Novel Approaches to the Treatment of Alzheimer's Disease ADVANCES IN BEHAVIORAL BIOLOGY Editorial Board Jan Bures Institute of Physiology, Prague, Czechoslovakia Irwin Kopin National Institute of Mental Health, Bethesda, Maryland Bruce McEwen Rockefeller University, New York, New York James McGaugh University of California, Irvine, California Karl Pribram Stanford University School of Medicine, Stanford, California Jay Rosenblatt Rutgers University, Newark, New Jersey Lawrence Weiskrantz University of Oxford, Oxford, England Recent Volumes in this Series Volume 23 THE AGING BRAIN AND SENILE DEMENTIA Edited by Kalidas Nandy and Ira Sherwin Volume 24 CHOLINERGIC MECHANISMS AND PSYCHOPHARMACOLOGY Edited by Donald J. Jenden Volume 25 CHOLINERGIC MECHANISMS: Phylogenetic Aspects, Central and Peripheral Synapses, and Clinical Significance Edited by Giancarlo Pepeu and Herbert Ladinsky Volume 26 CONDITIONING: Representation of Involved Neural Functions Edited by Charles D. Woody Volume 27 THE BASAL GANGLIA: Structure and Function Edited by John S. McKenzie, Robert E. Kemm, and Lynette N. Wilcock Volume 28 BRAIN PLASTICITY, LEARNING, AND MEMORY Edited by B. E. Will, P. Schmitt, and J. C. Dalrymple-Alford Volume 29 ALZHEIMER'S AND PARKINSON'S DISEASES: Strategies for Research and Development Edited by Abraham Fisher, Israel Hanin, and Chaim Lachman Volume 30 DYNAMICS OF CHOLINERGIC FUNCTION Edited by Israel Hanin Volume 31 TOBACCO SMOKING AND NICOTINE: A Neurobiological Approach Edited by William R. Martin, Glen R. Van Loon, Edgar T. Iwamoto, and Lay ten Davis Volume 32 THE BASAL GANGLIA II: Structure and Function-Current Concepts Edited by Malcolm B. Carpenter and A. Jayaraman Volume 33 LECITHIN: Technological, Biological, and Therapeutic Aspects Edited by Israel Hahin and G. Brian Ansell Volume 34 ALTERATIONS IN THE NEURONAL CYTOSKELETON IN ALZHEIMER' DISEASE Edited by George P. Perry Volume 35 MECHANISMS OF CEREBRAL HYPOXIA AND STROKE Edited by George Somjen Volume 36 NOVEL APPROACHES TO THE TREATMENT OF ALZHEIMER'S DISEASE Edited by Edwin M. Meyer, James W. Simpkins, and Jyunji Yamamoto A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher. Novel Approaches to the Treatment of Alzheimer's Disease Edited by Edwin M. Meyer, and James W. Simpkins University of Florida Gainesville, Florida and Jyunji Yamamoto Taiho Pharmaceuticals, Ltd. Tokushima, Japan PLENUM PRESS • NEW YORK AND LONDON Library Df CDngress CataIDglng-ln-PubllcatIDn Data SuncDast WDrkshop Dn the NeurobiolDgy of Aging (1st, 1989 Saint Petersburg. Fla.) Novel apprDaches tD the treat.ent of Alzheimer's disease I edited by Edwin M. Meyer and Ja.es W. Simpkins and Jyunji Va.amoto. p. cm. -- (Advances in behavioral biology; v. 36) "Proceedings of the First Annual Suncoast Workshop on t~e NeurobiolDgy of Aging. held February 26-March 1. 1989. in St. Petersburg. Florida"--T.p. verso. Includes bibliographical references. ISBN-13: 978-1-4684-5729-2 e-ISBN-13: 978-1-4684-5727-8 001: 10.10071978-1-4684-5727-8 1. Alzheimer's disease--Chemotherapy--Congresses. 2. Acetychol1ne--Receptors--Effect of drugs on--Congresses. 3. Neuropharmacology--Congresses. I. Meyer. Edwin M. II. Simpkins. Janes W. III. Vamamoto. Jyunjl. IV. TItle. V. Series. [DNLM, 1. Alzheimer's Dlsease--drug therapy--congresses_ 2. Psychotroplc Drugs--pharmacology--congresses. HM 220 S957n 1989] RC523.S86 1989 616.8'31061--dc20 DNLM!DLC for Library of Congress 89-26615 CIP Centel" 101" the Neul"o&iolof;JY 01 Af;Ji.nr:J ~ CN.it Uni.vel"si.ty 01 flol"ida Proceedings of the First Annual Suncoast Workshop on the Neurobiology of Aging, held February 26-March 1, 1989, in St. Petersburg, Florida © 1989 Plenum Press, New York Softcover reprint of the hardcover 1st edition 1989 A Division of Plenum Publishing Corporation 233 Spring Street, New York, N.Y, 10013 All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher This book is dedicated to the memory of the Honorable Claude Pepper, whose crusade for the rights and welfare of the elderly inspired us all. PREFACE Alzheimer's disease afflicts up to 1 in 5 people over the age of 65 years and causes untold suffering of the patient and their family. The cause of this disease is unknown; indeed, evidence increasingly suggests that there may be multiple Alzheimer-type syndromes with different etiologies, analogous to different types of psychosis. Currently there are no means to prevent the disease, slow its progress or reverse its neurodegenerative consequences. With few exceptions, clinical trials of a variety of compounds have resulted in patient responses that are disappointing with respect to both the proportion of responders and the magnitude of the responses. Novel approaches to the treatment of Alzheimer's disease are clearly warranted. For this reason, we organized the First Suncoast Workshop on the Neurobiology of Aging in St. Petersburg, Florida, which took place from February 26-March 1, 1989. This workshop focused on novel treatments and models for Alzheimer's disease and represented a cooperative venture among academia, government and industry, both in its participants and sponsorship. The Center for the Neurobiology of Aging at the University of Florida, the National Institute on Aging and Taiho Pharmaceutical Corporation in Japan sponsored the workshop in which scientists from the North America, Europe, Japan and other parts of Asia participated. While not an official proceedings of the Suncoast Workshop, this text does reflect the breadth and depth of the research presented there. A few additional chapters were received from investigators who could not attend the workshop but who wished to augment the book. The text is divided into sections that deal with animal and clinical models for Alzheimer's disease, novel treatment strategies based on a new generation of cholinergic agents, neurotrophic agents that prevent or even reverse neurodegeneration, grafting neural tissue into the brain, other types of therapeutic approaches, and novel approaches to improve the delivery of drugs to the brain . .collectively, this text reflects an advanced level of thought on a variety of related strategies aimed at treating neurodegenerative diseases such as Alzheimer's disease. In a field moving this quickly, it is imperative that new data and hypotheses be published as quickly as possible. Towards this end, we are indebted to Melanie Yelity and the others at Plenum Press who expedited the publication of this book in so many ways. The organization of this workshop and the production of this text required the cross continental efforts of many people. We are particularly grateful for the continuing intellectual, organizational and financial support of the following individuals at Taiho Pharmaceutical ·Company in Japan: Mr. Satoru Nakagami, who was so enthusiastic in his support of the Workshop; Dr. Takashi Suzui; and Dr. Katsuo Toide. Some of our best suggestions for organizing the workshop came from Dr. Ronald Micetish, President of Synphar, a North American affiliate of Taiho Pharmaceuticals. Our co-editor, Dr. Jyunji Yamamoto, graciously agreed to write a separate Preface for this volume. This text would have been impossible without Janice E. Goodson. Ms. Goodson's devotion to the project far exceeded our expectations; her professional touch was evident in every workshop-related activity, ranging from the organization and advertisement of the workshop over a year ago through the editing of the last submitted manuscript. Special contributions to the text were made by the following individuals: Dr. Jennifer Poulakos, Dr. Suzanne Evans, and Judy Adams vii Finally, we wish to acknowledge the support of the administration of the University of Florida, College of Medicine and College of Pharmacy, as well as the Office of the Vice President, J. Hillis Miller Health Science Center. Their support for this project and for the other activities of the Center for the Neurobiology of Aging daily facilitates our multidisiplinary approach to the problems of the aging brain, including Alzheimer's Disease. We believe that the knowledge base reflected in this text and the willing participation of eminent scientists from around the world, will similarly enhance our future workshops on novel treatments for Alzheimer's Disease. Edwin M. Meyer and James W. Simpkins Gainesville, Florida Date: August 14, 1989 viii AN OPINION FROM JAPAN Science, being an historically accumulated product, walks on one step after another with the achievements of scientists from each generation, with no possibility of leap frogging even one of the steps. It is no easy task to know the historical background of scientific progress, and there are many cases in which scientists cannot become so enlightened. At the time of its advancement and development, science is confronted with many difficulties; how to solve these difficulties hangs on the shoulders of each generation, as a mission. Each generation must also deal with the advancement of pharmacological products, which goes all the way from scientific research to social needs. Major social and medical problems in recent years are the age-related neurological disturbances Alzheimer's disease, dementia and senility, and researchers are burdened with the responsibility of tackling these problems squarely. Development of very highly advanced drugs such as those promoting memorization/learning capacities or inhibiting the aging process will be in greater demand in the future; further, scientific technologies in general have been progressing steadily and surely, along with individually specialized areas and techniques for dissemination of information. Under these evolving circumstances, solutions will almost undoubtedly involve group efforts and not those of any single investigator. The question here is how effectively research works in different specialized disciplines to solve problems in as short a time period as possible. For this purpose, it will be desirable to develop a new research system with the capacity to promote joint research and design components in various forms as required. Nowadays in Japan, the number of researchers and research-institutions studying the brain are steadily increasing. This state of affairs can also be commonly applicable to many countries in the world. The world abounds with people who have a variety of ideas. While cultures indigenous to each country exist, scientific differences will result. Combining these different sciences will make it possible to give rise to newer lines of research, widening the door open to a newer platform of prospects, which is really marvellous in itself. I have in mind always to watch my own contribution to science and humanity. J. Yamamoto, Ph.D. Director of Alzheimer's Disease Research Taiho Pharmac:euticals, LTD ix CONTENTS SECTION I. DRUGS THAT ACT AT CHOLINERGIC RECEPTORS A Functionalized Congener Approach to Muscarinic Ligands K. A. Jacobson, B. J. Bradbury and J. Baumgold AF102B: A Novel M1 Agonist as a Rational Treatment Strategy in 11 Alzheimer's Disease A. Fisher, R. Brandeis, I. Karton, Z. Pittel, S. Dachir, M. Sapir, Y. Grunfeld, A. Levy and E. Heldman Muscarinic Receptors, Phosphoinositide Hydrolysis and Neuronal 17 Plasticity in the Hippocampus F. T. Crews, N. J. Pontzer and L. J. Chandler Effects of Cholinergic Drugs on Extracellular Levels of Acetylcholine and 25 Choline in Rat Cortex, Hippocampus and Striatum Studied byu Brain Dialysis K. Toide and T. Arima Delayed Matching-to-Sample in Monkeys as a Model for Learning and Memory 39 Deficits: Role of Brain Nicotinic Receptors W. J. Jackson, K. Elrod and J. J. Buccafusco Muscarinic and Nicotinic Receptors in Alzheimer's Disease: Rationale for 53 Cholinergic Drug Treatment P. A. Lapchak, D. M. Araujo and R. Quirion SECTION II. CNS-ACTIVE NEUROTROPHIC FACTORS Potential Pharmacological Use of Neurotrophic Factors in the Treatment of 63 Neurodegenerative Diseases F. Hefti The Use of Reaggregating Cell Cultures and Immortalized Central Nervous 71 System Cells to Study Cholinergic Trophic Mechanisms B. H. Wainer, H. J. Lee, J. D. Roback, and D. N. Hammond xi