Advances in Alzheimer Disease Therapy Series Editors: Ezio Giacobini Robert Becker This series periodically brings up-to-date advances in basic and clinical sciences that are relevant to understanding the etiology, pathogenesis, diagnosis, and treatment of Alzheimer disease. Experts from the various fields relevant to understanding Alzheimer disease report their new research findings and discuss the newest developments in possible Alzheimer disease therapies. Cholinergic Basis for Alzheimer Therapy Robert Becker Ezio Giacobini Editors Springer Science+ Business Media, LLC Robert Becker Ezio Giacobini Departr.nentofPsyclriatry Department of Pharmacology School of Medicine School of Medicine Southern lllinois University Southern lllinois University Springfield, IL 62794 Springfield, IL 62794 U.S.A. U.S.A. Library of Congress Cataloging-in-Publication Data Cholinergic basis for Alzheimer therapy/edited by Robert Becker, Ezio Giacobini. p. cm.-(Advances in Alzheimer therapy) Includes bibliographical references and index. ISBN 978-1-4899-67404 1. Alzheimer's disease--Chemotherapy. 2. Cholinergic mechanisms. 3. Cholinesterase inhibitors--Therapeutic use. 4. Nerve growth factor Therapeutic use. I. Becker, Robert E. II. Giacobini, Ezio ill. Series. [DNLM: 1. Alzheimer's Disease--drug therapy. 2. Cholinesterase Inhibitors therapeutic use. 3. Neuroregulators--therapeutic use. 4. Parasympathomi metics--therapeutic use. 5. Receptors, Cholinergic-drug effects.] RC523.C49 1991 616.8'31061-dc20 DNLM/DLC 9126122 for Library of Congress CIP Printed on acid-free paper. © Springer Science+ Business Media New York 1991 Originally published by Birkhliuser Boston in 1991 Softcover reprint of the hardcover 1st edition 1991 Copyright is not claimed for works of U.S. Government employees. 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, photo copying, recording, or otherwise, without prior permission of the copyrightowner. The use of general descriptive names, trademarks, etc. in this publication, even if the former are not especially identified, is not to be taken as a sign that such names, as understood by the Trade Marks and Merchandise Marks Act, may accordingly be used freely by anyone. While the advice and information in this book are believed to be true and accu rate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied with respect to the material con tained herein. Permission to photocopy for internal or personal use of specific clients is granted by Springer Science+B usiness Media, LLC for libraries and other users registered with the Copyright ClearanceCenter {CCC), provided that the base fee of $0.00 per copy, plus $0.20 per page is paid directly to CCC, 21 Congress Street, Salem, MA 01970, U.S.A. Special requests should be addressed directly to Springer Science+Business Media, LLC. ISBN 978-1-4899-6740-4 ISBN 978-1-4899-6738-1 (eBook) DOI 10.1007/978-1-4899-6738-1 Camera-ready text prepared by the editors using WordPerfect 5.1 on an ffiM PS2 9 8 7 6 5 4 3 2 1 CONTENTS Introduction by the Editors: Therapy of the Cognitive Deficit in Alzheimer's Disease: The Cholinergic System ............ 1 Robert Becker Part I. Cholinesterases: Anatomy, Pathology and Human Genetics Cortical Cholinesterases in Alzheimer's Disease: Anatomical and Enzymatic Shifts from the Normal Pattern ..... 25 M.-Marsel Mesulam and Changiz Geula Cholinesterases in Human Degenerative Diseases . . . . . . . . . . 31 John R. Atack The Pathology of the Human Nucleus Basalis of Meynert and its Implications for a Specific Therapy . . . . . . . . . . 38 Thomas Arendt and Volker Bigl Structure-Function Relationship Studies in Human Cholinesterases as an Approach for Evaluating Potential Pharmacotherapeutic and/or Toxicity Effects of Cholinergic Drugs . . • 46 Hermona Soreq, Yael Loewenstein, Lewis F. Neville, Shlomo Seidman, Revital Ben-Aziz, Gal Ehrlich, Averell Gnatt, Dalia Ginzberg and Haim Zakut Structure of the Acetylcholinesterase Gene: Regulation of its Expression . . . . . • . . . • • • • . . . . . . . . 53 Palmer Taylor, Ying Li, Shelley Camp, Tara L. Rachinsky and Damon Getman Part II. Pharmacokinetics and Neurophysiology of Cholinesterase Inhibitors Kinetics and Mechanisms of Reversible and Progressive Inhibition of Acetylcholinesterase . . . . . . . . . . . . . . . . 63 Elsa Reiner, Vera Simeon and Mira Skrinjaric-Spoljar v Clinical Pharmacokinetics of Centrally Acting Cholinesterase Inhibitors . . . . . . . . . . . . . . . . . . 68 Per Hartvig, Lars WiklWid, Sten Magnus Aquilonius and Bjorn Lindstrom Pre- and Postsynaptic Effects of Cholinesterase Inhibitors . . . . 74 Lev G. Magazanik, Vadim Y. Bolshakov, Nera Y. Kukomskaya, Natalja N. Potapjeva, Marina V. Samojlova, Vladmir A. Snetkov, Rashid A. Giniatullin and Jordi Molgo Part III. Cholinergic Receptors, Immunocytochemistry and PET Scanning Immunocytochemistry of Muscarinic and Nicotinic Receptors in Human Brain .. . . . . . 85 Hannsjorg SchrOder Presynaptic Cholinergic Mechanisms in Human Cerebral Cortex of Adult and Aged Patients . . . . . . . . . . . . . . . . 92 Mario Marchi, Elisabetta Besana, Agnese Codignola, Paola Sanguineti, Maurizio Raiteri, Gian Carlo Andrioli and Antonio Ruelle Nicotinic Acetylcholine Receptors in the Human Nervous System . . . . . . . . . . . . . . . . . . . . . . . 98 Bice Chini, Paola Tarroni, Francesca Rubboli, Elena Raimondi and Francesco Clementi Nicotinic Receptors in the CNS as Vtsualized by Positron Emission Tomography . . . . . . . . . . . . . . . .... 107 Agneta Nordberg, Per Hartvig, Anders Lilja, Hans LWidqvist, Ulrika Warpman, Johan Ulin, Bengt Ungstrom, Kaarina Amberla, Matti Viitanen and Bengt Winblad Part IV. Cholinergic System: Models of Alzheimer Disease, Effects of Lesions and Aging Nucleus Basalis Lesions and Recovery . . . . . . . . . . . . . . 119 Vahram HaroutWiian, William Wallace and Kenneth L. Davis vi Experimental Autoimmune Dementia (EAD ): An Immunological Model of Memory Dysfunction and Alzheimer's Disease . . . . 126 Daniel M. Michaelson, Gil Alroy, Lior Soussan, Joab Chapman and Joram Feldon Aging of the Cholinergic Synapse in the Rat's Hippocampus: Effect of Acetyl-L-Carnitine _. . . . . . . • • • . • • . . . . . 134 Luciano Angelucci, G. Sebastiano Alema, Assunta Imperato, Massimo Castorina, M. Teresa Ramacci and M. Grazia Scrocco SDAT Models and Their Dynamics .... 141 Alexander G. Karczmar Part V. Cholinergic Pharmacotherapy: Toxicology and Drug Effects on Learning and Memory Toxicological Umitations to Cholinomimetic Therapy ........ 155 Bo R. Holmstedt and Ingrid Nordgren Learning and Memory Enhancement by Drugs Which Indirectly Promote Cholinergic Neurotransmission ........ 162 Harbans Lal and Michael J. Forster Functional Cholinergic Receptor Sensitivity: The Role of Drug Probes . . . • • . . . . . . . . . . . . . . . 170 Trey Sunderland, Susan Molchan, Ben Vitiello, Rick Martinez and Alex Martin Brain Phospholipids and Their Metabolites in Alzheimer's Disease: Possible Role of "Auto-Cannibalism" and Implications for Drug Development . . . . . . . . . . . . . . • . . . . . . . 183 Richard J. Wurtman, J. Krzysztof Blusztajn, Roger Nitsch and John H. Growdon Part VI. Non-Cholinomimetic Agents Galanin: Regulation of Cholinergic Function and Behavior . . . . . . 193 Sven Ove Ogren and Aladdin Pramanik Activation of Brain Cholinergic System by Noncholinomimetic Agents . . 200 Giancarlo Pepeu, Maria Grazia Giovannini, Fiorella Casamenti, Carla Scali and Paola Rodino vii Part Vll. Cholinesterase Inhibitors: The First Generation Physostigmine in Alzheimer's Disease • . • . • • • . . . . 209 Leon J. Thai Swedish Experiences ofTHA Therapy in Alzheimer's Disease • 216 Henrik Nyback, Arne Ahlin, Lars Gustafson and Lennart Minthon Status ofTHA as Therapy for Alzheimer's Disease . 224 Serge Gauthier and Louise Gauthier Responders and Nonresponders in Experimental Therapy of Alzheimer's Disease • . • • • • • . • • • • • • . . . . • 231 Karl J. Alhainen, Paavo J. Riekkinen Jr., Hilkka S. Soininen, Karl J. Reinikainen and Paavo J. Riekkinen Sr. ChoUnesterase Inhibitors in Alzheimer's Disease: Evaluation of Clinical Studies . • • • . . • . • • . . . . . . . . 238 Bengt Winblad, Abdu Adem, Lars Backman, Agneta Nordberg, Fredrik Blinder and Peter Arhem Part Vlll. Cholinesterase Inhibitors: The Second Generation The Second Generation of Cholinesterase Inhibitors: Pharmacological Aspects . . . . . . • . • . . . • . . . • . . . 247 Ezio Giacobini The Second Generation of Cholinesterase Inhibitors: CUnical and Pharmacological Effects • • • . . . •••.• 263 Robert E. Becker, Pamela Moriearty and Latha Unni Heptyl Physostigmine-Novel Acetylcholinesterase Inhibitor: Biochemical and Behavioral Pharmacology . . . • • . . • . 297 L.L. Iversen, G. Bentley, G. Dawson, S.B. Freedman, E.A. Harley, S.D. Iversen, N.MJ. Rupniak, S. Tye, P.O. Pagella and PL. Rugarli Clinical and Preclinical Studies with Huperzine . • •. 305 Israel Hanin, Xi Can Tang and Alan P. Kozikowski E 2020: The Pharmacology of a Piperidine ChoUnesterase Inhibitor . . 314 Sharon L. Rogers, Yoshiharu Yamanishi and Kiyomi Yamatsu viii Pharmacodynamics of Oral E2020 and Tacrine in Humans: Novel Approaches . • . . • . . . . . . . . . . . . . . . 321 Kathleen A. Shennan Preclinical and Clinical Studies with Galanthamine . . . . . . . . . 329 Torben Thomsen, Helmut Kewitz. Ulrich Bickel, Max Straschill and Gerhard Holl Alzheimer Therapy with Cholinomimetics: The Japanese Experience .. 337 Mitsuo Yoshida Part IX. Use of Cholinergic Agonists in Alzheimer Disease Novel Muscarinic Agonists for Treatment of Alzheimer's Disease . . 347 Roy D. Schwarz, Linda L. Coughenour, Robert E. Davis, David T. Dudley, Walter H. Moos, Michael R. Pavia and Haile Teele New Muscarinic Agonists with Special Emphasis on AF102B .. 354 Abraham Fisher, Rachel Haring, David Gurwitz, Claire M. Fraser, Zipora Pittel, Eliahu Heldman, lshai Karton, Rachel Brandeis and Dov Barak AF102B: Preclinical Experience . . . • . . . . . . . . . .. 363 Yoshinori Iga, Nobuo Ogane, Yasunari Saito, Sadao Samuraizono, Gosei Kawanishi and Haruo Kobayashi Muscarinic Agonists for Senile Dementia: Past Experience and Future Trends . . . . . . . . . . . . . . . 370 Albert Enz, Julian A. Gray and Rene Spiegel Part X. Effects of Nicotine and Nicotinic Agonists Some Novel Actions of Nicotine in Nucleus Basalis Lesioned Rats and in Hippocampal Slices . . . . . . . . . . 379 Nelida N. Sjak-Shie, Edwin M. Meyer and Bruce E. Hunter New Nicotinic Agonists and Cerebral Blood Flow . . . . . . . . . . 386 Stephen P. Americ Part XI. Nerve Growth Factors: Potential for Alzheimer Disease Therapy Pharmacological Actions of Recombinant Human Nerve Growth Factor on Lesioned Central Cholinergic Neurons: Rationale for the Treatment of Alzheimer's Disease . 397 Paul A. Lapchak and Franz Hefti ix