Pharmacologyof Endogenous NeurotoxÎns

A Handbook

Edited by Andreas Moser

Springer Science+Business Media, LLC

Editor: Andreas Moser Department of Neurology Medical University of Liibeck Liibeck, Germany

Library of Congress Cataloging-in-Publication Data

Pharmacology of endogenous neurotoxins / [edited by] Andreas Moser. p. cm.

Includes bibliographical references and index. ISBN 978-1-4612-7375-2 ISBN 978-1-4612-2000-8 (eBook) DOI 10.1007/978-1-4612-2000-8 1. Neurotoxicology. 2. Neurotoxins-Metabolism. 3. Neurotoxins­

Pathophysiology. 4. Neuropharmacology. 1. Moser, Andreas, 1960- . [DNLM: 1. Neurotoxins-pharmacology. QW 630.5.N4 P536 1997]

RC347.5.P48 1998 616.8'047-DC21 DNLMlDLC for Library of Congress

Printed on acid-free paper.

©1998 Springer Science+Business Media New York Originally published by Birkhauser Boston in 1998 Softcover reprint of the hardcover 1 st edition 1998

Copyright is not claimed for works of U.S. Government employees.

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ISBN 978-1-4612-7375-2 Typeset by Braun-Brumfield, Inc.

9 8 7 6 5 432 1

List of contributors

Gerhard Bringmann, Institute of Organic Chemistry, University of Wiirzburg, Am Hubland, D-97074 Wiirzburg, Germany

Hans-Willi Clement, Institute of Physiological Chemistry, Department of Neurochemistry, Univer­sity of Marburg, Hans-Meerwein-Stral3e, D-35033 Marburg, Germany

Michael A. Collins, Department of Molecular & Cellular Biochemistry, Loyola University Medical Center, 2160 South First Avenue, Maywood, Illinois 60153, USA

Philippe Dostert, Pharmacia-Upjohn, 1-20159 Milan, Italy

Glenn Dryhurst, Department of Chemistry and Biochemistry, University of Oklahoma, 620 Parring­ton Oval, Room 208, Norman, Oklahoma 73019-0370, USA

Doris Feineis, Institute of Organic Chemistry, University of Wiirzburg, Am Hubland, D-97074 Wiirzburg, Germany

Ralf God, Institute of Organic Chemistry, University of Wiirzburg, Am Hubland, D-97074 Wiirzburg, Germany

Christoph Grote, Institute of Physiological Chemistry, Department of Neurochemistry, University of Marburg, Hans-Meerwein-Stral3e, D-35033 Marburg, Germany

Hanka Haber, Research Institute for Molecular Pharmacology, A.-Kowalke-StraBe 4, D-10315 Berlin, Germany

Yoko Hirata, Laboratory for Genes and Motor Systems, Bio-mimetic Control Research Center, Insti­tute of Physical and Chemical Research, Shimoshidarni, Moriyama, Nagoya 463, Japan

Bernd Janetzky, University Hospital Carl Gustav Carus, Department of Neurology, University of Dresden, FetscherstraBe 74, D-01307 Dresden, Germany

Mitsuharu Kajita, Department of Pediatrics, Nagoya University School of Medicine, 65 Tsuruma­cho, Showa-ku, Nagoya 466, Japan

Wakako Maruyama, Laboratory of Biochemistry and Metabolism, Department of Basic Gerontol­ogy, National Institute for Longevity Sciences, Obu, Japan

Kazuo Matsubara, Qepartment of Hospital Pharmacy and Pharmacology, Asahikawa Medical Col­lege, A Schikawa 078, Japan

Matthias F. Melzig, Institute of Pharmacy, Humboldt University, Goethestr. 54, D-13086 Berlin, Germany

Andreas Moser (Editor), Department of Neurology, Medical University of Lubeck, Ratzeburger Allee 160, D-23538 Lubeck, Germany

v

vi Contributors

Toshiharu Nagatsu, Division of Molecular Genetics (II) Neurochemistry, Institute for Comprehen­sive Medical Science, School of Medicine, Fujita Health University, Toyoake, Aichi 470-11, Japan

Makoto Naoi, Department of Biosciences, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466, Japan

Edward J. Neafsey, Department of Cell Biology, Neurobiology & Anatomy, Stritch School of Med­icine, Loyola University Chicago, 2160 South First Avenue, Maywood, Illinois 60153, USA

Clemens Neusch, Department of Neurology, Medical University of LUbeck, Ratzeburger Allee 160, D-23538 LUbeck, Germany

Toshimitsu Niwa, Department of Preventive Clinical Medicine, Nagoya University Daiko Medical Center, 1-1-20, Daiko-minarni, Higashi-ku, Nagoya 461, Japan

George D. Prell, Department of Pharmacology, (box 1215) Mount Sinai School of Medicine of the City University of New York, 1 Gustave L. Levy Place, New York, New York 10029-6574, USA

Ingo Putscher, Research Institute for Molecular Pharmacology, A.-Kowalke-StraBe 4, D-10315 Berlin, Germany

Wolf-Dieter Rausch, Institute of Medical Chemistry, University of VeteIinary Medicine Vienna, Josef-Baumanngasse 1, A-12lO Vienna, AustIia

Heinz Reichmann, University Hospital Carl Gustav Carus, Department of Neurology, University of Dresden, FetschenstraBe 74, D-01307 Dresden, Germany

Peter Riederer, Clinical Neurochemistry, Department of Psychiatry, University of WUrzburg, Fuchs­leinstraBe 15, D-97080 WUrzburg, Germany

Matthias Rottmann, Research Institute for Molecular Pharmacology, A.-Kowalke-StraBe 4, D-l 0315 Berlin, Germany

Joachim Scholz, Department of Neurology, Medical University of LUbeck, Ratzeburger Allee 160, D-23538 LUbeck, Germany

Karl-Heinz Sontag, Max Planck Institute for ExpeIimental Medicine, Hermann-Rein-StraBe 3, D-37075 Gottingen. Germany

Wolfgang Wesemann, Institute of Physiological Chemistry, Department of Neurochemistry, Univer­sity of Marburg, Hans-Meerwein-StraBe, D-35033 Marburg, Germany

Josef Zipper, Research Institute for Molecular Pharmacology, A.-Kowalke-StraBe 4, D-10315 Berlin, Germany

Contents in Brief

Table of Contents ix Foreword by Hinrich Cramer xv Preface by Andreas Moser xvii

Part A Neurotoxins 1 1 Isoquinoline Derivatives . 3 2 TIQ Derivatives in the Human Central Nervous System 25 3 Animal Model of Parkinson's Disease Prepared by

N-Methyl-(R)-Salsolinol . . . . . . . . . . . . . . . . . 41 4 Putative Endogenous Neurotoxins Derived from the Biogenic

Amine Neurotransmitters ................ 63 5 j3-Carboline Derivatives ................. 129 6 Highly Halogenated Tetrahydro-j3-Carbolines as a New

Class of Dopaminergic Neurotoxins. . . . . . . . . . . 151 7 pros-Methylimidazoleacetic Acid: A Potential Neurotoxin

in Brain? . . . . 171

Part B Metabolism 189 8 Bioactivation of Azaheterocyclic Amines Via

S-Adenosyl-L-Methionine-Dependent N-Methyltransferases 191 9 Tyrosine Hydroxylase: Biochemical Properties and Short-Term

Regulation in Vitro and In Vivo ................. 209 10 Tyrosine Hydroxylase and Endogenous Neurotoxins . . . . .. 221 11 Monoamine Oxidase: Interaction with Isoquinoline Derivatives 237 12 Toxicity and Pharmacological Effects of Salsolinol in Different

Cultivated Cells 253 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 267

vii

Table of Contents

List of Contributors . . . . . v

Foreword by Hinrich Cramer xv

Preface by Andreas Moser xvii

Part A Neurotoxins 1 1 Isoquinoline Derivatives 3

by T. Niwa, M. Kajita, and T. Nagatsu 1. Introduction .......... 3 2. Tetrahydroisoquinoline (TIQ) . 4

2.1 Presence of TIQ in nature and in food 4 2.2 Methods for identification and measurement

ofTIQ ............ 5 2.3 Presence of TIQ in tissues .. 5 2.4 Endogenous synthesis of TIQ 6 2.5 Parkinsonism caused by TIQ . 6 2.6 Metabolism of TIQ in the brain 7

3. 1,2-Dihydroisoquinoline 8 4. 4-Hydroxy-TIQ ........... 8 5. 1-Benzyl-TIQ ............ 8 6. I-Phenyl-N-methyl-TIQ and I-phenyl-TIQ 10 7. Salsolinol (SAL) . . . . . . . . . . . . . . 10

7.1 Presence of SAL in tissues, body fluids, food, and nature .......... 10

7.2 Biosynthetic pathway of SAL 11 7.3 Neurotoxicity of SAL 11 7.4 Metabolism of SAL ..... 13

8. Norsalsolinol............ 13 9. N-Methyl-salsolinol and N-methyl-norsalsolinol 13

10. 1,2,3,4-Tetrahydro-2-methyl-4,6,7-isoquinolinetriol 14 1 1. Methods for identification and measurement of

catecholic TIQs ................... 16 12. The sites of toxicological activity .......... 17

12.1 Inhibition of mitochondrial respiratory enzymes 17 12.2 Hydroxyl radical formation . . . . . . . . . . . 17

2 TIQ Derivatives in the Human Central Nervous System 25 by A. Moser

1. History of the Presence of TIQ derivatives 25 2. Analytical Methods ........... 26

ix

x

2.1 Cerebrospinal Fluid (CSF) ............ . 2.1.1 Lumbar Puncture . . . . . . . . . . . . . . 2.1.2 High Performance Liquid Chromatography

2.2 Urine .................. . 2.2.1 Urine measurements of Salsolinol . . . . . 2.2.2 Affinity chromatography . . . . . . . . . . 2.2.3 High Performance Liquid Chromatography

3. Frequency and TIQ Levels measured by HPLC-ECD 3.1 N-Methyl-norsalsolinol ....... . 3.2 Salsolinol ............... .

4. TIQ Derivatives and Dopamine Metabolites 5. Stereospecifity and Enantiomeric Separation 6. Cerebral Lesions by TIQ Derivatives ..

6.1 TIQ, I-Methyl-TIQ, 2-Methyl-TIQ 6.2 N-Methyl-[R]-salsolinol ..... . 6.3 N-Methyl-norsalsolinol ..... . 6.4 N-Methyl-4-hydroxy-norsalsolinol

7. Hallucinosis and TIQ Derivatives ....

3 Animal Model of Parkinson's Disease Prepared by N-Methyl-R-Salsolinol ......... . by M. Naoi, W. Maruyama, and P. Dostert

1. MPTP and N-Methylation . . . . . . 2. Preparation of a rat model of Parkinson's disease

2.1 Materials ..... . 2.2 Animal experiments ......... .

3. Behavior observation ........... . 3.1 Behavior changes due to perturbation in

dopaminergic system . . . . 4. Biochemical analysis in the brain ..... .

4.1 Methods ............... . 4.2 Quantitative analyses of monoamines, their

metabolites and isoquinolines ...... . 4.3 Enantiomeric analysis of salsolinol derivatives 4.4 Assay of tyrosine hydroxylase activity . 4.5 Biochemical changes by infusion of

N-methyl-[R]-salsolinor and DMDHIQ+ 4.6 Changes of monoamines and their metabolites 4.7 Accumulation of N-methyl-[R]-salsolinol

and DMDHIQ+ . . . . . . . . . . . . . . .

4.8 Reduction of tyrosine hydroxylase activity 5. Histological study .......... .

5.1 Methods for histological analysis 5.2 Cytotoxicity in the striatum 5.3 Depletion of dopamine neurons in the

substantia nigra 6. Discussion ................ .

Contents

27 27 27 27 29 29 29 30 30 31 31 33 34 34 34 34 35 37

41

41 44 44 44 44

44 47 47

47 48 48

48

48

50 50 50 50 50

52 52

Contents

4 Putative Endogenous Neurotoxins Derived from the Biogenic Amine Neurotransmitters ...... .......... 63 by G. Dryhurst

1. Introduction .... 63 2. Alzheimer's disease 65 3. Ischemia-Reperfusion 68 4. Methamphetamine 69 5. In vitro oxidation chemistry of the biogenic

6.

7.

amine neurotransmitter .... 5.1 In vitro oxidation chemistry of

5-hydroxytryptamine . . . . . . . . 5.2 In vitro oxidation chemistry of dopamine .. 5.3 In vitro oxidation chemistry of norepinephrine In vivo oxidation chemistry of the biogenic amine neurotransmitter ...... . 6.1 In vivo oxidation of 5-hydroxytryptamine 6.2 In vivo oxidation of dopamine

and norepinephrine . . . . . . . .. .. Properties of putative aberrant oxidative metabolites of the biogenic amine neurotransmitters ..... . 7.1 Redox properties of putative aberrant oxidative

metabolites of 5-HT and 5-HTPP ..... . 7.2 Redox properties of putative aberrant oxidative

71

71 81 86

87 87

90

91

92

metabolites of DA and NE .......... 97 8. Neurochemical and neurobiological properties of

putative aberrant oxidative metabolites of 5-HT, DA andNE . . . . . . . . . . 97

9. Serotonin binding proteins 102 10. Discussion 104 11. Summary ....... 113

5 ~-Carboline Derivatives as Neurotoxins by M.A. Collins and EJ. Neafsey

1. Biosynthetic and organic synthetic routes to TH~C's

129

and ~C's ..... .... ...... ... 130 2. Overview of the effects of ~C's and their metabolic

derivatives on the nervous system . . . . . 130 3. Measurement and analysis ofTH~C's, ~C's and

their derivatives ........ .. ... 133 4. Enzymatic formation of N-methylated ~C cations from

nonpolar ~C's .. ............. 134 5. Uptake and intracellular actions of N-methylated

~C cations . . .. ...... ... .. 136 6. Neurotoxicity in vitro of N-methylated ~C cations 139 7. Neurotoxicity in vivo of N-methylated ~C cations 140 8. Endogenous presence ofTH~C's, ~C's and their

N-methylated derivatives in animals and humans 141

xi

xii Contents

6 Highly Halogenated Tetrahydro-j3-Carbolines as a New Class of Dopaminergic Neurons ................... 151 by G. Bringmann, D. Feineis, C. Grote, R. God, H.-W. Clement, K.-H. Sontag, B. lanetzky, H. Reichmann, W.-D. Rausch, P. Riederer, and W. Wesemann

1. Introduction ................... 151 2. Chloral-derived THBCs as potential mammalian

alkaloids with expected neurotoxic properties . . 153 2.1 Synthetic route for the preparation of TaClo 154 2.2 TaClo as a chiral compound: elucidation of the

absolute configuration ............. 154 2.3 Ability of TaClo to cross the blood-brain barrier 157 2.4 De novo formation of TaClo in rats treated with its

putative precursors . . . . . . . . . . . . . . . .. 158 3. Lesion studies ...................... 159

3.1 Effects of TaClo in cell culture on cell integrity and dopamin,e metabolism ............. 159

3.2 Inhibition of the mitochondrial respiration 160 3.3 Behavioral studies on rats after intraperitoneal

application of TaClo ............. 162 3.4 Striatal dopamine metabolism in the rat after

intranigral injection of TaClo 163 4. Outlook ............. 165

7 pros-Methylimidazoleacetic Acid: A Potential Neurotoxin in Brain? 171 by G.D. Prell . . . . . . . . . . . . . 171

1. Introduction .......... 171 2. Biochemical origin ofp-MIAA 172 3. Presence of p-MIAA in nature . 174 4. Methods of measurement of p-MIAA 174 5. Localization ofp-MIAA in brain 175 6. p-MIAA in CSF of patients with Parkinson's disease 176 7. p-MIAA and studies with mice given MPTP 178 8. p-MIAA and release of the excitoneurotoxin, glutamate 179 9. p-MIAA measured in CSF of patients with

chronic schizophrenia ..;........... 180 10. p-MIAA in brain and lack of changes with drugs 181 11. Summary and conclusions . . . . . . . . . . . . 181

Part B Metabolism........................ 189 8· Bioactivation of Azaheterocyclic Amines Via

S-adenosyl-L-methionine-dependent N-methyltransferases 191 by K. Matsubara

1. Methyltransferase ........... 192 1.1 Nicotinamide N-methyltransferase 192 1.2 Histamine N-methyltransferase 193 1.3 Phenylethylamine N-methyltransferase 193

Contents

1.4 Amine N-methyltransferase 1.5 Others

2. Assay procedures 3. Methyl donor, SAM 4. Substrate for N-methyltransferase,

neurotoxin precursor . . . . . . . . . . . . . 4.1 MPTP analogues . . . . . . . . . . . . 4.2 [3-Carbolines and their tetrahydro forms 4.3 TIQ and 6,7-DHTIQ ........ . 4.4 I-Aromatic substitution of TIQs . . .

5. Possible formation of azaheterocyclics via SAM-dependent N-methylation ..... .

9 Tyrosine Hydroxylase: Biochemical Properties and Short-term Regulation In Vitro and In Vivo byY. Hirata

1. Basic properties of tyrosine hydroxylase 2. Structure and function . . . . . . . 3. Assays for tyrosine hydroxylase . . 4. Regulation of tyrosine hydroxylase

4.1 Feedback inhibition .....

.....

.....

194 195 195 196

197 197 198 200 201

202

209

209 212 212 213 213

4.2 Enzyme phosphorylation and activation in vitro 213 4.3 Regulation of tyrosine hydroxylase by protein

phosphorylation and by dopamine autoreceptor in dopaminergic nerve terminals ........ 215

10 Tyrosine Hydroxylase and Endogenous Neurotoxins 221 by J. Scholz and A. Moser

1. Tyrosine hydroxylase ............... 221 1.1 Genetic aspects: Transcription and translation 221 1.2 Molecular structure ............. 223 1.3 Investigation of tyrosine hydroxylase expression 223 1.4 An assay of tyrosine hydroxylase enzyme activity 225

2. The effect of neurotoxins on tyrosine hydroxylase 226 2.1 Models of neurotoxicity involving

tyrosine hydroxylase . . . . . . . . . 226 2.2 Quinoline and isoquinoline derivatives 226 2.3 [3-Carbolines 230

3. Summary.............. 231

11 Monoamine Oxidase: Interaction with Isoquinoline Derivatives . by C. Neusch and A. Moser

1. Monoamine oxidase 1.1 Introduction 1.2 Classification 1.3 Genetic differences 1.4 Occurrence . . . .

237

237 237 237 238 239

xiii

xiv

1.5 Reaction mechanism . . . . . . . . . . . . . . . 1.6 Flavin cofactor ................. .

2. Interaction between MAO and isoquinoline derivatives 2.1 MPTP-model . . . . . . 2.2 MPTP-like substances ......... . 2.3 Isoquinoline derivatives ........ . 2.4 Isoquinoline derivatives as MAO inhibitor 2.5 Inhibition pattern of N-methyl-norsalsolinol 2.6 Chemical structure and inhibitory activity .

12 Toxicity and Pharmacological Effects of Salsolinol in

Contents

240 241 241 241 242 243 245 246 247

Different Cultivated Cells ............. .... 253 by M.F. Melzig, I. Putscher, H. Haber, M. Rottmann, and J. Zipper

1. Blood-brain barrier . 253 2. Technical procedures 254

2.1 Materials .. 254 2.2 Cell culture 254 2.3 Cytotoxicity 254 2.4 Electron microscopy 254 2.5 Effect of salsolinol on the ~-endorphin release of

AtT-20 cells ................... 255 2.6 Effect of salsolinol on the POMC gene expression 255 2.7 Receptor binding analysis ....... 255

2. Cytotoxicity of salsolinol .......... 256 3. Binding studies with salsolinol on dopamine

receptor subtypes .............. 261 4. Effect of salsolinol on POMC gene expression and

~-endorphin release of AtT-20 cells .. . . . . . . 262

Foreword

It is a great pleasure to write the foreword to this important volume for several reasons. First: As far as we know, already primitive societies had to cope with environmental toxins of many kinds and set up regulations to limit their effects on food and drug use. Modem science, synthesizing tens of millions of new compounds has incredibly magnified this challenge. Today, xenobiotic metabolism has become a crucial task for humans and many other species alike.

Second: When reading this book, one is impressed by the extraordinary speed at which neurotoxicology has advanced. Obviously, processing (and endogenous formation) oftox­ins has become an extremely relevant topic. When I had the chance, almost three decades ago, to work in chemical pharmacology with Bernard B. Brodie at NIH, the drug metabo­lizing system of the liver had just been recognized and characterized. We had just started to work on the biogenic amines, newly discovered cyclic nucleotides in rat brain, human cere­brospinal fluid, and on the effects of toxic drugs like amphetamines. Today, biochemical neuropharmacology is a mature field of neuroscience.

Third: As a clinical neurologist, I may underline the great importance of several con­tributions in the book for a new understanding of neurological diseases. The elucidation of endogenous neurotoxin formation, influenced by overcharge, genotoxicity, drug interac­tions, abuse and other factors, is promising to provide new insight into the origin and mech­anism of neurodegenerative diseases, and, of interest to a wider audience, into normal and abnormal aging. Since the editor's background also includes clinical neurology, these aspects are dealt sufficiently with in the book. I am sure that this volume will be acclaimed-both as a timely review and as an extremely helpful handbook and reference source for the researcher in the field.

xv

Hinrich Cramer Professor of Neurology and Neurochemistry

University of Freiburg Germany

Preface

"Since the discovery of MPTP .... " These introductory words appear at the beginning of a voluminous literature published by neuroscientists who are dealing with MPTP and the neurotoxicological aspects in pathogenesis of Parkinson's disease. Although many bio­chemical parallels do exist between Parkinson's disease and MPTP-induced parkinsonism, it should be clear that patients with idiopathic Parkinson's disease had never ingested MPTP in their lifetime. However, the nucleus of MPTP responsible for its toxicity is a com­mon chemical moiety and thus, may occur in many other substances.

The search for environmental toxins that are related to neurodegenerative disorders has so far been umewarding. There may be significant factors associated with industrialization, agrochemicals, or early exposure to a rural environment, including the use of well water for drinking.

The impact of these factors has, however, been relatively small and inconsistent in the studies undertaken. The potential involvement of MPTP-like compounds in Parkinson's dis­ease may not be restricted only to those found in the environment, but may also involve endogenous neurotoxins. Thus, the aim of this book is to survey some of the important areas of neurotoxicological research together with the impact of potentially endogenously syn­thesized heterocyclic neurotoxins on normal and pathophysiological regulation in the cen­tral nervous system, and also on a number of specific organs and diseases.

The first part of the book deals with the chemical and biochemical aspects of the origin, formation and degradation, and biochemical pathways, of those heterocyclic compounds, including tetrahydroisoquinolines, (3-carbolines, methylimidazoles, and tryptarnines and their association to alkaloids. Heterocyclicants are then considered as potentially endoge­nously synthesized substances from catecholarnines or other transmitter metabolites in mammals (including humans). The role of these substances in the understanding of disease processes is discussed by experts as the most intriguing problem. In the second part of the book, physiological, biochemical, and neuropharmacological aspects of enzymatic systems, including their interaction with heterocyclic neurotoxins, are treated, showing that the umaveling of the roles played by neurotoxins, may well become a key point in the under­standing of the metabolism in the central nervous system.

Altogether, though many umesolved and challenging problems are stated and dis­cussed in the text, this volume describes all of the potentially endogenously formed neuro­toxins and relevant enzyme systems known to date. In this capacity, we hope, it may be widely used as a handbook by the researchers in the field and by the clinical neurologists with a special interest in neurodegenerative diseases.

xvii

Andreas Moser Medical University of Liibeck

Germany