DOCSLIB.ORG

Antiepileptogenesis, Plasticity of AED Targets, Drug Resistance, and Targeting the Immature Brain

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Antiepileptogenesis, Plasticity of AED Targets, Drug Resistance, and Targeting the Immature Brain Jasper's Basic Mechanisms of the Epilepsies Jasper's Basic Mechanisms of the Epilepsies Antiepileptogenesis, Plasticity of AED Targets, Drug resistance, and Targeting the Immature Brain Heinz Beck1 Yoel Yaari2,3 1 Department of Epileptology, Laboratory of Experimental Epileptology and Cognition Research, University of Bonn Medical Center, Sigmund-Freud Str. 25, 53105 Bonn, Germany 2 Department of Medical Neurobiology, Institute of Medical Research Israel-Canada, Hebrew University- Hadassah School of Medicine, Jerusalem, Israel 3 The Interdisciplinary Center for Neuronal Computation, the Hebrew University, Jerusalem 91904, Israel Summary Resistance to currently available antiepileptic drugs is a major problem in the treatment of temporal lobe epilepsy that affects ~30% of patients. The antiepileptic drug targets are mostly voltage-gated ion channels or neurotransmitter receptors. Manifold changes in the molecular composition and pharmacology of common antiepileptic drug targets, such as sodium channels, hyperpolarization- activated cationic ion channels and GABA receptors have been described. Available evidence suggests that plasticity of antiepileptic drug targets, with a concomitantly decreased sensitivity to antiepileptic drugs, coexists with other cellular mechanisms to cause pharmacoresistance. A better understanding of the mechanisms of pharmacoresistance is crucial for the development of new antiepileptic therapies. Introduction The cellular basis of epileptic seizures consists of high frequency, synchronized discharges of neuronal ensembles. The ultimate goal of all antiepileptic therapies is to prevent the occurrence of such episodes or to substantially attenuate their severity. To this end, a multitude of antiepileptic compounds have been developed that are currently in clinical use. However, seizures remain uncontrolled by carefully monitored drug treatment in a substantial portion (~30 %) of epilepsy patients. Therefore, a better understanding of the mode of action of different antiepileptic drugs is mandatory, along with an improved understanding of why these compounds fail in some epilepsy patients, with the ultimate goal of developing new therapeutic avenues. So far, two hypotheses have been advanced to account for the cellular basis of pharmacoresistance in chronic epilepsy. The first hypothesis proposes that pharmacoresistance involves an up-regulation of multidrug-transporters at the blood-brain barrier. This up- regulation limits the access of antiepileptic drugs to the brain parenchyma, and therefore leads to a reduced drug concentration at the respective drug target. Because multidrug transporter proteins are of central importance to this hypothesis, it has been termed the ‘transporter hypothesis’. The second hypothesis contends that the molecular targets of antiepileptic drugs are modified in chronic epilepsy. Consequently, they are less sensitive to these compounds. This hypothesis has been coined the ‘target hypothesis’.1,2 Clearly, these two hypotheses are not mutually exclusive. Rather, the underlying mechanisms may co-exist and perhaps even act in synergy. The subject of the following review article is the target hypothesis. We describe the molecular mechanisms that alter the targets of antiepileptic drugs and how these mechanisms may interact with altered drug transporter function to cause pharmacoresistance. Page 2 Defining drug targets In general, antiepileptic drug targets are proteins involved in neuronal function, which mediate a reduction in excitability after binding the antiepileptic drug at clinically relevant Jasper's Basic Mechanisms of the Epilepsies Jasper's Basic Mechanisms of the Epilepsies concentrations. A plethora of drug targets has been identified in central neurons (see Table 1). By far most of these targets are neurotransmitter receptors or voltage-gated ion channels. A comprehensive review of the different ion channel types that are affected by antiepileptic drugs is beyond the scope of this review. However, a number of classes of ion channels are particularly prominent targets. Table 1 Drug targets for common antiepileptic drugs Voltage-gated ion channels Neurotransmission INaT INaP ICa IK IH GABA Glu Presynaptic. Primarily targeting voltage-gated ion channels Phenytoin + + + + Carbamazepine + + Oxcarbazepine + + Lamotrigine + + + + + Valproic acid + +/− + + Losigamone + Retigabine + Zonisamide + + Ethosuximide − + + + Mixed mechanism Felbamate + + + + Topiramate + + + + + + Primarily affecting neurotransmitter receptors, release or metabolism Levetiracetam − − + + + (SV2A) Phenobarbital + + Benzodiazepine + Vigabatrin + Tiagabin + Other Gabapentin, primary target alpha2delta-1 subunit − − − − + − − − INaP: persistent sodium current, INaT: transient sodium current, ICa: calcium currents, IK: voltage-gated potasium currents, IH: H-current, GABA: activity on the GABAergic system, Glu: activity on the glutamatergic system. Sodium channels Voltage-gated sodium channels are implicated in the mode of action of a large number of common antiepileptic drugs, such as phenytoin, carbamazepine, valproate, lamotrigine, lacosamide and eslicarbazepine.3–5 These channels are found in all excitable cells and are Antiepileptogenesis, Plasticity of AED Targets, Drug resistance, and Targeting the Immature Brain Page 3 capable of extremely rapid channel gating that mediates millisecond scale physiological processes.6 They open rapidly upon membrane depolarization, causing the upstroke of the action potential, and subsequently undergo fast inactivation, thus contributing to its Jasper's Basic Mechanisms of the Epilepsies Jasper's Basic Mechanisms of the Epilepsies downstroke. Upon repolarization of the cell membrane, sodium channels recover from inactivation with a complex time course. In many cells, however, a non-inactivating, persistent component of the sodium current is also observed in addition to the rapidly inactivating component. This current component activates even during subthreshold depolarizations, and therefore is important in controlling subthreshold activity. Both the transient and the persistent components of the sodium current are potently inhibited by antiepileptic drugs, such as phenytoin, carbamazepine and lamotrigine, in addition to other drugs. A characteristic effect of most of these sodium channel blockers is that they preferentially bind to channels that have entered an inactivated state following depolarization of the cell. In addition, a second major mechanism is that the recovery from depolarization-induced inactivation is prolonged by many antiepileptic drugs.5,4 These two effects together explain why these drugs preferentially block repetitive high-frequency neuronal activity and long-lasting depolarizations, both of which typically occur during epileptic seizures. Calcium channels Voltage-gated calcium channels are also targets for numerous antiepileptic drugs. CNS neurons express multiple types of calcium channels, which can be separated into two classes based on their biophysical properties, namely, high-threshold and low-threshold calcium channels.7 A number of antiepileptic drugs has been shown to inhibit high threshold calcium channels in native neurons at high therapeutic concentrations.8–10 and this has been proposed to inhibit neurotransmitter release via a reduction of presynaptic action potential-induced calcium rises.11 Some antiepileptic drugs potently inhibit low-threshold (also known as T-type) calcium channels, which are expressed in postsynaptic compartments,12–14 and powerfully control postsynaptic excitability and the propensity to generate burst discharges.15 Intriguingly, the antiepileptic drug gabapentin has been shown to exhibit strong and specific binding to the accessory calcium channel alpha2delta subunit,16 but this binding seems to have no effect on the functional properties of the channel complex, suggesting that gabapentin binding to these subunits exerts effects that are not dependent on calcium channel modulation.17 HCN channels HCN channels, responsible for generating the so called H-current, are cation permeable channels that are activated by hyperpolarization and deactivate upon depolarization of the membrane potential.18,19 H-currents modulate membrane resistance and resting potential, and can mediate pacemaker activity in some types of neurons due to their particular biophysical properties.19 H-currents, and their corresponding HCN channel subunits, appear to be located mainly in dendrites.20–22 Accordingly, they potently modify dendritic integration of excitatory input.22,23 Interestingly, dendritic H-currents are potentiated by application of the antiepileptic drugs lamotrigine or Gabapentin.24,25 Thus, H-currents appear to be dendritic antiepileptic drug targets. GABAA receptors A further group of antiepileptic drugs seems to exert its main actions via an increase in synaptic inhibition. Gamma-aminobutyric acid (GABA) is the predominent inhibitory neurotransmitter in the adult brain. The ionotropic GABAA receptor, which conducts chloride upon the binding of GABA, is an important target for antiepileptic drugs. GABAA receptor-active drugs include direct modulators such as benzodiazepines and barbiturates, which increase the GABAA receptor-mediated chloride currents via allosteric modulation.26 A number of additional antiepileptic drugs indirectly enhance GABAA receptor-mediated action by inhibiting the re- Antiepileptogenesis, Plasticity of AED Targets, Drug resistance, and Targeting the Immature Brain Page 4 uptake of GABA
Load more

Recommended publications
  • Calcium Channel Blocker As a Drug Candidate for the Treatment of Generalised Epilepsies
    UNIVERSITAT DE BARCELONA Faculty of Pharmacy and Food Sciences Calcium channel blocker as a drug candidate for the treatment of generalised epilepsies Final degree project Author: Janire Sanz Sevilla Bachelor's degree in Pharmacy Primary field: Organic Chemistry, Pharmacology and Therapeutics Secondary field: Physiology, Pathophysiology and Molecular Biology March 2019 This work is licensed under a Creative Commons license ABBREVIATIONS AED antiepileptic drug AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ANNA-1 antineuronal nuclear antibody 1 BBB blood-brain barrier Bn benzyl BnBr benzyl bromide BnNCO benzyl isocyanate Boc tert-butoxycarbonyl Bu4NBr tetrabutylammonium bromide Ca+2 calcium ion CACNA1 calcium channel voltage-dependent gene cAMP cyclic adenosine monophosphate CCB calcium channel blocker cGMP cyclic guanosine monophosphate CH3CN acetonitrile Cl- chlorine ion Cmax maximum concentration CMV cytomegalovirus CTScan computed axial tomography DCM dichloromethane DIPEA N,N-diisopropylethylamine DMF dimethylformamide DMPK drug metabolism and pharmacokinetics DNET dysembryoplastic neuroepithelial tumours EEG electroencephalogram EPSP excitatory post-synaptic potential FDA food and drug administration Fe iron FLIPR fluorescence imaging plate reader fMRI functional magnetic resonance imaging GABA γ-amino-α-hydroxybutyric acid GAD65 glutamic acid decarboxylase 65 GAERS generalised absence epilepsy rat of Strasbourg GluR5 kainate receptor GTC generalised tonic-clonic H+ hydrogen ion H2 hydrogen H2O dihydrogen dioxide (water)
    [Show full text]
  • 85 Mv Respectively. When the Membranewas Depolarized, Th
    J. Physiol. (1985), 360, pp. 161-185 161 With 14 text-figurem Printed in Great Britain COMPARISON OF THE ACTION OF BACLOFEN WITH y-AMINOBUTYRIC ACID ON RAT HIPPOCAMPAL PYRAMIDAL CELLS IN VITRO BY N. R. NEWBERRY* AND R. A. NICOLLt From the Departments of Pharmacology and Physiology, University of California, San Francisco, CA 94143, U.S.A. (Received 13 June 1984) SUMMARY 1. Intracellular recordings from CAI pyramidal cells in the hippocampal slice preparation were used to compare the action of baclofen, a y-aminobutyric acid (GABA) analogue, with GABA. 2. Ionophoretic application of GABA or baclofen into stratum (s.) pyramidale evoked hyperpolarizations associated with reductions in the input resistance of the cell. Baclofen responses were easier to elicit in the dendrites than in the cell body layer. 3. Blockade of synaptic transmission, with tetrodotoxin or cadmium, did not reduce baclofen responses, indicating a direct post-synaptic action. 4. (+ )-Bicuculline (10 ,UM) and bicuculline methiodide (100 /SM) had little effect on baclofen responses but strongly antagonized somatic GABA responses of equal amplitude. The bicuculline resistance of the baclofen response was not absolute, as higher concentrations of these compounds did reduce it. Pentobarbitone (100 /M) enhanced somatic GABA responses without affecting baclofen responses. (-)-Baclofen was approximately 200 times more potent than (+ )-baclofen. 5. The reversal potentials for the somatic GABA and baclofen responses were -70 mV and -85 mV respectively. When the membrane was depolarized, the baclofen response was reduced. This apparent voltage sensitivity was not seen with somatic GABA responses. 6. Altering the chloride gradient across the cell membrane altered the reversal potential of the somatic GABA response but not that ofthe baclofen response.
    [Show full text]
  • Assessment of Molecular Action of Direct Gating and Allosteric Modulatory Effects of Carisoprodol (Somartm) on GABA a Receptors
    Graduate Theses, Dissertations, and Problem Reports 2015 Assessment of molecular action of direct gating and allosteric modulatory effects of carisoprodol (SomaRTM) on GABA A receptors Manoj Kumar Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation Kumar, Manoj, "Assessment of molecular action of direct gating and allosteric modulatory effects of carisoprodol (SomaRTM) on GABA A receptors" (2015). Graduate Theses, Dissertations, and Problem Reports. 6022. https://researchrepository.wvu.edu/etd/6022 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. ASSESSMENT OF MOLECULAR ACTION OF DIRECT GATING AND ALLOSTERIC MODULATORY EFFECTS OF MEPROBAMATE (MILTOWN®) ON GABAA RECEPTORS Manish Kumar, MD, MS Dissertation submitted to the School of Pharmacy at West Virginia University in partial fulfillment of Requirements
    [Show full text]
  • Pregabalin Abuse: a Case Report Ilhan Yargic1, Filiz Alyanak Ozdemiroglu2
    Olgu Sunumları / Case Reports DOI: 10.5350/KPB-BCP201121110 Pregabalin Abuse: A Case Report Ilhan Yargic1, Filiz Alyanak Ozdemiroglu2 ÖZET: ABS TRACT: Pregabalin kötüye kullanımı: Bir olgu sunumu Pregabalin abuse: a case report Pregabalin epilepsi, nöropatik ağrı ve yaygın anksiyete Pregabalin is a gamma-amino butyric acid (GABA) analogue bozukluğunun tedavilerinde kullanılan bir gama-aminobu- used in the treatment of epilepsy, neuropathic pain, and tirik asit (GABA) analoğudur. Pregabalin Türkiye’de kontrole generalized anxiety disorder. Although pregabalin is not tabi ilaçlardan olmamasına karşın kötüye kullanılma potan- a controlled medication in Turkey, it has a potential risk 1M.D., Professor of Psychiatry, Istanbul siyeline sahiptir. Türkiye’de yaygın anksiteye bozukluğu gibi of abuse. It has not been approved for the treatment of University, Istanbul Faculty of Medicine, Psychiatry Department, Istanbul-Turkey psikiyatrik hastalıkların tedavisi için ruhsatlandırılmış olma- psychiatric disorders (such as generalized anxiety disorder) 2M.D., Istinye Devlet Hastanesi, Psikiyatri AD, dığı için henüz psikiyatri hastaları arasında popüler değildir. in Turkey, so it is not yet popular as a drug of abuse among Istinye, Istanbul-Turkey 37 yaşında, bipolar bozukluğu ve benzodiyazepin kötüye psychiatric patients. We report the first case of pregabalin Ya zış ma Ad re si / Add ress rep rint re qu ests to: kullanımı öyküsü olan bir erkek hastada Türkiye’den ilk pre- abuse in Turkey in a 37 year old male patient who has a İlhan Yargıç, M.D., Istanbul
    [Show full text]
  • Gamma-Aminobutyric Acid (GABA) Is a Major Neuro­Transmitter Widely Distributed Throughout the Central Nervous System (CNS)
    Alternative Medicine Review Volume 12, Number 3 2007 Monograph GABA Gamma-Aminobutyric O + Acid (GABA) H3N O- Introduction Gamma-aminobutyric acid (GABA) is a major neuro transmitter widely distributed throughout the central nervous system (CNS). Because too much excitation can lead to irritability, restlessness, insomnia, seizures, and movement disorders, it must be balanced with inhibition. GABA – the most important inhibitory neurotransmitter in the brain – provides this inhibition, acting like a “brake” during times of runaway stress. Medications for anxiety, such as benzodiazepines, stimulate GABA receptors and induce relaxation. Either low GABA levels or decreased GABA function in the brain is associated with several psy- chiatric and neurological disorders, including anxiety, depression, insomnia, and epilepsy. Studies indicate GABA can improve relaxation and enhance sleep. Both synthetic and natural GABA are available as dietary supplements in the United States. Natural GABA is produced via a fermentation process that utilizes Lactobacillus hilgardii – the bacteria used to ferment vegetables in the preparation of the traditional Korean dish known as kimchi. Biochemistry and Pharmacokinetics Within the brain, glutamic acid is converted to GABA via the enzyme glutamate decarboxylase and its cofac- tor pyridoxal 5’ phosphate (P5P; active vitamin B6). GABA is metabolized by gamma-aminobutyrate transaminase, also a P5P-dependent enzyme, forming an intermediate metabolite succinate semialdehyde. This metabolite can then be reduced to gamma-hydroxybutyrate, or oxidized to succinate and eventually converted to CO2 and water via the citric acid cycle. When plasma membrane depolarization induces the release of GABA from nerve terminals, GABA binds to GABA receptors – such as the GABAA and GABAB receptors – that are distributed on post-synaptic cell membranes.
    [Show full text]
  • Sternum. ^Sympathetic Chain \ to Prevertebral
    Durham E-Theses An electrophysiological study of the interaction between fenamate NSAIDs and the GABA(_A) receptor Patten, Debra How to cite: Patten, Debra (1999) An electrophysiological study of the interaction between fenamate NSAIDs and the GABA(_A) receptor, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/4561/ Use policy The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in Durham E-Theses • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full Durham E-Theses policy for further details. Academic Support Oce, Durham University, University Oce, Old Elvet, Durham DH1 3HP e-mail: [email protected] Tel: +44 0191 334 6107 http://etheses.dur.ac.uk 2 An electrophysiological study of the interaction between Fenamate NSAIDs and the GABAA receptor. Debra Patten Submitted for the Degree of Ph.D. The copyright of this thesis rests with the author. No quotation from it should be published without the written consent of the author and information derived from it should be acknowledged. 1 9 JUL 2000 Dept. of Biological Sciences University of Durham March 1999 March 1999 Table of Contents AN ELECTROPHYSIOLOGICAL STUDY OF THE INTERACTION BETWEEN FENAMATE NSAIDs AND THE GABAA RECEPTOR CHAPTER ONE: GENERAL INTRODUCTION 1.1.
    [Show full text]
  • Gabapentin in the Treatment of Bipolar Disorder
    Jefferson Journal of Psychiatry Volume 14 Issue 1 Article 5 January 1998 Gabapentin in the Treatment of Bipolar Disorder Wendy M. Waits Uniformed Services University of Health Sciences Donald P. Hall Jr., M.D. Walter Reed Army Medical Center; Uniformed Services University Follow this and additional works at: https://jdc.jefferson.edu/jeffjpsychiatry Part of the Psychiatry Commons Let us know how access to this document benefits ouy Recommended Citation Waits, Wendy M. and Hall, Donald P. Jr., M.D. (1998) "Gabapentin in the Treatment of Bipolar Disorder," Jefferson Journal of Psychiatry: Vol. 14 : Iss. 1 , Article 5. DOI: https://doi.org/10.29046/JJP.014.1.004 Available at: https://jdc.jefferson.edu/jeffjpsychiatry/vol14/iss1/5 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Jefferson Journal of Psychiatry by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected]. Gabapentin in the Treatment ofBipolar Disorder Wendi M. Waits and Donald P.Hall, MD Abstract Gabapentin, a relatively new anti-epileptic drug (liED), is emerging as a therapeutic option JO r treatment refractory and rapid-cycling bipolar illnesses.
    [Show full text]
  • Gabapentin As an Antiepileptic Drug in Man
    J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.50.6.682 on 1 June 1987. Downloaded from Journal of Neurology, Neurosurgery, and Psychiatry 1987;50:682-686 Gabapentin as an antiepileptic drug in man P CRAWFORD, E GHADIALI, R LANE, L BLUMHARDT, D CHADWICK From the Department ofNeurology, Walton Hospital, Liverpool, UK SUMMARY Gabapentin, -(aminomethyl) cyclohexane acetic acid, is a GABA analogue whose anti- epileptic properties were tested in a double blind cross-over trial design as add-on therapy in a dose ranging study which compared 300 mg, 600 mg, and 900 mg/day (each dose given for 2 months) in 25 patients with severe partial and generalised epilepsies. A dose related antiepileptic effect was observed. All three doses were well tolerated and no psychometric impairment was noted. No significant drug interactions were seen. The drug appears worthy of further assessment. Gabapentin, l-(aminomethyl) cyclohexane acetic acid when seizure frequency and side effects were documented. (fig 1), is a GABA analogue that is well absorbed and Serum antiepileptic drug concentrations were recorded at penetrates the blood brain barrier. It is effective each visit as well as levels of gabapentin. against a variety of seizures in animals particularly Phenytoin, carbamazepine, primidone and pheno- with trans- barbitone concentrations were measured by the method of those caused by interference GABAergic Perchalski et al,2 valproate levels by the method of Chard.3 Protected by copyright. mission or provoked by excitatory amino acids.' In Plasma gabapentin concentrations were estimated by an spite of this the precise mechanism of its antiepileptic HPLC method.4 Routine haematological, serum biochem- properties is unclear as gabapentin does not appear to istry and urine analyses were performed at each visit.
    [Show full text]
  • Methoxy-6-Methylflavone and Kavain at Recombinant GABAA Receptors
    Pharmacology profile of 2′-methoxy-6-methylflavone and kavain at recombinant GABAA receptors Han Chow Chua BPharm (Hons) A thesis submitted in fulfilment of the requirements for the award of Doctor of Philosophy Faculty of Pharmacy The University of Sydney 2016 Acknowledgements Firstly, I would like to express my sincere gratitude to my supervisor Professor Mary Collins for her continuous support, guidance, patience and motivation throughout my PhD. Besides my supervisor, I would like to thank Professor Jane Hanrahan, Dr Nathan Absalom and Dr Petra van Nieuwenhuijzen for their insightful comments and encouragement, which were precious for the writing of this thesis. My sincere appreciation also goes to Associate Professor Philip Ahring for providing me with valuable guidance in molecular biology and electrophysiology; Associate Professor Thomas Balle for his immense knowledge in molecular modelling; Dr Raja Viswas for the synthesis of various chemicals used in this study. I would also like to thank my colleagues and lab buddies (in no particular order): Vivian, Irene, Radhika, Zirong, Taima, Leonny, Jia, Bryan, Ting, Steve, Terry, Tim, Izumi, Ida and Maja for their friendship, support, shared knowledge and experiences over the years, which helped me stay sane through those hair-pulling moments. Last but not least, my heartfelt gratitude goes to my family, as none of this would have been possible without their support. They have been a constant source of love, concern, support and strength throughout all these years and I deeply appreciate their faith in me. Abstract GABAA receptors (GABAARs) are a class of physiologically- and therapeutically- important ligand-gated ion channels.
    [Show full text]
  • The Effects of Early L-Baclofen Administration on the Development of Tinnitus Induced by Acoustic Trauma, And
    The Effects Of Early L-Baclofen Administration On The Development Of Tinnitus Induced By Acoustic Trauma, And GABAB-R2 Expression, In Rats Kate McPherson A Thesis Submitted For The Degree Of Master Of Science At The University Of Otago, Dunedin, New Zealand August 2013 i Acknowledgements Firstly, I’d like to thank my supervisor Professor Paul Smith for his guidance throughout all aspects of this process. Your wealth of knowledge on all-things-tinnitus continued to astound and aid me as I not only carried out this research, but also wrote my thesis. Furthermore, you were somewhat of a god-send when it came to navigating my way through the statistics and SPSS program, and for that I am truly grateful. I would also like to thank Dr Yiwen Zheng for her constant support and encouragement. You made yourself available at all times, and were the calm amidst the storm when I was learning how to do things in the lab. Furthermore, I would like to express my thanks for your help with the brain perfusions of my rats, which could not have been carried out without your expertise. To Lucy Stiles, I will be forever in your debt. I cannot thank you enough for not only your help with the brain perfusions and data analysis, but for also being the go-to within the lab. If I didn’t know something, I could always count on you to be there and to have the answer. To Phillip Aitkin, for teaching me the ins-and-outs of acoustic brainstem responses and immunohistochemistry, as well as your involvement in the brain perfusions.
    [Show full text]
  • Assessment and Treatment of Alcohol Dependence Suggested Citation: Quigley, A., Connolly, C., Palmer, B., & Helfgott, S
    A brief guide to the Assessment and Treatment of Alcohol Dependence Suggested citation: Quigley, A., Connolly, C., Palmer, B., & Helfgott, S. (2015) A brief guide to the assessment and treatment of alcohol dependence (2nd ed.). Perth, Western Australia: Drug and Alcohol Office. ISBN: 978-1-876684-63-1 © Western Australian Drug and Alcohol Authority 2015 Note – The Drug and Alcohol Office is the business name of the Western Australian Alcohol and Drug Authority, which is an independent statutory authority established in November 1974. Its functions are set out in the Alcohol and Drug Authority Act 1974. This booklet is produced by Next Step Drug and Alcohol Services and Workforce Development Branch, Drug and Alcohol Office. It may be reproduced in whole or in part for study or training purposes subject to an inclusion of an acknowledgement of the source and no commercial usage or sale. Reproduction for purposes other than those above requires the written permission of: Drug and Alcohol Office, PO Box 126, Mount Lawley WA 6929 Website: www.dao.health.wa.gov.au Next Step DRUG AND ALCOHOL SERVICES ii A brief guide to the Assessment and Treatment of Alcohol Dependence Contents Introduction ................................................................................................................................................................2 Assessment .................................................................................................................................................................2 History .........................................................................................................................................................................2
    [Show full text]
  • Antiepileptic Drug Mechanisms of Action
    E/~l/tp\lo,34(Suppl. 5):Sl-SR. 1993 Raven Press, Ltd.. New York International League Against Epilepsy Antiepileptic Drug Mechanisms of Action *?Robert L. Macdonald and *Kevin M. Kelly Deparlmenls qf*Neurology and tPhysio1og.v. University of Michigan Medical Cmter, Ann Arbor, Michigan. U.S.A Summary: Clinically used antiepileptic drugs (AEDs) de- trigine may decrease sustained high-frequency repetitive crease membrane excitability by interacting with ion channels firing. The mechanisms of action of felbamate are unknown. or neurotransmitter receptors. Currently available AEDs ap- Gabapentin (GBP) appears to bind to a specific binding site pear to act on sodium channels, GABAAreceptors, or calcium in the central nervous system with a restricted regional channels. Phenytoin, carbamazepine, and possibly valproate distribution, but the identity of the binding site and the (VPA) decrease high-frequency repetitive firing of action po- mechanism of action of GBP remain uncertain. Key Words: tentials by enhancing sodium channel inactivation. Benzo- Anticonvulsants- Neuropharmacology -Neurotransmitten- diazepines and barbiturates enhance GABAA receptor- GABA -Phen ytoi n -Carbamazepi ne- Ethosuxi mide-Tri- mediated inhibition. Ethosuximide and possibly VPA reduce methadione-Benzodiazepines-Barbiturates-Valproate- a low-threshold calcium current. The mechanisms of action Felbamate-Gabapentin-Lamotrigine-Neural inhibi- of AEDs currently under development are less clear. Lamo- tion-Sodium-Calcium. A limited number of antiepileptic drugs (AEDs) are PHENYTOIN AND CARBAMAZEPINE available for use in the treatment of patients with epi- lepsy. In the United States, AEDs are limited primarily PHT and CBZ have been shown to interact with to phenytoin (PHT), carbamazepine (CBZ), barbitu- sodium channels at concentrations found free in the rates and primidone (PRM), benzodiazepines (BZDs), plasma of patients being treated for epilepsy (Macdon- valproate (VPA), and ethosuximide (ESM).
    [Show full text]