ( ) , which is the most abundant combi - 1 α1 2 β2 2 γ2 4.23 and pK = 10.43.
    [Show full text]
  • Treatment Protocol Copyright © 2018 Kostoff Et Al
    Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al PREVENTION AND REVERSAL OF ALZHEIMER'S DISEASE: TREATMENT PROTOCOL by Ronald N. Kostoffa, Alan L. Porterb, Henry. A. Buchtelc (a) Research Affiliate, School of Public Policy, Georgia Institute of Technology, USA (b) Professor Emeritus, School of Public Policy, Georgia Institute of Technology, USA (c) Associate Professor, Department of Psychiatry, University of Michigan, USA KEYWORDS Alzheimer's Disease; Dementia; Text Mining; Literature-Based Discovery; Information Technology; Treatments Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al CITATION TO MONOGRAPH Kostoff RN, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's disease: treatment protocol. Georgia Institute of Technology. 2018. PDF. https://smartech.gatech.edu/handle/1853/59311 COPYRIGHT AND CREATIVE COMMONS LICENSE COPYRIGHT Copyright © 2018 by Ronald N. Kostoff, Alan L. Porter, Henry A. Buchtel Printed in the United States of America; First Printing, 2018 CREATIVE COMMONS LICENSE This work can be copied and redistributed in any medium or format provided that credit is given to the original author. For more details on the CC BY license, see: http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License<http://creativecommons.org/licenses/by/4.0/>. DISCLAIMERS The views in this monograph are solely those of the authors, and do not represent the views of the Georgia Institute of Technology or the University of Michigan. This monograph is not intended as a substitute for the medical advice of physicians. The reader should regularly consult a physician in matters relating to his/her health and particularly with respect to any symptoms that may require diagnosis or medical attention.
    [Show full text]
  • Cell Surface Mobility of GABAB Receptors Saad Bin
    Cell surface mobility of GABAB receptors Saad Bin Hannan September 2011 A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy of the University College London Department of Neuroscience, Physiology, and Pharmacology University College London Gower Street London WC1E 6BT UK Declaration ii ‘I, Saad Hannan confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis.' ____________________ Saad Hannan September 2011 To Ammu, Abbu, Polu Abstract ivi Abstract Type-B γ-aminobutyric acid receptors (GABABRs) are important for mediating slow inhibition in the central nervous system and the kinetics of their internalisation and lateral mobility will be a major determinant of their signalling efficacy. Functional GABABRs require R1 and R2 subunit co-assembly, but how heterodimerisation affects the trafficking kinetics of GABABRs is unknown. Here, an α- bungarotoxin binding site (BBS) was inserted into the N-terminus of R2 to monitor receptor mobility in live cells. GABABRs are internalised via clathrin- and dynamin- dependent pathways and recruited to endosomes. By mutating the BBS, a new technique was developed to differentially track R1a and R2 simultaneously, revealing the subunits internalise as heteromers and that R2 dominantly-affects constitutive internalisation of GABABRs. Notably, the internalisation profile of R1aR2 heteromers, but not R1a homomers devoid of their ER retention motif (R1ASA), is similar to R2 homomers in heterologous systems. The internalisation of R1aASA was slowed to that of R2 by mutating a di-leucine motif in the R1 C-terminus, indicating a new role for heterodimerisation, whereby R2 subunits slow the internalization of surface GABABRs.
    [Show full text]
  • Tanibirumab (CUI C3490677) Add to Cart
    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2005/0215521 A1 Lalji Et Al
    US 20050215521A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0215521 A1 Lalji et al. (43) Pub. Date: Sep. 29, 2005 (54) MODAFINIL COMBINATION THERAPY FOR Publication Classification IMPROVING SLEEP QUALITY (51) Int. Cl.' .................. A61K 31/724; A61K 31/7008; (76) Inventors: Karim Lalji, Sudbury, MA (US); A61K 31/4164; A61K 31/195; Timothy J. Barberich, Concord, MA A61K 31/165 (US) (52) U.S. Cl. ............................ 514/58; 514/221; 514/389; 514/561; 514/557; 514/23; Correspondence Address: 514/618; 514/469 FOLEY HOAG, LLP PATENT GROUP, WORLD TRADE CENTER WEST (57) ABSTRACT 155 SEAPORT BLVD One aspect of the present invention relates to pharmaceutical BOSTON, MA 02110 (US) compositions comprising a compound that modulates the orexin System and a Sedative agent. In a preferred embodi (21) Appl. No.: 11/018,869 ment, the compound that modulates the orexin System is (22) Filed: Dec. 21, 2004 modafinil and the Sedative agent is eSZopiclone. The phar maceutical compositions of the invention are useful in the Related U.S. Application Data treatment of various sleep disorders. In addition, the present invention relates to a method of treating a patient Suffering (60) Provisional application No. 60/531,822, filed on Dec. from a sleep abnormality or insomnia comprising adminis 22, 2003. Provisional application No. 60/541,684, tering a therapeutically effective amount of a pharmaceutical filed on Feb. 4, 2004. composition of the invention. Patent Application Publication Sep. 29, 2005 Sheet 1 of 2 US 2005/0215521 A1 Figure 1 (RS)-Zopiclone D-Malic Acid Acetone Mixing/Heating Methanol Methanol-DCooling/Crystallizatio (S)-Zopiclone D-Malate See Methanol Filtration/Washing Mother Liquors/Washes -Ge IPC (S)-Zopiclone D-Malate Patent Application Publication Sep.
    [Show full text]
  • DAS Gabaerge SYSTEM
    DIPLOMARBEIT Titel der Diplomarbeit „In vivo Untersuchung ausgewählter GABAA-Liganden auf das Verhalten von c57Bl/6N-Mäusen“ Verfasserin Sandra Maurer angestrebter akademischer Grad Magistra der Pharmazie (Mag.pharm.) Wien, 2013 Studienkennzahl lt. Studienblatt: A 449 Studienrichtung lt. Studienblatt: Diplomstudium Pharmazie Betreuer: Univ.-Prof. Dr. Steffen Hering DANKSAGUNG In erster Linie möchte ich mich bei Univ. Prof. Dr. Steffen Hering für die Ermöglichung dieser Diplomarbeit am Department für Pharmakologie und Toxikologie, sowie für die Bereitstellung dieses interessanten Themas bedanken. Ein Dankeschön gilt auch Mag. Dr. Sophia Khom für die hilfreichen und kompetenten Ratschläge zum Anfertigen dieser Arbeit. Herzlicher Dank gilt vor allem Mag. Juliane Hintersteiner, die mich bei allen praktischen Arbeiten begleitet, all meine Fragen geduldig beantwortet und mich mit großem Engagement unterstützt hat. Bedanken möchte ich mich weiters bei Mag. Barbara Strommer, die sich für mich eingesetzt hat, diesen Diplomarbeitsplatz zu bekommen. Auch bei meiner Familie möchte ich mich recht herzlich bedanken, dass sie mir das Studium der Pharmazie ermöglichten und mich auch in schwierigen Phasen des Studiums immer unterstützten. Besonderer Dank gilt auch meinem Freund Christoph, der immer an meiner Seite ist. INHALT A) ALLGEMEINER TEIL ................................................................................................................. 1 1. DAS GABAerge SYSTEM .....................................................................................................
    [Show full text]
  • Low Cerebral Exposure Cannot Hinder the Neuroprotective Effects of Panax Notoginsenosides
    DMD Fast Forward. Published on October 23, 2017 as DOI: 10.1124/dmd.117.078436 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 78436 Low cerebral exposure cannot hinder the neuroprotective effects of panax notoginsenosides Haofeng Li, Jingcheng Xiao, Xinuo Li, Huimin Chen, Dian Kang, Yuhao Shao, Boyu Shen, Zhangpei Zhu, Xiaoxi Yin, Lin Xie, Guangji Wang, Yan Liang Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China Downloaded from dmd.aspetjournals.org at ASPET Journals on September 25, 2021 1 DMD Fast Forward. Published on October 23, 2017 as DOI: 10.1124/dmd.117.078436 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 78436 Running Title Page Panax notoginsenosides exert neuroprotective effects Corresponding author: Yan Liang Co- corresponding author: Guangji Wang Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China. Tel: +86-25-83271060 Email: [email protected] [email protected] H.L. and J.X. contributed equally to this work. Downloaded from Number of text pages: 39 Number of figures: 8 Number of references: 59 dmd.aspetjournals.org Number of words in the Abstract: 217 Number of words in the Introduction: 929 Number of words in the Discussion: 1327 at ASPET Journals on September 25, 2021 Abbreviations:
    [Show full text]
  • Paired Pulse Depression in Cultured Hippocampal Neurons Is Due to a Presynaptic Mechanism Independent of GABA, Autoreceptor Activation
    The Journal of Neuroscience, March 1994, 74(3): 1775-l 788 Paired Pulse Depression in Cultured Hippocampal Neurons Is Due to a Presynaptic Mechanism Independent of GABA, Autoreceptor Activation Karen S. Wilcoxi,a and Marc A. Dichter* ‘Department of Physiology and *Departments of Neurology and Pharmacology, University of Pennsylvania, School of Medicine, and Graduate Hospital, Philadelphia, PA 19104 Most rapid synaptic inhibition in the vertebrate forebrain is Under physiological conditions, synaptic inhibition in the mam- mediated by GABA acting via GABA, and GABA, postsyn- malian CNS is very labile and a downregulation of inhibitory aptic receptors. GABAergic neurotransmission exhibits fre- neurotransmissionappears to be critical for the development of quency-dependent modulation; sequential inhibitory post- someforms of synaptic plasticity, such as that occurring during synaptic currents (IPSCs) evoked with interstimulus intervals long-term potentiation. In addition, and perhaps even more between 25 msec and 4 set routinely result in the attenuation significantly, activity-dependent disinhibition is also associated of the amplitude of the second IPSC. This form of synaptic with the generation and spread of epileptic seizure activity plasticity is known as paired pulse depression (PPD). The (Dichter and Ayala, 1987). Therefore, an understanding of the mechanism of PPD is presently unknown and the experi- basic principles of inhibitory plasticity is vital to the under- ments performed in this study were designed to determine standing of both physiological and pathological synaptic plas- directly the location of the mechanism of PPD in hippocampal ticity in the CNS. neurons maintained in low-density tissue culture. Evoked Paired pulsedepression (PPD) of GABAergic inhibitory post- IPSCs were recorded between pairs of cultured neurons synaptic currents (IPSCs) is a robust example of synaptic plas- grown in relative isolation that were simultaneously being ticity in the mammalian CNS; depressionof the amplitude of recorded with the whole-cell, patch-clamp technique.
    [Show full text]