MAO — The Mother of all Amine Oxidases

359 Pages·1998·21 MB·English

by  J. C. Shih Ph.D.

J. P. M. Finberg, M. B. H. Youdim, P. Riederer,
K. F. Tipton (eds.)
MAO-The Mother of all
Amine Oxidases
Springer-Verlag Wien GmbH
Prof. Dr. J. P. M. Finberg
Prof. Dr. M. B. H. Youdim
Department of Pharmacology, The Bruce Rappaport Faculty of Medicine,
Technion - Israel Institute of Technology, Haifa, Israel
Prof. Dr. P. Riederer
Clinical Neurochemistry, Department of Psychiatry, University of Würzburg,
Federal Republic of Germany
Prof. Dr. K. F. Tipton
Biochemistry Department, Trinity College, Dublin, Ireland
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© 1998 Springer-Verlag Wien
Originally published by Springer-Verlag Wien New York 1998
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SPIN: 10636439
With 76 (partly coloured) Figures
ISBN 978-3-211-83037-6 ISBN 978-3-7091-6499-0 (eBook)
DOI 10.1007/978-3-7091-6499-0
Preface
The 6th Rappaport Symposium and 7th Amine Oxidase Workshop was held in
lune 1996 at Shavei Zion, on the northern coast ofIsrael, some 25 km from the
Lebanese border. In view of the tense security situation which preceded the
symposium, the organisers are particularly grateful to all the participants for
their support.
lust one year before this conference we all learned of the death of our dear
colleague, Dr Moise Da Prada, to whose memory this meeting was dedicated.
Induded in these Proceedings are two appreciations of his life's work by
dose colleagues. We were honoured to be able to host his widow, Maria
Strauss-Da Prada, at the meeting and hope that all the Da Prada family
receive comfort from this record to the memory of Moise, whose passing is
such a loss to our field. He will be remembered for his kindness and exuber
ance as weil for his scientific distinction and his steadfastness in promoting the
therapeutic value of MAO inhibitors through aperiod when they had,
temporarily, fallen into disfavour.
The monoamine oxidases are enzymes which constantly produce surprises,
and one of the aspects which we chose to highlight in the meeting was the
recent discovery of patient groups bearing selective genetic deficiencies in
MAO-A or MAO-B. The importance of such genetic alterations in the patho
genesis of mental and neurological disorders is currently under debate. In
particular, the possibility that selective MAO-A deficiency could be respon
sible for violent behaviours in general was raised in the popular press
immediately before the meeting, and we were happy to receive important con
tributions from Drs. D. Murphy and H. Brunner and their groups which help to
darify the situation.
Another surprise in the MAO field has been the discovery of the neuro
protective or neuro-rescuing actions of some propargyl-derivative MAO-B
inhibitors, and the role ofMAO in oxidative stress. Such aspects are covered
in several places within this book together with many other advances in our
understanding ofthe structure, behaviour and functions ofthe amine oxidases.
We hope this volume will be of value to all those wishing to learn about cur
rent knowledge and opinions of the roles of the amine oxidases in health and
disease.
We wish to acknowledge with thanks the sponsorship and financial support
ofthe following in enabling our meeting to take place:
Rappaport Family Institute far Research in the Medical Sciences; Bruce
VI Preface
Rappaport Faculty of Medicine, Technion, Israel Institute of Technology; the
International Union of Biochemistry and Molecular Biology (lnterest Group
IG 156); Hoffman-La Roche Ud, Switzerland; Synthelabo Recherche
(L.E.R.S), France; DeVries & Co Ud, Roche, Israel; Teva Pharmaceutical
Industries Ud, Israel.
J. P. M. Finberg
M. B. H. Youdim
P. Riederer
K. F. Tipton
Prof. Mose Da Prada
1934-1995
Mose Da Prada: Development ofan outstanding scientist
A. Pletscher
In 1963 Mose Da Prada became a member of my personal research group at
Hoffmann-La Roche Basel. At that time, he did not have much research expe
rience. Nevertheless, I decided to accept his application for a position in my
group, because I was intrigued by his high motivation to enter the field of bio
chemical pharmacology. Thus, I could closely follow his remarkable develop
ment as a scientist and the rising recognition of his human qualities by his
environment. These aspects will be briefly dealt with in the following.
From Bologna to Basel
Three circumstances were at the origin ofDa Prada's decision to leave his job
as assistant at the Medical University Clinic of Bologna and to join our
research group at Hoffmann-La Roche in Basel.
Firstly, he was attracted by Roche's activities in the then new field of bio
chemical neuropsychopharmacology. With its first, long acting, synthetic
monoamine oxidase (MAO)-inhibitor, iproniazid, Roche had opened a new
approach to the treatment of mental depression and had entered the field of
biogenic monoamines. Da Prada, as a graduate in medicine and pharmacy, was
much interested in these developments.
A second attractor in Roche Basel was Mose's close friend Giuseppe Bar
tholini, with whom he had been working in Bologna and who had joined our
group about a year before. Bartholini very much liked the scientific approach
es and the working facilities at·Roche. Since he was aware of the "scientific
potential" of Mose, he wanted hirn to work with us and motivated hirn to join
our group.
A third reason for Da Prada's decision to leave Bologna was the unfavour
ab1e research situation in the medical clinics of its university. Due to insuffi
cient salaries, many of the young MD's had to earn their living by performing
part-time private practice in addition to their daily clinical work. Also, the
infrastructure for research was poor. This made serious scientific work impos
sible. No wonder that a research-motivated young man like Da Prada tended to
leave such a place.
Thus, the decision ofMose Da Prada to change from Bologna to Basel was
motivated by a "push and pull" situation.
x
A. Pletscher
Scientific development
During this stay in oUf group, two lines of research were in the center of Da
Prada's activities, i.e. the biology of monoamines at the cellular and subcellu
lar level and the action of neUfopsychotropic drugs on the monoaminergic sys
tems of the central nervous system. Since, as already mentioned, he had no
experience in biochemical pharmacology, I asked hirn to start work with isolat
ed blood platelets, which were used in our laboratory as relatively simple, par
tial models for certain aspects ofcerebral monoamine dynamies. The method
ological skills ofMose soon became apparent. He developed chromatographie
methods by which he clarified the metabolism of5-hydroxytryptamine (5-HT)
in platelets and the effect ofdrugs, like reserpine, benzoquinolizines and phen
ylalkylamines, on the formation ofmetabolites, e.g. 5-hydroxyindolacetic acid
and 5-hydroxytryptophol. Later, Da Prada and Tranzer, using electron micros
copy and biochemical techniques, played an essential role in the discovery of
the intracellular storage sites of 5-HT in platelets of various species and in
megakariocytes. Mose succeeded for the first time in isolating the 5-HT-stor
age organelles (storage granules, dense bodies) in pure form by sophisticated
fractionation methods. This allowed the direct elucidation of the action of
drugs at the level of the storage organelles, showing, for instance, that reser
pine exerts its effect at the granular membrane. The collaboration ofDa Prada
with physico-chemists also led to the clarification of the intragranular storage
mechanism of biogenie amines in platelets and chromaffine granules of the
adrenal medulla. Their experiments presented evidence for the existence of
polymerie complexes of the monoamines with the intragranular nucleotides
like ATP, and in the case ofchromaffine granules, also with proteins.
These findings, in which Da Prada played an essential role, helped to estab
lish platelets as partial models for other tissues, including brain, with regard to
monoamine uptake, storage and metabolism. The platelet model is still being
used, especially in clinical studies.
Later, Mose also proceeded to the central nervous system. His first activi
ties in this field were devoted to the elucidation of the mode of action ofneu
ropsychotropic drugs, in order to find clues for the design ofnovel compounds
with therapeutic action. He started with work on neuroleptics and phenylethy
lamines. These investigations, carried out together with his colleagues, helped
to clarify the mechanism of action of chlorpromazine on cerebral dopamine
metabolism. They also showed that phenylethylamines had different effects on
cerebraI monoamines, depending on their substituents at the aromatic ring and
the nitrogen ofthe side chain. For instance, methamphetamine, with a chlorine
substituent in 4-position of the ring, caused a marked, specific decrease of
cerebral 5-HT and 5-hydroxyindolacetic acid (indicating an inhibition of 5
HT-biosynthesis). Thus, the 4-chloro derivative has an effect similar to that of
methylene-3,4-dioxymethamphetamine (MDMA, "ecstasy"), a derivative,
missed in oUf series, which was discovered later by another group.
Mose was now "grown up" and promoted to become head of his own
Mose Da Prada: Development ofan outstanding scientist XI
research group. Equipped with experience gained in his more basic work, he
became engaged in the development ofnew drugs. His efforts were concentrat
ed on MAO-inhibitors and anti-Parkinson-drugs, both elassical areas ofRoche
research. With the members of his group, he created sophisticated screening
tools, ineluding novel, highly sensitive and specific radioenzymatic tests for
monoamines, which were soon also used by the international "monoamine
community". With the help of these tests, potent and specific inhibitors of
MAO-A and -B and catechol-3-0-methyltransferase (COMT) were discovered
and developed in Da Prada's group. Several of these compounds show thera
peutic actions in neuropsychiatric disorders. Moelobemide (inhibitor ofMAO
A) is on the market as an antidepressant, Tolcapone (inhibitor of COMT) is
being prepared for marketing as adjuvant in Parkinson's disease and Lazabe
mide shows promising clinical effects in Alzheimer's disease. In all these
achievements Mose played an essential role as creative spirit and leader ofthe
experimental work, which got wide international recognition. These research
activities will be reported in the following presentations.
The human side
The start in Basel was not easy for Mose. His move from the lovely south to
the "barbaric" north brought changes in his personal life which were not all to
his liking. He complained about the quality of food, the lack of sunshine, the
unfriendliness ofthe people, etc. Thus, he did not appreciate the fines for traf
fic violations, such as those imposed on hirn for making U-turns over double
security lines with his Alfa Romeo. However, as time passed, Mose started to
adapt to his new environment. His generous and friendly character and his
readiness for collaboration helped hirn to establish friendly relations with
many ofhis colleagues. Due to his rising recognition in the international scien
tific community, he also attracted foreign collaborators, from his horne coun
try, Italy, and from other parts ofthe world. Forthem he was not only an inspir
ing and charismatic scientific leader, but he also showed great sympathy for
their personal problems. Mose's hospitality was overwhelming, his fabulous
laboratory parties. at which he offered the delicacies of his horne country, will
certainly remain in our memories.
The culmination in Mose's personal life was his late matrimonial union
with Maria. In her he found a companion who showed great understanding for
his work and whose love supported hirn in difficult situations, from which he
was not spared. With Maria his successful adjustment to life in the north was
accomplished.
Nevertheless, Mose remained attached to his family in Italy. Above all, his
elose connection with his brother Don Giovanni, a priest and well-known
painter in Fusine, a village of the valley Valtellina, has to be mentioned. The
brothers had many interests in common, e.g. their love for arts and literature.
A sign of the high esteem which Mose enjoyed in the Valtellina was the crea-