Frontiers in Clinical Neuroscience: Neurodegeneration and Neuroprotection A Symposium in Abel Lajtha’s Honour

199 Pages·2004·8.06 MB·English

by  Mario E. Götz, Peter Riederer (auth.), László Vécsei (eds.)

FRONTIERS IN CLINICAL
NEUROSCIENCE
A Symposium in Abel Lajtha's Honour
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK, State University ofNew YorkatBuffalo
IRUN R.COHEN, The WeizmannInstitute ofScience
DAVIDKRITCHEVSKY,WistarInstitute
ABEL LAJTHA, N.S. Kline Institutefor Psychiatric Research
RODOLFO PAOLETTI, University ofMilan
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FRONTIERS IN CLINICA L
NEUROSCIENCE
Neurodegeneration and Neuroprotection
A Symposium in Abel Lajtha's Honour
Edited by
Lasz16 Vecsei
University of Szeged
Szeged, Hungary
Springer Science+Business Media, LLC
ISBN 978-1-4613-4740-8 ISBN 978-1-4419-8969-7 (eBook)
DOI 10.1007/978-1-4419-8969-7
©2004 Springer Science+Business Media New York
Originally published by Kluwer / Plenum Publishers, New York in 2004
Softcover reprint ofthe hardcover lst edition 2004
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AN INTRODUCTION TO DR. ABEL LAJTHA
Abel Lajtha enjoyed the benefits ofbeing raised in a family in which, besides his
worldrenowned father, LaszloLajtha (a musician, composer, and professor), his beloved
mother created a spirit ofculture, peace, and deep love. Abel Lajtha, after receiving his
Ph.D. at the Peter Pazmany University ofBudapest, began working with Albert Szent
Gyorgyi in the Department ofBiochemistry. AfterWorld War II Hungary was occupied
bythe Russianarmy, and when the Communistscameinto powerhis father wasremoved
from his job and Abel and his brother Laszlo Lajtha, Jr., a well respected cancer
researcher, leftthe country.He went to Italy (Naples) on apostdoctoral fellowship and in
1949 settled down inthe United States.When Abel married his fiancee Marie his parents
could not getpassportstotravel to Vienna, 250 Ianfrom Budapest,where the couplewas
staying. This very happy event, his marriage to Marie, enriched his entire life as Marie
recognized, understood, and activelysupported his dedicationto science and made every
effort toensure thatdespitethis commitmenttheir lives togetherwouldbe very happy.
Dr. Lajtha is one ofthe founders ofmodernneurochemistryand a founding member
of several journals and societies. Over the past fifty-five years, he has earned his
reputation as a first-class scientist, editor of several books and journals, and his
HandbookofNeurochemistry.
Dr. Lajtha has been an editor ofabout 20 journals, has served on several advisory
boards, and has organized numerous conferences and symposia. He has received several
honours, including an honorary M.D. degree from the University of Padua, has been
President ofthe International Society for Neurochemistry and ofthe American Society
for Neurochemistry, and has been the Editor-in-Chief of the journal Neurochemical
Research since its foundation in 1975. He was elected as foreign or corresponding
memberofthe SlovenianAcademyofSciences,the HungarianAcademyofSciences,the
IndianAcademyofNeuroscience,and the ArmenianNational AcademyofSciences, and
is an honorary member ofinstitutes and societies in many countries. He has published
about 660 journal articles and 90 reviews or chapters. He was fortunate to practice
science during the last half of the previous century, when many basic neurochemical
concepts could be experimentally addressed for the first time. He has personally
pioneered several discoveries. However, when we asked him what pleases him most
abouthis scientificaccomplishments, he answered(verycharacteristicallyofhim), "most
rewarding was the feeling that I was helping young scientists from all over the world
experience the pleasure ofperforming creative research." In his life there has been no
v
vi ANINTRODUCTIONTODR.ABELLAJTHA
change whatsoever in his commitment to quality science---that is what he has always
stood for.
In 1963,Dr.Lajtha wasappointed Director oftheNew York State Research Institute
forNeurochemistryand DrugAddiction atWard'sIsland,New York City, with astaffof
about 60 people. Scientists from many countries spent profitable time with Dr. Lajtha in
his lab. He was appointed Research Professor of Psychiatry at New York University
School ofMedicine in 1971. His Institute later merged with the N.S. Kline Institute for
Psychiatric Research, where he is now Director ofthe Center for Neurochemistry. At
Ward's Island and at the N.S. Kline Institute Dr. Lajtha contributed to neurochemical
research inmany important ways.
Neurochemical research at the bench level and collaboration with other colleagues
has always been important tohim.Itwasan additional pleasure for him to have informal
contacts with foreign scientists of different cultural backgrounds. Such contacts and
collaborations, carried out in several laboratories, have fostered many long-lasting
friendships. The Hungarians have been extremely proud ofhim, his role in supporting
Hungarian scientists, andhisrole indeveloping thestudyofneurochemistry.Not only the
Hungarians, but also colleagues from all over the world, are very grateful to him for his
help.
Hispersonalityisunique.Hehasmanyfriends, realfriends, and almost everyday he
plays tennis-his forehand isstill very good, he very rarely makes unforced error, and is
in very good physical shape. At the age of 80, he continues to derive a great deal of
pleasure and satisfaction from working in the laboratory writing grant applications and
setting up collaborations and making friends. There are a number of young scientists
being trained at this time inhis laboratory, andhe is now working on the third edition of
his Handbook ofNeurochemistry-now planned at about 25 volumes with 500 or more
chapters.
OnbehalfofthescientificcommunitywehopethatAbelcankeep thisspirit alive for
another twenty years. Clearly, the respect and admiration that we have for him and his
scientific accomplishments and leadership are shared across the ocean. On this, the year
ofhis 80thbirthday,hiscolleagues worldwidehailaremarkable career andoffer ourhope
andexpectationthatthereismuchmoretocome.
His many pupils and friends are honoured to have the opportunity to contribute to
this Festschrift in recognition ofthe work ofDr. Lajtha as a scientist, a teacher, and a
goodfriend.
E.Sylvester Vizi(Budapest) andL.Battistin (Padua)
PREFACE
Over the last decade, the considerable progress made in biochemistry, molecular
biology,geneticsandneuropharmacologyhasrevealedsomeoftheintimatemechanisms
ofthe neurodegenerativedisorders.There is increasingevidence linking genetic defects
affecting mitochondria to Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, Huntington's disease and some other neurological disorders. Advances in
knowledge are fueled through improved animal models that use mitochondrial toxins,
excitotoxins, and transgenic animals. Therapeutic studies in these models have
strengthened the possibility for effective treatments in man. By defining the
pathomechanisms, we hope to be in the position to prevent cell death by protecting
neurons. Indeed serious preclinical and clinical research is going on in the field of
neuroprotection in stroke, Parkinson's disease, epilepsy, demyelinating disorders and
dementia.Based on these scientific ideas, the Symposium in honour ofProfessor Abel
LajthawasorganizedbytheEuropeanSocietyforClinicalNeuropharmacology(ESCNP)
and the Danube Symposium for Neurological Sciences in Budapest, Hungary, October
24-25, 2002. Professor Lajtha was born in Budapest in 1922 and his home town is an
ideal venue for strengthening the bonds between Western and Eastern European
Neuroscientists. Professor Peter Riederer (Wurzburg) held the 2002 special "Dezso
Miskolczy Memorial Lecture" in Abel Lajtha's Honour. Thanks are due to the invited
speakersofthisSymposiumfortheirexcellentcontribution.
LaszloVecsei
vii
CONTENTS
Advancesin NeuroprotectionResearchfor NeurodegenerativeDiseases 1
Mario E.Gotz andPeter Riederer
NeurotransmitterRelease in ExperimentalStrokeModels: The Roleof
Glutamate-GABAInteraction 21
LaszloG.Harsing, Jr.,Gabor Gigler,Mihaly Albert,Gabor Szenasi,
Annamaria Simo,Krisztina Moricz,Attila Varga, Istvan Ling, Erzsebet Bagdy,
IstvanKiraly, Sandor Solyom,andZsoltJuranyi
Neuroprotectionin IschemiclHypoxicDisorders: Fromthe Preclinical tothe
ClinicalTesting 39
ZoltanNagy and Laszlo Simon
Neuroprotectionand DopamineAgonists 55
Zvezdan PirtosekandDusan Flisar
COMTInhibitionin the TreatmentofParkinson'sDisease: Neuroprotection
and FuturePerspectives 75
Vladimir S.Kostic
NeuroprotectionandEpilepsy 91
Peter Halasz andGy6rgy Rasonyi
Neuroprotection and GlatiramerAcetate: The Possible Rolein the Treatment
ofMultipleSclerosis III
TjalfZiemssen
CausesandConsequencesofDisturbancesofCerebralGlucose Metabolismin
SporadicAlzheimerDisease: TherapeuticImplications 135
Siegfried Hoyer
Neuroprotection: ARealisticGoal for AgedBrain? 153
LauraCalza and Luciana Giardino
Kynureninesin NeurodegenerativeDisorders: TherapeuticConsideration 169
Peter Klivenyi, JozsefToldi,andLaszlo Vecsei
Index 185
ix
ADVANCES IN NEUROPROTECTION RESEARCH
FORNEURODEGENERATIVE DISEASES
Mario E.Gotz and PeterRiederer!
1.INTRODUCTION
Recent advances in science enable new and closer insights into brain structure and
function. The extent of CNS damage due to ischemia, or neurodegeneration can be
followed by the use of modem brain imaging technology such as positron emission
tomography (PET) or single-photon 'emission computed tomography (SPECT) and
radiolabeled tracers. Ex vivo the systematic use ofgene expression arrays is becoming
more and more important to select sensitive genes as targets for neuroprotection. And
gene therapy is considered as an alternative approach to trigger neuroprotection in
experimental models of neurodegeneration. At the same time as these modem
technologies pave their way, new promising pharmacological intervention concepts to
halt disease progression of Parkinson's and Alzheimer's disease, and to diminish
ischemiareperfusion injury,haveemerged.
This review summarizes some of the recent results of experimental preclinical
research in the fieldofneuroprotection against excitotoxic and oxidative stress mediated
neuronal damage. These pathogenetic mechanisms are considered important for the
progression of chronic neurodegenerative diseases and stroke induced brain damage.
Despite considerable scientific progress many more efforts have to be undertaken
however, to understand the complex time dependent and thus fluctuating interactions of
excitotoxicity, mitochondrial damage and oxidative stress as causative factors for
neuronal apoptotic andnecrotic death.
Although, it has to be always kept in mind that the complexity of the human
neuropathology cannot easily be mimicked by animal models, cell culture experiments
IMarioE.Gotz,InstituteofPhannacologyandToxicology.97078Wilrzburg,Germany.PelerRiederer. DepartmentofPsychiatry,
HeadDivisionofClinicalNeurochemistry.97080Wilrzburg.Gennany.
2 M.E.GOTZANDP.RIEDERER
and in vivo data give a hint for the assessment ofnew therapeutic concepts in clinical
trials. With preclinical research a significant number of promising drugs has been
developed that inanimal studies conferneuroprotectionbut await clinical trials.A failure
to induce neuroprotection inman withcurrentlyavailable drugs would suggestthat either
the animal models employed are not truly representative ofthe diseases, or that a single
drug would not be effective enoughforasuccessful neuroprotection.
This implies that combinations of drugs with each of it having a well defined
pharmacologic dose response on specific, but different molecular targets, ought to be
investigatedin future invitroand invivostudies.This concepthas long been accepted for
the therapyofcardiovasculardiseases,AIDS, cancer and neuropsychiatric disorders. Itis
important to mention that a variety of pathogenetic mechanisms exists, but that these
mechanisms are linked and not necessarily independent of each other. Some of them
might be activated only forcertain periods within the disease progression. So it iscrucial
to offer the correctremedyatthe correct time period when the pathogenetic mechanisms
are active.To fmd out these time frames suitable for therapeutic intervention will be the
task for future prospective trials of neuroprotective drugs utilising new brain imaging
technology.
Here we want tohighlightsome ofthepharmacological conceptsthat might be worth
to proceed in their preclinical developments. Ideally, relevant drugs in focus should first
be able to alleviate disease syndromes and second to decrease or even halt disease
progression.
In animal models for neurodegeneration iron chelators, nitric oxide synthase
inhibitors, monoamine oxidase inhibitors,antioxidants, dopamine agonists and glutamate
receptorblockershave demonstratedmild tomoderate protection1.2 and inclinicalstudies
selegiline, a selective MAO-B inhibitor as well as several dopamine agonists delay the
necessity for L-DOPA therapy in parkinsonian patients'. The most promising classes of
drugs for the treatment of age-related chronic neurodegenerative diseases such as
Alzheimer's and Parkinson's disease that will be disussed in the following might
currently be propargylamines, dopamine agonists, glutamate receptor antagonists, and
antioxidantcompounds such as estradiol derivatives, coenzyme Q, vitamin A, vitaminC,
vitaminE,and 6,8-dithiooctanoicacid,known as lipoic acid.
2.PROPARGYLAMINES
N-Methyl-N-propargyl-I-phenyl-2(R)-propylamine might be the most prominent
propargylamine, betterknown as selegiline. Selegiline, a selective MAO-B inhibitor, has
proved to be as well an effective radical scavenger.t" increases neurotrophic factor
synthesis7inculturedastrocytes and inhibits apoptosis."
Interestingly, several clinical prospective studies have shown that selegiline delays
the need for L-DOPAin newly diagnosed parkinsonian patients.f" In contrast, treatment
ofAlzheimer's disease sufferers with selegiline does not result in aclinically measurable
benefitas reportedby ameta-analysisofseveral clinical studies.15
To date however, beside direct symptomatic effects ofselegiline in PD which may
be relatedto decreasedmonoamine turnover, the nature ofthe potentiallyneuroprotective
effect could not yetbe elucidated.16.17