Table Of ContentW
(cid:53)(cid:22)(cid:8)(cid:47)(cid:77)(cid:90)(cid:84)(cid:73)(cid:75)(cid:80)(cid:20)(cid:8)(cid:50)(cid:22)(cid:8)(cid:44)(cid:77)(cid:75)(cid:83)(cid:77)(cid:90)(cid:92)(cid:20)(cid:8)(cid:51)(cid:22)(cid:8)(cid:44)(cid:87)(cid:93)(cid:74)(cid:84)(cid:77)(cid:20)(cid:8)(cid:45)(cid:22)(cid:8)(cid:51)(cid:87)(cid:93)(cid:92)(cid:91)(cid:81)(cid:84)(cid:81)(cid:77)(cid:90)(cid:81)(cid:8)(cid:16)(cid:77)(cid:76)(cid:91)(cid:22)(cid:17)
(cid:54)(cid:77)(cid:93)(cid:90)(cid:87)(cid:88)(cid:91)(cid:97)(cid:75)(cid:80)(cid:81)(cid:73)(cid:92)(cid:90)(cid:81)(cid:75)(cid:8)(cid:44)(cid:81)(cid:91)(cid:87)(cid:90)(cid:76)(cid:77)(cid:90)(cid:91)
(cid:41)(cid:86)(cid:8)(cid:49)(cid:86)(cid:92)(cid:77)(cid:79)(cid:90)(cid:73)(cid:92)(cid:81)(cid:94)(cid:77)(cid:8)(cid:41)(cid:88)(cid:88)(cid:90)(cid:87)(cid:73)(cid:75)(cid:80)
(cid:50)(cid:87)(cid:93)(cid:90)(cid:86)(cid:73)(cid:84)(cid:8)(cid:87)(cid:78)(cid:8)(cid:54)(cid:77)(cid:93)(cid:90)(cid:73)(cid:84)(cid:8)(cid:60)(cid:90)(cid:73)(cid:86)(cid:91)(cid:85)(cid:81)(cid:91)(cid:91)(cid:81)(cid:87)(cid:86)
(cid:59)(cid:93)(cid:88)(cid:88)(cid:84)(cid:77)(cid:85)(cid:77)(cid:86)(cid:92)(cid:8)(cid:31)(cid:26)
(cid:59)(cid:88)(cid:90)(cid:81)(cid:86)(cid:79)(cid:77)(cid:90)(cid:63)(cid:81)(cid:77)(cid:86)(cid:54)(cid:77)(cid:95)(cid:65)(cid:87)(cid:90)(cid:83)
Prof. Dr. M. Gerlach
KlinikundPoliklinikfu¨rKinder-undJugendpsychiatrieundPsychotherapie
Wu¨rzburg,Germany
Prof. Dr. Ju¨rgen Deckert
KlinikundPoliklinikfu¨rPsychiatrieundPsychotherapie
Wu¨rzburg,Germany
Dr. K. Double
PrinceofWalesMedicalResearchInstitute,Sydney,Australia
Dr. E. Koutsilieri
Institutfu¨rVirologieundImmunobiologie
Wu¨rzburg,Germany
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Preface
antiparkinsoniantherapyin1967 – andhisyoungcolleague
Moussa Youdim – who also proceeded to a stellar career
in PD research and became a close friend of Peter’s –
cemented his lifelong interest in the investigation of PD.
Rising to the position of Head of Clinical Neurochem-
istryatLudwigBoltzmannInstituteforClinicalNeurobiol-
ogy at Lainz Hospital (Vienna) in 1971, Peter achieved a
seriesofsignificantinsightsintothenatureofPDandother
neurological disorders, resulting in a number of attrac-
tive offers to head neurochemistry departments at various
Universities.In1986,Peterassumedhiscurrentpositionas
Professor of Clinical Neurochemistry at the University of
W€uurzburg. During his two decades in Franconia he has
assiduously builtthe international reputation of his depart-
ment, the success of which was recognized in 1999 by its
being awarded the status of a National Parkinson Founda-
This supplementum of the Journal of Neural Transmis- tion Center of Excellence (USA). Among his significant
sion was conceived as a celebration of the professional contributions from this period, is his body of work on the
life and work of Professor Peter Riederer, Professor of neurochemistry of schizophrenia and mechanisms of neu-
Clinical Neurochemistry in the Clinic for Psychiatry and rodegeneration in Alzheimer’s disease (AD) and PD. Most
PsychotherapyattheUniversityofW€uurzburg,Germany,on recently the role of iron in PD and the possibility of neu-
the occasion of his retirement in April 2007. Many of roprotectiveand neurorestorativestrategies in neurodegen-
Peter’s colleagues and friends have contributed manu- erative disease (together with Moussa Youdim and two of
scripts to this issue. The international character of this us, M.G. and K.D.) attracted his attention.
issue, and the broad range of topics it includes, isrecogni- Peter has authored over 900 scientific papers and chap-
tioninitselfofthehighregardenjoyedbyPeterinthefield ters, a body of work which has contributed much to our
of neurochemistry. understanding of the aetiology and possible new treatment
Peter Riederer was born in K€oonigsberg (Germany) in strategies for PD and other brain disorders, including AD,
1942 but completed most of his early schooling and uni- depression and schizophrenia. As an exampleof his stand-
versity education in Vienna, where he completed his doc- ing it is worth noting that in 2004 he was the most cited
torateinchemistryattheViennaUniversityofTechnology chemist in medical research. He has been recognized per-
in1970.Hefirstmadehismarkonthefieldofneurochem- sonally with numerous international and national awards
istry asayoung PostdoctoralFellow,with hisinstrumental and honours, including the Burda Prize for research in
andinitiatingroleinthediscoveryin1975ofthebeneficial PD, the Eli Lilly Prize in Neuropsychopharmacology
effects of L-deprenyl (selegiline), the first selective mono- (which he was awarded twice). He shared the Claudius
amine oxidase B inhibitor, in the therapy of Parkinson’s Galenus Gold Prize (for his deprenyl research) and was
disease (PD). This discovery, made jointly with Professor awarded with the honorary membership of the Hungarian
Walther Birkmayer – who had introduced the combined Pharmacology Society. He has served on numerous journal
L-DOPA=decarboxylaseinhibitor(benserazide)strategyinto editorialboards, mostprominently asEditor-in-Chiefofthe
VI Preface
Journal of Neural Transmission. He has also organized have been fruitfully pursued for years, even decades, says
many successful congresses in his areas of expertise, most much about the esteem and admiration with which he is
notably serving as the Congress President of the Sixteenth regarded.Asacolleagueandperson,Peterisvaluedforhis
International Congress of Parkinson’s Disease and Related wide-ranging knowledge, his sense offairness and last but
Disorders inBerlinin2005and serving asChairmanofthe not least his Viennese charm. Many of his colleagues and
local organising committee of the World Congress on Bio- collaborators have also been lucky enough to benefit from
logical Psychiatry in Berlin 2001. Peter’s generous hospitality and that of his equally charm-
Popular with his students, Peter inspired many students ing wife, Inge.
to enter neurochemistry research, and he has mentored On the occasion of his retirement we congratulate Peter
manyyoungscientistsembarkinguponsuccessfulresearch for a lifetime of achievement, for his many valuable con-
careers: K. Double (Australia), N. Durany (Spain), M. E. tributions to neurochemistry, and for enriching the livesof
G€ootz (Germany), E. Gr€uunblatt (Germany), C. Konradi allthestudentsandcolleagueswhohaveworkedwithhim.
(USA), E. Koutsilieri (Germany), G. M€uunch (Australia), Wealsothankhimforthefriendshipandwarmthwhichhe
W.-D. Rausch (Austria), G Reynolds (UK) and E. Sofic has unstintingly extended to the editors of this special
(Bosnia-Herzegovina)tonameonlyafew.Hisinternational issue, and to so many others, throughout the years. We
reputation is underlined by the number and breadth of his hope to continue both our professional and personal rela-
collaboratorsfromcountriesaroundtheglobe.Thefactthat tionships with Peter for many years to come.
manyofthesecollaborations,includingthosewiththeedi-
tors of this issue, as well as those with other long- Manfred Gerlach, W€uurzburg, May 2007
term colleagues such as S. Hoyer (Germany), K. Jellinger J€uurgen Deckert, W€uurzburg, May 2007
(Austria), W. Maruyama (Japan), T. Nagatsu (Japan), M. Kay Double, Sydney, May 2007
Naoi (Japan), T. Saito(Japan) andM.B.H.Youdim(Israel) Eleni Koutsilieri, W€uurzburg, May 2007
Contents
Youdim, M. B. H.: The meeting of minds and times with Peter Riederer: an appreciation . . . . . . . . . . . . . . . 1
Foley, P.: Succi nervorum: a brief history of neurochemistry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Basic neuroscience
Constantinescu, R., Constantinescu, A. T., Reichmann, H., Janetzky, B.:
Neuronal differentiation and long-term culture of the human neuroblastoma line SH-SY5Y . . . . . . . . . . . 17
Crumeyrolle-Arias, M., Medvedev, A., Cardona, A., Tournaire, M.-C., Glover, V.:
Endogenous oxidized indoles share inhibitory potency against [3H]isatin binding in rat brain . . . . . . . . . . 29
Dedov, V. N., Griffiths, F. M., Garner, B., Halliday, G. M., Double, K. L.:
Lipid content determines aggregation of neuromelanin granules in vitro . . . . . . . . . . . . . . . . . . . . . . . . . 35
Holmquist, L., Stuchbury, G., Steele, M., Mu¨nch, G.:
Hydrogen peroxide is a true first messenger. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Koutsilieri, E., Rethwilm, A., Scheller, C.: The therapeutic potential of siRNA in gene therapy
of neurodegenerative disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Tribl, F., Arzberger, T., Riederer, P., Gerlach, M.: Tyrosinase is not detected in human
catecholaminergic neurons by immunohistochemistry and Western blot analysis . . . . . . . . . . . . . . . . . . . 51
Wruck, C. J., Claussen, M., Fuhrmann, G., Ro¨mer, L., Schulz, A., Pufe, T., Waetzig, V.,
Peipp, M., Herdegen, T., Go¨tz, M. E.: Luteolin protects rat PC12 and C6 cells against MPPþ
induced toxicity via an ERK dependent Keap1-Nrf2-ARE pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Wultsch, T., Chourbaji, S., Fritzen, S., Kittel, S., Gru¨nblatt, E., Gerlach, M.,
Gutknecht, L., Chizat, F., Golfier, G., Schmitt, A., Gass, P., Lesch, K.-P., Reif, A.:
Behavioural and expressional phenotyping of nitric oxide synthase-I knockdown animals . . . . . . . . . . . . . 69
Parkinson’s disease and allied conditions
Hirsch, E. C.: Animal models in neurodegenerative diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Jellinger, K. A.: Morphological substrates of parkinsonism with and without dementia:
a retrospective clinico-pathological study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Lin, W.-M., Zhang, Y.-M., Moldzio, R., Rausch, W.-D.: Ginsenoside Rd attenuates
neuroinflammation of dopaminergic cells in culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Nagatsu, T., Sawada, M.: Biochemistry of postmortem brains in Parkinson’s disease:
historical overview and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Naoi, M., Maruyama, W., Yi, H., Akao, Y., Yamaoka, Y., Shamoto-Nagai, M.:
Neuroprotection by propargylamines in Parkinson’s disease: intracellular mechanism
underlying the anti-apoptotic function and search for clinical markers . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Offen, D., Barhum, Y., Levy, Y.-S., Burshtein, A., Panet, H., Cherlow, T., Melamed, E.:
Intrastriatal transplantation of mouse bone marrow-derived stem cells improves motor
behavior in a mouse model of Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Pollak, L., Dobronevsky, Y., Prohorov, T., Bahunker, S., Rabey, J. M.:
Low dose methylphenidate improves freezing in advanced Parkinson’s disease during off-state . . . . . . . . . 145
Sontag, T. A., Lange, K. W., Heim, Ch., Kolasiewicz, W., Tucha, O., Sontag, K.-H.:
The long-term effects of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-b-carboline
(TaClo) on cognitive performance in rats. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
VIII Contents
Van Der Werf, Y. D., Berendse, H. W., van Someren, E. J. W., Stoffers, D., Stam, C. J.,
Wolters, E. Ch.: Observations on the cortical silent period in Parkinson’s disease . . . . . . . . . . . . . . . . . . 155
Viaggi, C., Vaglini, F., Pardini, C., Sgado`, P., Caramelli, A., Corsini, G. U.:
CYP 2E1 mutant mice are resistant to DDC-induced enhancement of MPTP toxicity . . . . . . . . . . . . . . . . 159
Magyar, K., Szatma´ry, I., Szebeni, G., Lengyel, J.: Pharmacokinetic studies of ((cid:1))-deprenyl
and some of its metabolites in mouse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Alzheimer’s disease and related disorders
Cagnin, A., Zambon, A., Zarantonello, G., Vianello, D., Marchiori, M., Mercurio, D.,
Micciche`, F., Ermani, M., Leon, A., Battistin, L.: Serum lipoprotein profile and APOE
genotype in Alzheimer’s disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
Fischer, P., Krampla, W., Mostafaie, N., Zehetmayer, S., Rainer, M., Jungwirth, S., Huber, K.,
Bauer, K., Hruby, W., Riederer, P., Tragl, K. H.: VITA study: white matter hyperintensities
of vascular and degenerative origin in the elderly. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Hager, K., Kenklies, M., McAfoose, J., Engel, J., Mu¨nch, G.: a-Lipoic acid as a new treatment
option for Alzheimer’s disease – a 48 months follow-up analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Hoyer, S., Lannert, H.: Long-term abnormalities in brain glucose=energy metabolism after inhibition
of the neuronal insulin receptor: implication of tau-protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
Kogan, E. A., Verchovsky, R. G., Neufeld, M. Y., Klimovitsky, S. Sh., Treves, T. A.,
Korczyn, A. D.: Long-term tetrahydroaminoacridine treatment and quantitative EEG
in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Leuner, K., Pantel, J., Frey, C., Schindowski, K., Schulz, K., Wegat, T., Maurer, K.,
Eckert, A., Mu¨ller, W. E.: Enhanced apoptosis, oxidative stress and mitochondrial dysfunction
in lymphocytes as potential biomarkers for Alzheimer’s disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Salkovic-Petrisic, M., Hoyer, S.: Central insulin resistance as a trigger for sporadic
Alzheimer-like pathology: an experimental approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Tahirovic, I., Sofic, E., Sapcanin, A., Gavrankapetanovic, I., Bach-Rojecky, L.,
Salkovic-Petrisic, M., Lackovic, Z., Hoyer, S., Riederer, P.: Brain antioxidant capacity in rat
models of betacytotoxic-induced experimental sporadic Alzheimer’s disease and diabetes mellitus. . . . . . . 235
Teipel, S. J., Mitchell, A. J., Mo¨ller, H.-J., Hampel, H.: Improving linear modeling of cognitive
decline in patients with mild cognitive impairment: comparison of two methods . . . . . . . . . . . . . . . . . . . 241
Biological psychiatry
Lange, K. W., Tucha, L., Walitza, S., Gerlach, M., Linder, M., Tucha, O.:
Interaction of attention and graphomotor functions in children with attention deficit
hyperactivity disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
Laux, G., Baumann, P., Hiemke, C., The TDM group of the Arbeitsgemeinschaft
Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP):
Therapeutic drug monitoring of antidepressants – clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Mu¨ller, N., Schwarz, M. J.: The immunological basis of glutamatergic disturbance
in schizophrenia: towards an integrated view . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Nudmamud-Thanoi, S., Piyabhan, P., Harte, M. K., Cahir, M., Reynolds, G. P.:
Deficits of neuronal glutamatergic markers in the caudate nucleus in schizophrenia . . . . . . . . . . . . . . . . . 281
Pfuhlmann, B., Gerlach, M., Burger, R., Gonska, S., Unterecker, S., Jabs, B.,
Riederer, P., Deckert, J.: Therapeutic drug monitoring of tricyclic antidepressants in everyday
clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
Reif, A., Melchers, M., Strobel, A., Jacob, C. P., Herterich, S., Lesch, K.-P., Zimmer, M.:
FZD3 is not a risk gene for schizophrenia: a case-control study in a Caucasian sample . . . . . . . . . . . . . . 297
Schneider, M., Retz, W., Freitag, C., Irsch, J., Graf, P., Retz-Junginger, P., Ro¨sler, M.:
Impaired cortical inhibition in adult ADHD patients: a study with transcranial
magnetic stimulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
Walitza, S., Melfsen, S., Herhaus, G., Scheuerpflug, P., Warnke, A., Mu¨ller, T.,
Lange, K. W., Gerlach, M.: Association of Parkinson’s disease with symptoms of attention
deficit hyperactivity disorder in childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Contents IX
Other disorders
Kneitz, S., Meisner, F., Sopper, S., Kaiser, F., Gru¨nblatt, E., Scheller, C., Riederer, P.,
ter Meulen, V., Koutsilieri, E.: Biostatistical analysis of gene microarrays reveals diverse
expression clusters between macaque subspecies in brain SIVinfection . . . . . . . . . . . . . . . . . . . . . . . . . 317
Rajda, C., Bergquist, J., Ve´csei, L.: Kynurenines, redox disturbances and neurodegeneration
in multiple sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Yoshinaga, T., Hashimoto, E., Ukai, W., Toki, S., Saito, S., Saito, T.:
Neural stem cell transplantation in a model of fetal alcohol effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
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The meeting of minds and times with Peter Riederer: an appreciation
M. B. H. Youdim
Technion-RappaportFamiltyFacultyofMedicine,EveTopfCentreofExcellenceforNeurodegenerativeDiseasesResearch,Haifa,Israel
‘‘The harder you work, the harder it is to surrender.’’ human brain regions (Collins et al., 1970; Youdim et al.,
Vince Lombardi 1972).Thebasalganglia,hadahigheractivitytowardsthe
MAO-B substrate benzylamine and dopamine than the
It is fair to say that if I had not received a phone call at
other regions, suggesting that predominance of MAO-B
OxfordUniversityfromProf.MertonSandlerinsummerof
in this brain region. It was decided I should stop over in
1973, that a young chap by the name of Peter Riederer,
ViennatogivealectureonMAOforBirkmayersake,since
from Prof. Walter Birkmayer Department, was in London
IwasgoingtomeetJosephKnollinBudapest,andpresent
andwantedtodiscusssomeaspectsofmonoamineoxidase
a paper at the Hungarian Pharmacology Society.
(MAO) inhibitors for Parkinson’s disease (PD), I probably
IhadoncebeforebeeninViennaasastopover,butthis
wouldnotbewhereIamtoday.Ifthereweretwocontrast-
time Peter was a great host. After the lecture at the Neu-
ing people, that were us. Here was this large but soft spo-
rologicalInstitutewelandedinaHeurigerestaurant,drink-
ken, rather gentle and austere Viennese, meeting a small
ing a significant amount of the young wine and thinking
rather assertiveindividualfrom Iran. It was meeting of the
that the Hungarians might have a gold mine in L-deprenyl
minds and an instant connection that has lasted some 34
that they were not aware of. The ensuing headache that
years, with a result of some near one hundred joint pub-
evening was worth what was to come eventually with
lications,some25booksandhopefullyadvancingthepros-
L-deprenyl. Peter explained to me why he was looking
pect for treatment of PD. Peter wanted to know was there
foranMAO-inhibitingsubstancewithoutmajorsideeffects
anMAOinhibitorthatdidnotcausea‘‘CheeseReaction’’,
andwedecidedtoconvinceBirkmayertotryL-deprenylin
a side effect of first generation of non-selective MAO in-
parkinsonian patients with on–off-phases. I let have some
hibitors,thatcouldbeemployedinthetreatmentofPD.In
5mg of L-deprenyl, which I had received from Joseph
1961 Birkmayer and colleagues had used MAO inhibitors
Knoll in Budapest and transferred to Peter Riederer and
totreatPD,gastrointestinalandbloodpressureproblemsin
Birkmayer at a lunch in the Sacher restaurant in Vienna,
such patients was a limiting factor. My instant reaction to
withtheemphasisthatifitshouldcausehypertensioninthe
his request was that the Hungarian pharmacologist, Joseph
PD subject, we should abandon the project. Later Joseph
Knoll,whomIhadmetattheMAOmeetinginSardiniain
Knoll did not appreciate our hypothesis about the useful-
1971, in honour of Hugh Blaschko, had described a failed
ness of L-deprenyl as dopaminergic drug for PD, when I
MAO-B inhibitor anti-depressant called L-deprenyl, that
toldourintention.HeinsistedthatthatL-deprenylactedas
did not give a cheese reaction in isolated pharmacological
psychoenergizer like amphetamine with phenylethylamine
preparations and in vivo (Knoll and Magyar, 1972). The
being its major action. Some months later at Oxford our
other logic of using L-deprenyl was that in 1970 with
secretary informed me that I have a call from an excited
Merton Sandler we had studied MAO activity in different
person by the name of Riederer from Vienna. My first re-
actionwasthattheuseofL-deprenylbyBirkmayerhashad
Correspondence: Prof. Dr. Moussa B. H. Youdim, Technion – Israel a major side effect in PD subjects. But Peter assured me
InstituteofTechnology,TheBruceRappaportFacultyofMedicine,De-
that L-deprenyl was given to 44 PD subjects and the drug
partmentofPharmacology,EfronStreet,31096Haifa,Israel
e-mail:[email protected] works (Birkmayer et al., 1975, 1977; Lees et al., 1977).
2 M.B.H.Youdim
Thelackofvideointhosedaysresultedinmakingafilmof 1924and1968hadshownthatironisincreasedinsubstan-
someofthepatients.Theclinicalresultswerepresentedat tia nigra of PD and this could be relevant to the pathology
the5thInternationalCongressofPDinViennaandMelvin of the disease. His response was that he had similar data
Yahr,whowasthesecondinvestigatortostudyL-deprenyl, and which were presented at meeting in Austria in May
assertedinthesummaryofthecongressthatthisisanovel 1985,wellbeforethepublishedletterofDexteretal.inthe
new direction for the treatment of PD (Yahr, 1975). The Lancet (1987). So for the second timewe had the meeting
rest is history except that it took nearly 15 years before ofthemindstoexploretheroleofironinPDandthatledto
L-deprenyl,renamedinUSAasselegiline,reachitsshores. extensive collaborations and publications on brain iron in
The next stage in this collaboration was the long term PDanditsanimal models,whichhasnowbecomeamajor
effect of L-deprenyl, which we (Birkmayer et al., 1983, topic of interest in neurodegenerative processes and other
1985) had studied in more than 800 subjects since in 1975. neurodegenerative diseases, including Alzheimer’s disease
It was apparent that L-deprenyl as adjuvant to L-DOPA (Riederer et al., 1989; Gerlach et al., 1994; Berg et al.,
(L-3,4-dihydroxyphenylalanine, levodopa) may alter the 2002, 2004; G€ootz et al., 2004; Zecca et al., 2004). This
progression of the disease and we wrote in the summary topic led to my collaboration with Avraham Warshawsky
of the paper presented at the MAO meeting in Heidelberg in 1989 for the development of brain permeable iron che-
‘‘The prolongation of the evolution of Parkinson’s disease lators as therapeutic agents for PD and other neurodegen-
with long-term ((cid:1))-deprenyl treatment shows for the first erative disorders including Alzheimer’s disease, which we
time that the degeneration of the dopaminergic nigrostria- havedoneverysuccessfully(Youdimetal.,2004;Galetal.,
tal fibers can be depressed to some extent’’ (Birkmayer 2005; Zheng etal., 2005a, b),demonstrating thatiron che-
et al., 1983). This was prior to the identification of MPTP lators are neuroprotective in 6-hydroxydopamine kainate
(N-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine) as a do- and MPTP models of PD.
paminergic neurotoxin and its prevention by L-deprenyl The collaboration with Peter did not weaned there and
in1984(Heikkilaetal.,1984).Therestishistoryresulting tookanotherturnwhenwedecidedtostudythemechanism
in the publication of thousands of publications on various ofdopamineneurodegeneration intheMPTPmodelofPD
aspects of L-deprenyl, pharmacology and neuroprotection. and in sporadic PD brains employing for the first time
ItalsoledtothedevelopmentofanumberofotherMAO-A transcriptomics and proteomic profilingof substantia nigra
and B inhibitors as anti-Parkinson drugs by manypharma- parscompacta.WithoutPeter’sabilitytoobtainPDbrains
ceutical companies, which all failed to reach the market. from the brain banks in Austria and Germany this project
+
The exception being rasagiline (Azilect ) a restricted ana- wouldhaveneverhavegotofthegroundanditwasthefirst
logueofL-deprenyl,whichJohnFinbergandIco-developed timethatthisapproachwasmadeforthestudyofsporadic
with Teva Pharmaceutical Company (Youdim et al., 2005). PD.Iconsiderthisasprobablythemostimportantandsig-
The other aspect of our collaboration has been thework nificant work we done, since it brings a new dimension to
we initiated on brain iron metabolism in PD, a subject I the study of neurodegenerative processes in PD and opens
startedatOxfordin1974,atthetimewhennoonehadpaid up novel avenues on the mechanism ofneurodegeneration,
much attention to the role of iron in brain function and novel drug development and even development of pheno-
dysfunction (Youdim, 1985). It was Sheila Callender, the typicmodelofsporadicPD(Gr€uunblattetal.,2004;Mandel
Reader in Department of Haematology at Oxford Univer- et al., 2005).
sity who had read one of my earlier papers on iron meta- The meeting of the minds between Peter and I was not
bolism and MAO and asked why I had not continued the directed entirely in our research interests. It included ex-
work on brain iron metabolism. As a consequence my change of students, post-doctoral fellows, organization of
group started the work on brain iron metabolism, which numerous symposia, conferences and congresses and edit-
waspresentedattheCibaFoundationsymposium(Youdim ingofmanybooksandtravelingtoallcornersoftheworld
and Green, 1976) and summarized in the Handbook of and presenting the results of our collaboration.
Neurochemistry (Youdim, 1985) with some emphasis on Above all these events, there is the human side of Peter
role of iron in oxidative stress and PD. 1985 was another Riederer as a friend, colleague and teacher. His humanity
turning point for Peter and I when we met at the Interna- canbemeasuredbytheconstantsupporthehasgiventohis
tional Society for Neurochemistry in Copenhagen, where colleagues, the young students, Israeli scientists, Israel and
Paul Mandel had invited me to talk about iron and brain myself. He is the only person who has never failed to visit
function. The subject of human brain iron metabolism Israel,toparticipateinconferencesandsupportitnomatter
cameup,IimpartedtoPeterthatseveralpublicationsfrom if there was a conflict in Israel with its Arab neighbors.
