Acta Neurol Scand 1983: Suppl 9557-80

Deprenyl (selegiline): the history of its

development and pharmacological action
J. KNOLL
Department of Pharmacology, Semmelweis University of Medicine, Budapest, Hungary

ABSTRACT - Deprenyl inhibits MAO-B selectively in different animal

species and in man. Its safety margin is remarkable. We were able to block
MAO-B activity in the brain selectively in vivo in four species (mouse, rat, cat,
dog) with S.C. administration of 0.17-0.31 Yo of LD,,. The usual oral dose
range in clinical practice, 5-20 mg daily (0.05-0.2 mg/kg), is about ten times
lower than the orally active dose in the rat.
Deprenyl proved to be a safe drug in man. Neither hypertensive reactions nor
the need for any special dietary care were ever encountered during long-term
(2-8 years) daily administration of the drug.
The most important effect of deprenyl in the brain is the sensitization of
dopaminergic neurons to physiological and pharmacological influences, but in
contrast to levodopa or bromocrytine, deprenyl does not elicit an acute increase
in dopaminergic activity. The effect of deprenyl is due, on the one hand, to the
inhibition of MAO-B and, on the other hand, to inhibition of the uptake of
dopamine.
In agreement with its peculiar spectrum of pharmacological activity, deprenyl
proved to be a useful adjuvant to levodopa alone or in combination with a
peripheral decarboxylase inhibitor. In addition, a supplement of deprenyl in
Parkinson’s disease led to significant prolongation of the duration of the illness.
This has not been observed so far with other antiparkinsonian drugs.
The dopamine content of the human caudate nucleus decreases by 13 Yo per
decade over the age of 45.
The hypothesis has been put forward that the significant increase of in-
cidence of depression in the elderly, the age-dependent decline in male sexual
vigour and the frequent appearance of parkinsonian symptoms in the later
decades of life might be attributed to a decrease of dopamine and ’trace amines’
in the brain. The possibility of countering these biochemical lesions of ageing
by long-term administration of deprenyl, a selective inhibitor of MAO-B which
facilitates dopaminergic and ’trace-aminergic’ activity in the brain, and is a safe
drug in man, is considered in detail.

Key words: deprenyl’); selective inhibition of MAO-B; Parkinson’s disease;

depression; dopaminergic mechanisms; uptake of biogenic amines; levodopa
sparing effect; aphrodisiac effect; age-related biochemical changes.

I) In this supplement deprenyl (selegiline) always means (-)deprenyl unless otherwise stated.
J. Knoll
Both as experimental tools and as therapeutic
agents, monoamine oxidase (MAO) in-
hibitors have exercised an important in-
fluence on the development of the widely ac-
cepted hypothesis that depression is
associated with diminished monoaminergic
tone in the brain and that depressed patients,
treated with antidepressants, become elated
because of enhanced biological activity of
monoamine transmitters in the CNS.
The discovery of the mood-elevating effect
of M A 0 inhibitors was quite fortuitous. In
1951, isoniazid and its isopropyl derivative,
iproniazid, were successfully introduced for
the treatment of tuberculosis. In contrast to
isoniazid, iproniazid was found to produce
undesirable stimulation in some patients. In
1952, Zeller and his co-workers demonstrated
that iproniazid is capable of inhibiting MAO,
whereas isoniazid is ineffective (1). In 1956,
Crane analysed the ”psychiatric side-effects
of iproniazid” and came to the conclusion
that it might be beneficial in the treatment of
depression. Kline introduced it as a ”psychic
energizer” in 1957. A substantial number of
hydrazide (isocarboxazide, nialamide, phen-
eIzine, etc.) and nonhydrazide (tranyl-
cypromine, pargyline, etc.) M A 0 inhibitors
were developed and introduced into clinical
practice, but because of serious side-effects
there was a rapid turnover in the introduction
and withdrawal of M A 0 inhibitors.
In 1963, a calamitous number of clinical
reports, demonstrating the occurrence of
dangerous hypertensive attacks in patients
treated with tranylcypromine (2-6) or with
other M A 0 inhibitors (7) were published.
Such hypertensive crises are associated with
the ingestion of cheese. Asatoor et al. (1963)
demonstrated that after cheese consumption,
there is a considerable increase in the excre-
tion of tyramine metabolites (8). Blackwell’s
suggestion that tyramine is responsible for
the “cheese effect” was subsequently sup-
ported by many authors.
Horwitz et al. (1964) proved that small
amounts of cheese (e.g. 20 g of Cheddar) are
sufficient to produce hypertensive crises (9).
Many other foods (yeast products, chicken
liver, snails, pickled herring, red wines, some
varieties of beer, canned figs, broad beans,
58
chocolate and cream products, etc.) contain
indirectly-acting amines (mainly tyramine)
which may provoke hypertensive episodes in
patients treated with M A 0 inhibitors.
These drugs also potentiate the effect of a
number of compounds with quite different
chemical stuctures. Analgesics, anorectics,
anticholinergics, anticonvulsants, antihista-
mines, antimalarials, antiparkinsonian
agents, antitussives, CNS stimulants, diure-
tics, neuroleptics, nasal vasoconstrictors, oral
hypoglycaemics, pressor agents, sedatives,
tranquillizers, hypnotics and tricyclic anti-
depressants have all been claimed to interact
with M A 0 inhibitors. The unpredictable
hazards of M A 0 inhibitors in combination
with a variety of foods and drugs limited
their use in psychiatric patients, despite their
therapeutic value in depression, in narcolepsy
and in certain phobic-anxiety states.
M A 0 inhibitors for clinical use still tend to
be chosen from among a group of non-
selective inhibitors such as tranylcypromine,
phenelzine, isocarboxazide and nialamide.
But because of the development of two selec-
tive M A 0 inhibitors, clorgyline against
MAO-A and deprenyl against MAO-B, we
now have strong evidence for the existence of
two distinct forms of MAO. As the selective
inhibitors are remarkably different from the
non-selective inhibitors in their pharmacolo-
gical spectrum and potential toxicity, the in-
troduction of the first selective inhibitor,
deprenyl, into clinical practice might provide
a fresh start in the therapeutic usefulness of
M A 0 inhibitors. Much clinical work,
however, is needed to establish the ap-
propriate indications for members of these
second-generation M A 0 Inhibitors.
The development of deprenyl
In 1935, Prinzmetal and Bloomberg (10) in-
troduced racemic amphetamine as a central
stimulant to treat narcolepsy. Amphetamine,
as well as its dextrorotatory isomer (dex-
troamphetamine) and methamphetamine,
both more potent stimulants than racemic
amphetamine, are still in clinical use for a
variety of diseases. Amphetamines are highly
effective in preventing sleep in narcoleptic pa-

tients, are the most potent drugs for calming
abnormally hyperactive children, are highly
effective anorexogenics, produce certain
beneficial effects in parkinsonian patients
(improvement of sleep, muscle strength and
rigidity, and elevation of mood), and are
useful in milder forms of depression, as well
as in #chronic nervous exhaustion and
ps ychoneuroses.
Amphetamines probably produce all their
CNS effects by releasing noradrenaline,
dopamine (DA) and serotonin (5-HT) from
the cytoplasmic pools in the nerve terminals.
In the rat, lower doses of amphetamine
(0.5-2 mg/kg) activate the catechola-
minergic system only, and higher doses are
needed for the release of 5-HT in the brain.
In 1960, we were attracted by the finding
that amphetamine improved (in lower doses)
or disturbed (in higher doses) the perform-
ance of the rat in a one-way avoidance test.
Pharmacological analysis of this difference
revealed that in small and medium doses am-
phetamine and methamphetamine selectively
enhanced catecholaminergic tone in the brain
but that with high doses serotonergic tone
became dominant. Starting with metham-
phetamine, we began an extensive study of
structure-activity relationships, aiming to
develop new derivatives with more selective
actions on the CNS than the parent com-
pound. We synthesized and analysed a series
of new methamphetamine derivatives and
learned that proper substitution at the para
position leads to structures with remarkable
selectivity for catecholaminergic or seroton-
ergic systems. From among the newly syn-
thesized compounds, p-bromo-metham-
phetamine (V-Ill)was selected and used in
further experiments as a primarily
serotonergic amphetamine. Another meth-
amphetamine derivative, denoted 1-1703,
with a bulky substitution at the para position
(N l-0-carboxyphenyl-N2-p-/2-methylamino-
propyl-l/-phenylacetamidine) was selected as
a prototype of a selective catecholaminergic
amphetamine (11-18).
In 1963, the “cheese effect” focussed our
attention on M A 0 inhibitors and we decided
to extend our structure-activity relationship
study with metamphetamine derivatives in an
Pharmacology of deprenyl (selegiline)
MA0 inhibitor direction. Methamphetamine
itself is a reversible inhibitor of M A 0 (19).
We knew from our unpublished observations
with newly synthesized methamphetamine
derivatives that compounds with substitu-
tions at the nitrogen moiety might, by com-
parison with the parent compound, practi-
cally lose the ability to release biogenic
amines from the cytoplasmic pools of the
nerve endings. As we learned from the struc-
ture of pargyline, which had been introduced
at that time into clinical practice, the attach-
ment of a propargyl group to the nitrogen in
benzylamine inhibits M A 0 irreversibly; we
therefore synthesized a number of new
methamphetamine derivatives containing this
group and analysed their M A 0 inhibitory
ability and the changes in their phar-
macological spectrum. As methamphetamine
was the parent compound, we naturally at-
tached the propargyl group to it in our first
series of experiments. Racemic phenylisopro-
pylmethylpropargylamine HCI (E-250)was
soon selected as a highly potent irreversible
M A 0 inhibitor with a peculiar spectrum of
pharmacological activity (20, 21). The new
substance proved to possess mild central
stimulatory effects combined with a long-
lasting psycho-energizing ability. To diminish
further the amphetamine-like acute CNS
stimulatory effects, we decided to develop the
levorotatory isomer which proved to have ad-
vantages over the racemic form. The most
remarkable finding was that, in striking con-
trast to methamphetamine, its propargyl
derivative, especially the levorotatory isomer,
inhibited the release of biogenic amines from
nerve terminals and acted in vivo and in vitro
as a potent antagonist against tyramine (22,
23). We expressed the hope ”that this
tyramine inhibiting property of E-250may be
highly valuable for human therapy” (23),and
argued that (-) isopropyl-methylpropargy-
lamine HC1, later named deprenyl, is the first
highly potent M A 0 inhibitor to be found
which does not have the “cheese effect”.
In the same year as we arrived at this con-
clusion with deprenyl, two new MA0 in-
hibitors were described in the same number
of ”Biochemical Pharmacology”, one by
Johnston (1968)(24), MB 9302, and one by
59
J. Knoll
Fuller (1968) (25), Lilly 51641. Although the
two compounds were shown later to be of
equal significance from a scientific point of
view, Johnston’s substance came into world-
wide use as an experimental tool, because
Johnston realized the basic importance of his
substance and introduced a still serviceable
nomenclature for the two forms of M A 0 it
identifies. MB 9302 (clorgyline) has
structural similarities to deprenyl, being also
a methamphetamine derivative. There are
two differences from deprenyl. In clorgyline
we find, on the one hand, an oxygen bridge
between the aromatic ring and the carbon
chain and, on the other hand, the aromatic
ring is halogenated. We knew from earlier
studies that halogenation of the ring in
methamphetamine increases the affinity of
the compound to the serotonergic system (26,
11). The new findings with MB 9302 seemed
to be in good agreement with these observa-
tions.
Johnston realized that his substance
preferentially inhibits the deamination of
5-HT and proposed the existence of two
forms of MAO, one highly sensitive to MB
9302 and one relatively insensitive to it. He
introduced the terms ’type A’ and ’type B’
MAO, MAO-A being selectively inhibited by
MB 9302, whereas MAO-B was insensitive to
this substance. Johnston’s nomenclature has
become widely accepted and is still in use.
According to this classification Lilly 51641
(25) was also a selective inhibitor of MAO-A.
Fuller’s substance shows essentiaI struc-
tural similarities to clorgyline. Unlike
clorgyline and deprenyl, which are phenyl-
isopropylmethylamine derivatives, Fuller’s
substance is a close structural relative of
phenylethylamine, but this is as insignificant
from the point of view of selectivity as the
chemical nature of the enzyme-killing group,
which is a propargyl in the case of deprenyl
and clorgyline, and a cyclopropyl ring in Lilly
51641. What seems to be of crucial import-
ance, however, for MAO-A selectivity is the
oxygen bridge between the aromatic ring and
the side chain, and the fact that the chlorine
atom is in the ortho position, common to
clorgyline and Lilly 51641. It is worth men-
tioning here that short-acting selective in-
60
hibitors of A-type MAO, which block the en-
zyme reversibly and differ chemically from
the selective suicide inhibitors of MAO-A,
have recently been described by Strolin
Benedetti et al. (1983) (27).
A further study by Hall et al. (1969) (28)
with MB 9302, thereafter named clorgyline,
made it clear that a new pharmacological
tool, a highly selective inhibitor of MAO-B
was badly needed for final verification and
detailed in vivo mapping of the two main
forms of MAO. The two enzymes proved to
be too similar to each other to be separated
biochemically or even differentiated im-
munochemicall y.
We were lucky to discover in 1970 that our
own substance, deprenyl, which proved to be
a highly selective inhibitor of MAO-B, was
the missing link. We presented the evidence at
the first international meeting on M A 0 held
in Cagliari in 1971 and organized in honour
of Hermann Blaschko. The proceedings of
this meeting were published as Volume 5 of
Advances in Biochemical Psychopharmac-
ology, in 1972 (29).
Despite convincing pharmacological
evidence for the existence of two main forms
of M A 0 and the possibility of blocking each
separately in vivo, using deprenyl or
clorgyline, the scientific community took
little interest in selective M A 0 inhibitors un-
til the 2nd international meeting on MAO, a
CIBA Foundation Symposium held in Lon-
don in 1975 and organized in honour of
Mary L. Bernheim. This meeting gave a new
impetus to experimental research and at last
aroused the interest of clinicians.
Deprenyl: the first highly potent irreversible
M A 0 inhibitor without the “cheese effect’:
Evidence for its safety in man.
The peculiar spectrum of pharmacological
activity of deprenyl becomes evident if we
compare it, on the one hand, to pargyline, a
so-called semi-selective MAO-B inhibitor and
close structural relative of deprenyl, and on
the other hand, to clorgyline, a selective in-
hibitor of MAO-A.
Deprenyl inhibits MAO-B selectively in
 Pharmacology of deprenyl (selegiline)

different animals. Its safety margin is

remarkable, as shown in Table I. As will be
seen from the data in this table, we were able
to block MAO-B activity in the brain selec-
tively in vivo in four species with the sub-
cutaneous administration of 0.17-0.36 070 of
the LDSo, The highest dose of deprenyl
which blocked MAO-B activity, leaving
MAO-A activity unaffected from a func-
tional point of view, was 0.25-0.5 mg/kg. In
higher doses, deprenyl begins to block MAO-
A activity considerably.
The orally-active daily dose of deprenyl in
the rat is about 2-4 times higher than the
subcutaneous dose and lies between 0.5 and
2 mg/kg. Deprenyl is highly effective in man
by the oral route of administration. The usual
oral dose range in clinical practice, 5-20 mg
daily (0.05-0.2 mg/kg), is about ten times
lower than the orally-active dose in the rat. In

We also demonstrated that daily administra-

I 2 1:
tion of 0.25 mg/kg deprenyl for 21 days does
not change the selectivity of MAO-B inhibi-
tion (30).
Because of the high selectivity of deprenyl
for B-type MAO, the intestinal enzyme,
which is A-type, remains unaffected in both
animals and man treated with deprenyl (31,
32). Table I1 shows that in vivo pargyline is 6
times and clorgyline 60 times more potent
than deprenyl in inhibiting intestinal MA0 in
the rat. This phenomenon, in itself, works
against the “cheese effect” because deprenyl
leaves the gut wall MAO-A barrier intact, so
that tyramine access to the circulation can be
controlled; clorgyline inactivates the barrier
(33, 34). I
Deprenyl inhibits the uptake of tyramine,
thus reducing the pressor effect of this amine
(23, 33, 34), whereas both pargyline and
clorgyline potentiate the pressor response to
tyramine (16, 33). This effect of deprenyl is of
high importance for the safety of the drug, in
comparison with other MA0 inhibitors.
Deprenyl inhibits the release of
noradrenaline from synaptosomes, whereas
pargyline (29) and clorgyline (33) facilitate
the release of this transmitter. This is an addi-
tional factor allowing the administration of
deprenyl without dietary restriction.
Our claim that deprenyl is an MA0 in-
 .I. Knoll
Table 11. In vivo inhibition of rat intestinal M A 0 by deprenyl, pargyline and clorgyline, using
’‘C-tyarnine as substrate
mg/kg
Deprenyl
Pargyline
Clorgyline
hibitor without the “cheese effect” was
substantially supported by the experience of
clinicians, who never observed hypertensive
reactions, even during long-term administra-
tion of the drug. There was never any need
for special dietary care. In some volunteers
treated with deprenyl, Varga tried to provoke
the “cheese effect” in his first clinical trial in
1966, by administering huge amounts of
tyramine-rich cheeses; however, no signifi-
cant change in blood pressure could be
detected (E. Varga, unpublished results).
Elsworth et al. (1978) (35) and SandIer et al.
(1978) (36) demonstrated that subjects were
able to consume up to 200 mg of tyramine
during deprenyl treatment before a rise in
blood pressure and slowing of the pulse oc-
curred. This amount of tyramine is unlikely
to be encountered during the course of a nor-
mal diet.
The safety of deprenyl in man was further
demonstrated by Pare et al. (1978) (37) and
Mendis et al. (1981) (38). The authors used
the tyramine pressor test (39) and found that
even high doses of deprenyl failed to increase
sensitivity to intravenous tyramine, whereas
moderate doses of standard M A 0 inhibitors
increased it considerably. Clinical advantage
of the peculiar pharmacological spectrum of
deprenyl was first taken in connection with
the levodopa treatment of parkinsonian pa-
tients. The possibility of potentiating the
levodopa effect by concurrent administration
of an M A 0 inhibitor had always been ap-
parent, and was soon checked by Birkmayer
and Hornykiewicz (1962) (40). M A 0 in-
hibitors, however, potentiated the unwanted
effects of levodopa and the danger of
hypertensive crises supervening made such a
combination impossible.
62
ID50 Relative
S.C. potency
15.0 1
2.5 6
0.25 60
Deprenyl, an M A 0 inhibitor without the
“cheese effect”, lent itself particularly well to
this purpose because it could be safely com-
bined with levodopa. Birkmayer et al. (1977)
(41) demonstrated the clinical benefit of con-
current administration of levodopa plus a
peripheral decarboxylase inhibitor plus
deprenyl. Their finding was corroborated by
many authors (for reviews, see 42-44).
Deprenyl was proved conclusively to poten-
tiate the therapeutic effect of levodopa,
without increasing its side-effects.
As has been mentioned previously, non-
selective M A 0 inhibitors are known to poten-
tiate in an unpredictable manner the effect of
drugs belonging to many different classes
and differing widely in their chemical struc-
ture. The most plausible explanation for this
side-effect is the non-specific inhibition of
hepatic microsomal enzymes by the non-
selective M A 0 inhibitor. As to selective in-
hibitors, this aspect needs further detailed
study. With regard to deprenyl itself, it is
worth mentioning that during 2-8 years of
continuous administration of the drug in
Parkinson’s disease, many different com-
pounds have been given concomitantly with
levodopa-benserazide or levodopa-carbidopa
plus deprenyl but, up to the present time,
there has been no mention in literature of any
noticeable drug interaction. To evaluate more
precisely, however, any difference in this
respect between deprenyl and the non-
selective M A 0 inhibitors probably needs
planned studies. One example showing that,
from the point of view of drug interactions,
deprenyl is a remarkably safe M A 0 inhibitor
is provided by the study of Jounela et al.
(1977) (45). It is known from some early work
of Goldberg (1964) (46) that pethidine may be

responsible for serious adverse reactions in
patients treated with an M A 0 inhibitor. In
the rabbit, phenelzine, a non-selective M A 0
inhibitor, strongly potentiates the effects of
pethidine and during their combined ad-
ministration, excitation, hyperthermia and
hypertension may be elicited. Deprenyl,
however,. when administered with pethidine,
failed to provoke such adverse reactions (45).
Evidence that the most important effect of
deprenyl in the brain is sensitization of
dopaminergic neurons to physiological and
pharmacological influences
It is now firmly established that the main
form of M A 0 in the human brain is the B
type. The predominance of this enzyme
variant in the human striatum was first
demonstrated by Glover et al. in 1977 (47). As
deprenyl is a selective inhibitor of MAO-B,
and dopamine is a substrate for this form of
the enzyme, deprenyl enhances dopaminergic
tone in the brain by, inhibiting MAO-B.
Deprenyl, however, might also increase
dopaminergic tone in the brain by inhibiting
DA uptake. This action probably plays an im-
portant role in the effect of the drug on the
isolated striatum of the rat, which is a good
experimental model for testing the effect of
drugs on the dopaminergic system. From the
nerve terminals of the nigrostriatal dopamin-
Table 111. The effect of deprenyl on ouabain-induced release of acetylcholine from isolated striatal slices
taken from untreated and 6-OHDA pretreated rats.
Treatment
in vivo in vitro
1 Saline none
2 Saline deprenyl
3 6-OHDA none
4 6-OHDA deprenyl
1:2 p < 0.01
1:3 p < 0.005
3:4 p < 0.01
t statistic for two means. Methodological details described in this article.
Pharmacology of deprenyl (selegiline)
ergic neurons, a continuous release of DA
can be measured. DA exerts a tonic inhibitory
effect on the release of acetylcholine (ACh)
from the cholinergic interneurons of the
caudate nucleus. If we measure the release of
ACh in pmols/g/min, we have an index of the
physiological activity of the striatum, and
dopaminergic tone plays a rate-limiting role
in the net release of ACh. If we remove the
striatum from a rat pretreated with 6-
hydroxydopamine (6-OHDA), i.e. when the
overwhelming majority of the nigrostriatal
dopaminergic neurons are chemically dener-
vated, the release of ACh is considerably in-
.creased, showing the important inhibitory
role of DA in ACh release. The striatum of
the 6-OHDA pretreated rat may serve as an
experimental model for parkinsonism,
because of its greatly reduced dopaminergic
activity.
Table 111 shows the dramatic increase in
release of ACh in the striatum of rats
pretreated with 6-OHDA and the capacity
of deprenyl to re-establish dopaminergic in-
fluence in the isolated striatum, thereby nor-
malizing ACh release. This effect of deprenyl
is reversible, and independent of the
MAO-inhibiting potency of the drug (34).
The most plausible explanation for the im-
pressive effect of deprenyl is the capacity of
the compound to inhibit MAO-B activity and
DA re-uptake, because U-1424, an MAO-B
inhibitor without uptake inhibitory effect,
Release of ACh
(pmol g-lmin-l)
S.E.M.
481.0 i 83.2 (4)
226.1 i 26.8 (6)
777.2 k 91.0 (4)
280.6 f 38.2 (4)
deprenyl: 2.2 x rnole/l
63
J. Knoll
did not influence the release of ACh in this
test (34). Deprenyl probably enhances the ac-
tivity of those dopaminergic neurons which
survive 6-OHDA pretreatment. Because of
the well-known supersensitivity of post-
synaptic DA receptors manifested after
chemical denervation, very small amounts of
physiologically released DA might be suffi-
cient to inhibit the release of ACh.
Dopaminergic nerve terminals in the
striatum of the rat contain MAO-A; thus the
only possibility of deprenyl’s influencing the
metabolism of DA in a selective dose-range
remains via glial MAO-B. The considerable
distance in the rat striatum between dopa-
minergic nerve terminals and cholinergic
interneurons supports a possible role of glial
MAO-B activity in controlling dopaminergic
tone in the striatum. Experiments are now in
progress in our laboratory to clarify this rela-
tionship.
To understand better the mechanism of the
effect of deprenyl on the catecholaminergic
system, we have measured the content and
turnover rate of DA in the striatum and of
noradrenaline in the brain stem of the rat
under the influence of a subcutaneous injec-
tion of the drug. We found that 24 h after the
injection of a single dose of 0.25 mg/kg
deprenyl, which is known to inhibit MAO-B
activity selectively in the brain, the content
and turnover rate of the catecholamines re-
mained unchanged. We were, however, able
to detect important changes in monoamine
metabolism after daily subcutaneous injec-
tions of 0.25 mg/kg deprenyl for 14 days
(48).
Table IV shows that the repeated admin-
istration of small daily doses of deprenyl
significantly increased the turnover rate of
DA in the rat striatum, whereas no signifi-
cant change in the teldi-encephalon minus
the striatum could be detected, as measured
23 h after the last injection. The increase in
the turnover rate of DA in the striatum was
due to the enhancement of the fractional rate
constant of DA efflux and the slight, but
significant, increase in DA content (60.3 ver-
sus 52.7 nmoles/g). With regard to noradren-
aline, ,a significant decrease in its turnover
rate, with unchanged level in the brain stem,
64
was found. No change in the turnover rate of
noradrenaline could be detected in the teldi
-encephalon minus the striatum (Table V).
This finding substantially supports our view
(49-51), that deprenyl facilitates
dopaminergic modulation in the brain.
An increase in the DA turnover rate due to
a change in efflux rate from its storage site is
in keeping with the possibility that deprenyl,
which increases the amount of DA by in-
hibiting MAO-B, also increases the rate of
utilization of this important modulator in the
striatum. Presumably this increase in the
rate of utilization is due to an increase in the
firing rate of the dopaminergic neurons.
Because, in contrast to the situation in the
rat, MAO-B seems to be the main form of the
enzyme in human nigrostriatal dopaminergic
neurons (47), conditions for deprenyl to
facilitate dopaminergic modulation in the
human brain are particularly favourable.
As we usually measure the effects of dep-
renyl 24 h after its injection, only traces of
either the unchanged drug molecule or its
metabolites can be present in the organism.
The elimination of deprenyl and its
metabolites is practically complete within 24
hours (52). The possibility, however, of reten-
tion of trace amounts of deprenyl metabolites
in brain tissue, which might still exert a small,
continuous, releasing effect on DA and
noradrenaline in the nerve terminals cannot
be ruled out completely. The participation of
traces of amphetamine-like metabolites of
deprenyl in the complex total phar-
macological effect of the drug is not
necessarily inconsistent with experimental
and clinical observations of a complete lack
of amphetamine-like symptoms during the
long-term administration of standard daily
doses of deprenyl. It must be borne in mind,
however, that even if we do not rule out the
possibility of the accumulation of traces of
amphetamine-like metabolites of deprenyl
and, in addition, take their releasing effect
into account, the well-known accumulation
of PEA, an endogenous trace amine with
greater catecholamine-releasing potency than
(-)amphetamine in the deprenyl-treated
animal or man, is likely to exceed any such
releasing effect by the metabolites.
 As facilitation of dopaminergic modula- the possible contribution of an aocumulation
tion in the brain by deprenyl is likely to be of of amphetamine-Iike metabolites to this ef-
great therapeutic importance, we investigated fect. As demonstrated in Table IV, the daily

Table IV. The effect of deprenyl on dopamine (DA) content, turnover rate of dapamine (TRm) and fmc-
tional rate constant (kb) of dopamine efflux

DA

Striatum nmoles/g nmol&&hr h-1

Control (saline) 52.7 1.6 13.3 i= 1.3 0.26

Deprenyl 60.3 + 2.2* 20-4 ie 0-98* 0.34
14 x 0.25 mg/kg
daily

Teldiencephalon-
striatum

Control (saline) 2.8 0.1 1-3 0.45

Deprenyl 3.5 t 0.2* 1.6 0.e
14 x 0.25 mg/kg

* p < 0.05
Animals were injected subcutaneously with 0.25 mg/kg deprenyl daily for 14 days, CsntroIs were treated
with saline. Animals were killed 24 hours after the last injection of deprenyl and saline, respectively. Rats
were injected with 250 mg/k i.p., a-methyl-p-tyrosin methy1 ester HCI 1 and 2 hours before decapitation.
Each time point had six values. TR =(steady state)x x k,. Brains were dissected according to Glowinski
and Iversen (102). Catecholamine content was determined fluorimetrically according to Carlsson and
Waldeck (103). Turnover rates were measured according to Tozer et al. (104).

Table V. The effect of deprenyl on noradrenaline (NA) content, turnover rate of noradrenaline (TR~JA)
and fractional rate constant (kb) of noradrenaline efflux

NA kb

Brain stem nmoles/g nmoles/g/hr hr-’

Control (saline) 3.1 & 0.2 0.81 026

Deprenyl 3.2 + 0.1 0.39 0.I2
14 x 0.25 mg/kg

Teldiencephalon
-striaturn

Control (saline) 1.2 & 0.1 0.30 096

Deprenyl 1.5 & 0.P 0.36 0.24
14 x 0.25 mgAg

*p < 0.05 For details see Table IV.

65
 J. Knoll
administration of 0.25 mg/kg deprenyl for 14
days significantly increased the turnover rate
of DA in the rat striatum. We therefore also
tested the effect of ( k ) amphetamine on the
striatal dopaminergic system by injecting 0.25
rng/kg of this drug daily for 14 days. Table
VI shows the results. In contrast to deprenyl,
amphetamine significantly deckeased the
content of DA in the striatum and even the
turnover rate showed a tendency to decrease.
(k ) amphetamine influenced the turnover
rate of noradrenaline in the brain stem (Table
VII) in a similar manner to deprenyl (Table
V). Thus,' we must conclude that the
metabolites of deprenyl do not play any
substantial role in the facilitation of
dopaminergic modulation induced by this
drug in the brain.
The pharmacological properties of
deprenyl, in particular its peculiar activation
of the dopaminergic neuron, seem to be
essentially different from the effects of drugs
which are used clinically as dopaminergic
system stimulants. At present, levodopa and
bromocriptine are mainly employed for this
purpose. The effect of levodopa is complex.
It is thought to be an agonist acting through
uptake and release mechanisms in the
Table VI. The effect of (*)amphetamine on dopamine (DA), the turnover rate of dopamine (TR,)
the fractional rate constant (k,) of dopamine efflux
DA
Striatum nmoles/g
Control (saline) 53.9 * 1.8
Amphetamine 47.7 f 1.5'
14 x 0.25 mg/kg
'- Teldiencephalon
-striaturn
Control (saline) 2.4 k 0.2
Amphetamine 2.6 k 0.2
14 x 0.25 mg/kg
*p < 0.05
Animals were injected subcutaneously with 0.25 mg/kg (*)amphetamine (base) daily for 14 days. For
other details see Table IV.
66
presynaptic neuron. However, because of the
rapid conversion of levodopa to DA in the
brain, the possibility of stimulation of
postsynaptic DA receptors and, when high
doses are given, even of stimulation of
presynaptic DA receptors, thereby causing in-
hibition of dopaminergic neuronal activity,
cannot be ruled out. Such a mechanism may
be of major importance in long-term
levodopa treatment of parkinsonian patients.
Bromocriptine acts as a pure postsynaptic
dopamine-receptor agonist. But deprenyl acts
differently. By itself, it does not elicit any
acute increase in dopaminergic activity as
would levodopa or bromocriptine. It seems
only to make dopaminergic neurons more
sensitive to physiological stimulus by block-
ing MAO-B and DA uptake. Clinical ex-
perience with deprenyl supports this view. In
parkinsonians, it potentiates the effect of
levodopa without increasing the side-effects.
When given with deprenyl, a smaller amount
of levodopa is sufficient to exert the same
therapeutic effect as the larger dose.
Further support for the existence of this
unusual effect of deprenyI on the dopa-
minergic system is given by Koulu and Lam-
mintausta (1981) (53) who investigated its ef-
and
TRDA kb
nmoles/g/hr hi'
23.9 0.45
17.8 0.37
0.9 0.38
1.1 0.41
 Pharmacology of deprenyl (selegiline)

Table VII. The effect of (+)amphetamine on noradrenaline (NA) content, the turnover rate of
noradrenaline (TRNA)and the fractional rate constant (kb) of noradrenaline efflux

NA TRNA kb

Brain stem nmoles/g nmoles/g/hr hr-‘

Control (saline) 3.4 f 0.2 0.85 0.25

Amphetamine 3.3 f 0.2 0.41 0.12
14 x 0.25 mg/kg

Teldiencephalon
-striaturn

Control (saline) 2.2 f 0.1 0.83 0.38

Amphetamine 2.4 f 0.2 0.96 0.41
14 x 0.25 mg/kg

Animals were injected subcutaneously with 0.25 mg/kg (*)amphetamine (base) daily for 14 days. For
other details see Table IV.

fect on human growth hormone secretion in Parkinson’s disease

healthy volunteers. 5 mg deprenyl was given
Parkinson’s disease, the cause of which is
orally 24 h and an additional 10 mg 10 h unknown, is incurable at the present time and
before the test. Deprenyl did not change the
none of the agents used in its treatment stops
basal growth hormone secretion rate, but
its progression. Even though levodopa only
significantly enhanced levodopa-stimulated
provides symptomatic replacement therapy,
hormone release. 200 mg levodopa plus 50
its introduction revolutionized the medica-
mg benserazide, given orally, increased secre- tion of Parkinson’s disease and alone, or in
tion from 1.8. f0.2 ng/ml to a maximum of
combination with a decarboxylase inhibitor,
11.3 f4.88 ng/ml. After deprenyl pretreat-
it is now the standard drug of choice all over
ment levodopa raised the basal concentration
the world. The major problem with levodopa
of 1.8. f0.3 ng/ml to 23.3. k 6.14 ng/ml, and
therapy lies in the large number of adverse
levels remained significantly higher during
reactions, mainly of central origin, associated
the 150 min observation period. Deprenyl did
with the progressive deterioration of parkin-
not, however, alter the effect of bromocrip-
sonian clinical features during long-term ad-
tine on growth hormone secretion. These
ministration of the drug.
findings support the view that deprenyl
The severe side-effects accompanying con-
renders the dopaminergic neuron more sen-
tinuous administration of levodopa alone in-
sitive to physiological and pharmacological
itiated the search for adjuvants with a
influences.
levodopa-sparing effect. Comparative clini-
cal trials of levodopa alone and in combina-
tion with either benserazide or carbidopa
Pharmacological considerations regarding
clearly demonstrated the advantages of the
the usefulness of deprenyl in therapy
combined therapy of levodopa with one of
Because deprenyl facilitates dopaminergic these peripheral decarboxylase inhibitors.
tone in the brain, three clinical indications It was reasonable to expect further poten-
for its use, Parkinson’s disease, depression tiation and prolongation of the effect of
and ageing, deserve discussion. levodopa in parkinsonians with concurrent

67
 administration of MA0 inhibitors. A
number of irreversible inhibitors of this type
were tested in combination with levodopa,
and potentiatiou of the antiakinetic effect of
the latter was demonstrated; however, the
supervention of distressing side-effects
(greatly increased involuntary movements,
hypertensive reactions, toxic delirium) ter-
minated any further work along this line.
There was a consensus that to give MA0 in-
hibitors concurrently with levodopa was
contra-indicated. This conclusion was called
in question, however, by the development of
deprenyl.
In excellent agreement with the distinct
pharmacological spectrum observed in ani-
mal experiments, Birkmayer et al. showed in
1975 (54) that deprenyl potentiates the anti-
akinetic effect of levodopa in parkinsonians
and that even a single oral dose of deprenyl
can reduce the functional deficit within 60
min; this beneficial effect can last up to three
days.
In 1977, Birkmayer and his co-workers
published the first study of the long-term use
of deprenyl, demonstrating that the
therapeutic benefit can be maintained for
more than two years when the drug is com-
bined with levodopa-benserazide (41). This
important observation was first corroborated
by Stern and his co-workers (55), and later
confirmed by a number of clinicians (56-
64).
As to the place of deprenyl in the treatment
of Parkinson’s disease, the following factors
must be taken into account. Barbeau (1980)
(65), who performed one of the first large
scale studies, both with levodopa alone and
in combination with a peripheral decarbox-
ylase inhibitor, recently analysed his ex-
periences with a total of 1,052 parkinsonian
patients treated over a period of 12 years and
concluded that ”Long-term side effects are
numerous . . . although we recognize that
levodopa is still the best available therapy, we
prefer to delay its onset until absolutely
necessary”. In view of this opinion, the ap-
proach of Yahr with regard to deprenyl seems
to be promising: ”It may have additional
usefulness as a primary drug in the early
phase of parkinsonism, a therapeutic
68
response which we are presently investi-
gating” (63).
The value of deprenyl in the treatment of
Parkinson’s disease, either as an adjuvant to
levodopa alone or in combination with a
peripheral decarboxylase inhibitor, was firm-
ly established by Birkmayer and his group
(see 66). In a recent paper Birkmayer et al.
(67) compared 323 outpatients with Parkin-
son’s disease who received levodopa-bense-
razide or levodopa-carbidopa daily (mean
duration, 8.2 years) without deprenyl and 285
outpatients on combined levodopa therapy
for 8.7 years plus deprenyl 10 mg/day at
breakfast and lunch. The duration of the
deprenyl medication was from two to eight
years. Birkmayer et al. also made a retrospec-
tive comparison between 141 deceased pa-
tients on a conventional therapeutic regimen,
with a mean duration of 8 years of combined
levodopa treatment without deprenyl, and a
group of 96 deceased patients who had had
combined levodopa treatment for an average
of 9 years plus deprenyl for two to six years.
In both studies it was found that there had
been a significant improvement of disability
in the deprenyl-treated patients, compared
with those on conventional therapy only.
These data are in agreement with the earlier
finding that deprenyl is a valuable adjuvant
to standard antiparkinsonian therapy,
especially in patients with on-off phenomena
(for review, see 42). The more important, and
indeed unique, finding of this recent study by
Birkmayer et al. was that the duration of ill-
ness was different in the groups with and
without deprenyl. The supplementary use of
deprenyl in treating Parkinson’s disease led to
a significant prolongation of the duration of
the illness, i.e. the life span of the patients
was prolonged. This is an extremely import-
ant observation. Such a change, a conse-
quence perhaps of the effect of deprenyl in
increasing dopaminergic tone in the brain,
deserves attention.
The possibility of slowing down the evol-
ution of Parkinson’s disease by supplement-
ing conventional therapy with deprenyl shows
for the first time that the degeneration of the
dopaminergic nigrostriatal fibres can be
retarded to some extent. This finding has not

so far been made with other antiparkinson-
ian drugs. Levodopa treatment counters the
so-called early death rate of patients with
Parkinson's disease, but has not been shown
to influence the long-term duration of the
disease (68, 69). In contrast, high doses of
combined levodopa therapy may accelerate
the disease process, as the sensitivity of
postsynaptic dopamine receptors decreases
progressively during long-term administra-
tion of dopamine receptor agonists (70).
As long-term deprenyl treatment seems to
prolong the life span of parkinsonian pa-
tients significantly, the possibility of treating
patients in the early stages of the disease with
deprenyl and giving it, concurrently with any
other drug therapy, until death, must be
seriously considered.
Depression
Non-selective MA0 inhibitors are known to
be effective antidepressants in non-endo-
genous depression (71) and have some effect
also in bipolar depression (72).
Amphetamines are usually considered to
be highly effective antidepressants in certain
types of depression. Unlike tricyclics, they do
not cause central or peripheral effects and do
not carry the potential for hypertensive crises
as do the non-selective and A-selective M A 0
inhibitors. Many experienced psychiatrists
are against limiting the use of these drugs to
the treatment of narcolepsy and childhood
hyperactivity, and the claim that ampheta-
mines should be used, despite their potential
for abuse, as primary agents for treating
depressive illness, is frequently made in
literature (73).
Deprenyl was originally introduced as a
compound integrating some amphetamine-
like CNS effects with an irreversible, highly
potent, M A 0 inhibitory ability. Varga and
Tringer performed the first clinical trials
with racemic phenylisopropylmethylpropar-
gyl HC1 (E-250) in 1966, administering the
drug to "negativistic" patients irrespective of
diagnosis (74). The patients (34 men, 5
women) displayed lack of initiative and
scanty emotions and impulses, target symp-
Pharmacology of deprenyl (selegiline)
toms connected with disturbed drive. The
drug was not given to patients with predomi-
nant anxiety, confusion, psychomotor excite-
ment, disintegration of personality or manic
manifestations. Out of the 39 patients so
treated, 17 were also suffering from
depression. The conclusion drawn from this
early study was that the target symptom of
E-250 is lack of initiative (stupor, inhibition,
negativism, etc.). The dosage at that time
varied between 1.25-2.5 mg/kg, whereas the
selective dose range used today in clinics
varies from 0.05 mk/kg to 0.2 mg/kg. On the
other hand, the racemic compound was
employed in that study and deprenyl has been
found, in our animal experiments, to be a
more potent stimulant than the levorotatory
form (75). To reduce amphetamine-like ac-
tivity, we selected for further clinical trial the
levorotatory optical isomer of phenylisopro-
pyl methylpropargylamine, HC1, and the ef-
fect of this substance (coded 1-E-250, and
later named deprenyl) was studied by Tringer
et al. in 1968-69 and a report published in
1971 (76). Thirty patients with endogenous
depression were treated with 10 mg of
deprenyl twice daily for ten days or two
weeks. The Hamilton rating scale was used in
the analysis. Tringer at al. (1971) (76) con-
cluded that deprenyl has a favourable effect
in endogenous depression. It was claimed by
these authors that the racemic form elicited
agitation, anxiety and sleep disturbances
more frequently than the (-) isomer.
The first clinical trial using the selective
dose range of deprenyl was performed by
Mann and Gershon (1980) (77). Twelve endo-
genously depressed patients, who failed to
respond to a week of placebo medication,
were given 5 mg per day deprenyl for the first
week, followed by 10 mg and 15 mg daily in
the second and third weeks, respectively. The
group included 6 unipolar and 6 bipolar pa-
tients and consisted of 8 females and 4 males.
The Hamilton depression scale was used to
evaluate the effect of the drug. Deprenyl pro-
duced a significant improvement over the
whole range of depressive symptomatology.
Patients began to respond after 3 days of
treatment. According to the authors mention-
e d "Of particular interest is the improvement
69
J. Knoll
in factor I (anxiety-somatization) where the
main improvement was in anxiety scores, and
in factor VI (sleep disturbance) where benefit
was seen despite the well-known problems of
activation and initial insomnia associated
with M A 0 inhibitors . . .”
In a second open study, Mann et al. (1982)
(78) analysed the effect of deprenyl in a
group of 25 depressed patients classified as
having nonendogenous and endogenous (uni-
polar or bipolar) depression. After a one
week single-blind placebo treatment to screen
out strong placebo responders, deprenyl was
given, 5-10 mg/day, building up to a max-
imum of 15-20 mg/day over four weeks of
treatment. Although this drug improved both
groups significantly, there was a greater
overall improvement in the nonendogenous
group. 16/25 patients responded to deprenyl.
The response rate in nonendogenous patients
(10/12) was statistically significantly greater
than in the endogenous patients (6/13). Fur-
thermore, bipolar patients had a response
rate of 5/7 compared with 1/6 for unipolar
patients.
Since deprenyl, in a selective dose range, is
known to elevate DA and phenylethylamine
(PEA) concentrations selectively in the brain,
leaving noradrenaline and 5-HT levels un-
changed, the authors concluded that DA and
PEA play significant roles in nonendogenous
and bipolar depression subgroups whereas by
contrast, noradrenaline and 5-HT may be
more important in the pathogenesis of
unipolar endogenous depression; they em-
phasized that deprenyl is a potentially impor-
tant tool for identifying the biochemical sub-
divisions of depressive disorders.
The effect of deprenyl was studied by
Mendlewicz and Youdim (1978) (79) in 14
depressed patients (10 bipolar and 4 unipolar
cases) who were kept drug-free for 8 days and
from the ninth day onwards treated with 300
mg 5-hydroxytryptophan (5-HTP) plus 75 mg
benserazide plus 5 mg deprenyl three times
daily for 32 days. Deprenyl potentiated the
antidepressant response to 5-HTP in 10 out
of 14 patients and there was no increase in the
side-effect score. In the four patients who did
not respond to the combination, platelet
MA0 activity was considerably higher (in-
70
hibition < 85 070) than in the responders. Fur-
ther clinical studies must be carried out to
determine whether deprenyl may be a useful
and safe antidepressant agent in DA and/or
PEA-dependent depressive subgroups.
Much experimental and clinical work is
still needed in order to explore the factors in-
volved in the antidepressant effect of depre-
nyl. Patients usually begin to respond after
3-4 days of treatment and clinical improve-
ment develops within the first and third
weeks (77). This finding is in complete agree-
ment with the changes in DA turnover noted
in rats treated daily with 0.25 mg/kg doses
of deprenyl. No change in DA turnover was
found within 24 h of the first injection, but
daily administration of deprenyl for 14 days
was highly effective in increasing DA turn-
over in the striatum (48). The question,
however, as to how many important
biochemical parameters in the brain are
changed concurrently with DA metabolism in
deprenyl-treated rats, remains to be
answered. Binding studies with a number of
different monoamine receptors are now in
progress in our laboratory.
Several independent lines of investigation
indicate that typical and atypical anti-
depressants affect brain function by down-
regulating the binding sites for ligands of
noradrenaline (80, 81) and 5-HT recognition
sites (82-83). Antidepressants also decrease
the stimulus amplification elicited by nor-
adrenaline on the adenylate cyclase coupled
to 0-adrenergic receptors in the rat brain (84,
85).
Treatment with clorgyline, i.e. MAO-A in-
hibition, down-regulates serotonergic 5-HT2
recognition sites and noradrenergic receptor
functions (86), an effect resembling that of
tricyclic antidepressants. In a recent study, we
were able to demonstrate (87) that in rats the
daily injection of deprenyl in a selective in-
hibitory dose (1 gmol/kg) for 21 days at-
tenuates noradrenaline-dependent stimulat-
ion of cortical adenylate cyclase and reduces
the number of brain recognition sites for 8-
adrenergic receptor ligands. Pargyline (2.5
gmol/kg/day for 21 days) acts similarly, but
(+) amphetamine proved to be ineffective.
Hence deprenyl, a selective inhibitor of
 Pharmacology of deprenyl (selegiline)

MAO-B, and pargyline, a semi-selective in- characteristics of ()H)imipramine binding to

hibitor of B-type MAO, mimic responses that
are typically elicited by antidepressants. Im-
portant differences, however, were detected in
this study between pargyline and deprenyl
with regard to the recognition sites of (3H)
imipramine.
In 1979, Raisman et al. (88) demonstrated
the existence of specific tricyclic antide-
pressant binding sites in the rat brain. Rehavi
et al. (1980) (89) showed the presence of spe-
cific high affinity binding sites for (3H)
4mipramine in the human brain. The (3H)
-imipramine binding sites are preferentially
located on 5-HT axon terminals (90).
Deprenyl treatment (1 pmol/kg, s.c., 21 days)
significantly increased the number of (3H)
imipramine recognition sites in crude synap-
tic membranes prepared from the frontal
cortex and hippocampus of the rat. Neither
pargyline (2.5 pmol/kg or 100 pmol/kg i.p.,
21 days) nor (+) amphetamine (1 pmollkg,
s.c., 21 days) induced any change in the
cortical crude synaptic membranes (87).
Table VIII gives numerical data proving the
specific efficiency of deprenyl in increasing
(3H)imipramine binding in the rat brain. The
physiological significance of imipramine bind-
ing sites, as well as the physiological Iigands
to them, are unknown at present; thus the
pharmacological significance of this finding
remains obscure for the moment. The fact,
however, that deprenyl produces a highly
specific alteration at the molecular level, not
brought about by either pargyline or (+)
amphetamine, in a function which seems
closely related to the effect of anti-
depressants, underlines again the peculiar
pharmacological spectrum of deprenyl. It
speaks in favour of the potential value of this
drug as an antidepressant with a characteris-
tic profile, and arouses hope that it may be
used as a research tool in further studies into
the nature of endogenous and nonendo-
genous depression.

Table VIII. Kinetic 'characteristicsof (3H)imipramine specific binding to crude synaptic membranes
prepared from the cortex or hippocampus of rats repeatedly injected with deprenyl, (+)amphetamine and
pargyline.

Treatment Cortical membranes Hippocampal membranes

KD Bmax KD Bmax
(nM) (fmol/mg prot) (nM) (fmollmg prot)

Saline 5.3 k 0.7 650 f 100 5.2 k 0.7 5 6 0 i 50

Deprenyl
(1 pmol/kg,
s.c., 21 days) 8.2 k 1.5* 1065 k 150* 7.0 f 0.5 800 k 90.
(+ )amphetamine
(1 p mollkg,
s.c., 21 days) 4.5 f 0.6 620 k 90
Pargyline
(2.5 pmol/kg
i.p., 21 days) 5.1 f 0.5 690 k 80
Pargyline
(100 pmol/kg,
Lp., 21 days) 6.9 f 0.5 650 f 85 - -

Each Scatchard analysis was performed by plotting the data obtained in binding assays with 8 different
concentrations of ligand (from 0.5 to 10 nM); each experiment was repeated at least three times.

* p < 0.01 when compared to values obtained in saline treated rats.

71
Ageing
In 195'7, Montagn (91) detected the presence
of DA in the central nervous system and
Bertler and Rosengren reported in 1959 (92)
that about 80 VCJof DA in the human brain
is localized in the basal ganglia. An age-
dependent de- in the DA content of the
basal ganglia in man was soon detected by
Bectler (1%1) (93) and c o r r o b o d by many
otfiers. This change in brain DA is not only
statistically but also biologicaily highly
significant. The DA content of the human
caudate nucleus, for example, decreases by
13 % per decade over the age of 45. The age-
related progressiw decline of dopaminergic
control in the brain now seems to be the first
firmly established biochemical lesion of age-
ing (50).
Year by year we learn more and more about
the biochemical and morphological changes
within the ageing brain which Seem to com-
pose the intertwining chains of a vicious cir-
cle which results in the irresistible decline of
dopaminergic tone in senescence McGeer et
al. reported in 1971 (94) that the activity of
tyrosine h y h x y h s e , the enzyme catalysing
the rate-limiting step in catecholamine bio-
synthesis, decreases substantially in human
brain tisslle with increasing a g e In the same
year, Robinson et al. (1971) (95) demon-
strated that MA0 activity progressively in-
creases in the ageing brain, perhaps securing
more favourable conditions for the cata-
bolism of brain DA in senescence.
The age-dependent change in MA0 activ-
ity has been studied in detail in a number of
publications, leading to the unequivocal con-
clusion that B-type M A 0 activity increases
selectively with advancing age in both the
human and the rat brain and that the age-
dependent increase is due entirely to higher
enzyme concentration in brain tissue (96).
When looking for an explanation of this
phenomenon, it must be remembered that in
both animals and humans, MAO-B is pre-
dominantly localized in the neuroglia. Cell
loss is a general feature of the ageing brain.
A more or less constant pattern of cortical
neuron loss, up to 30 Sh of the totd neuronal
pool, has been identified in the human brain
72
as it gets older. In an up-to-date study by
Ball, published in 1977 (97), a drop in the
number of neurons, from 7,890/mrn3 at the
age of 45 to 5,800/m3 at 90, a loss of 26 Yo,
was found in the hippocampal cortex with
the aid of a highly sophisticated counting ar-
rangement. As loss of neurons is always com-
pensated for by gliai cells, the progressive and
cumulative loss in the ageing brain gives a
satisfactory explanation of the selective in-
crease of extmsynaptosomal MAO-B activity
with increasing age (49, 50).
As a functional consequence of such a
change in the brain, we have to consider the
possible physiological significance of extra-
neuronally localised MAO-B for inter-
neuronal communication in the central ner-
vous system. As an example let us take DA,
which is a substrate of MAO-B, and may
possess some way of transmitting a message
from one neuron to another. The dopamin-
ergic nerve terminal might be in synaptic con-
tact with the target neuron. In this case, the
released DA molecules immediately reach the
target cell, to be eliminated rapidly by re-
uptake. On the other hand (and perhaps this
is more usual), DA may be released from the
nerve terminals without synaptic contact.
Thus the molecules have to scatter, and travel
a considerable distance, to reach the target
cell. Whereas in the case of synaptic contact
between the neurons, extraneuronal MAO-B
activity would be unable to influence the ef-
fectiveness of the chemical message delivered
by DA, in the case of non-synaptic inter-
neuronal communication the situation is
essentiaily different. Here, the chances of the
slowly-diffusing molecules reaching their
target cell and modulating its activity might
essentially depend on the concentration of
glial MAO-B in the environment.
Considering the fact that an unavoidable
loss of neurons leads inescapably to increased
MAO-B activity with increasing age, it is ob-
vious that dopaminergic modulation de-
creases progressively in the ageing brain. As
PEA is the monoamine with the highest af-
finity to MAO-B, an age-related decrease in
brain concentration of this trace-mine also
seems to be unavoidable in the ageing brain.
Although the physiological significance of

PEA in the brain is still obscure, we know
that this indirectly acting sympathomimetic
amine is a potent stimulant. Thus, the par-
ticipation of a PEA deficit in the develop-
ment of age-related depression is a possibility
which deserves further experimental and
clinical analysis.
It is piomatic that any age-dependent
change of brain-function must be attributed
to a biochemical lesion of nervous tissue. A
survey of the clinical literature enables us to
identify the following ageing changes, which
might be considered together:
a) a significant increase in the incidence of
depression in the elderly;
b) an age-dependent decline in male sexual
vigour; and
c) the frequent appearance of parkinsonian
symptoms in the latter decades of life.
These three ageing phenomena might be
attributed, at least partially, to age-depend-
ent changes in brain dopamine metabolism,
for dopaminergic modulation is known to
play an important role in the control of
mood, male sexual behaviour and motor
co-ordination, and there is a progressive
decline in the activity of the dopaminergic
system in the brain with increasing age.
Depression and ageing. It is an old clinical
experience that the elderly are more suscep-
tible to depression than other age groups.
Even if we accept the view that ”in old age,
death ought to be considered more as the
’finishing touch’ of life than as a horrifying
experience against which younger people
rebel” (98), the extremely high incidence of
suicide in the elderly is a serious and objec-
tive sign of a depressed mood, alien to
healthy people of all age groups.
During some field studies of depression in
old age, performed on random samples of
sexagenarians with the aim of identifying
mild and moderate cases of depression, some
degree of depressive disorder was noted in
about 25 per cent of persons over the age of
65 (99). This high incidence of depression in
the elderly cannot be explained, however,
simply by the fact that old age is the ”season
of losses” (loss of spouse, children, job,
Pharmacology of depmnyl (selegiline)
status, etc.) and a period of general decline in
health, because about 75 per cent of old
people cope with these problems without the
advent of a depressed mood, sadness and re-
duced activity. Not all old people are depress-
ed. But when this condition does supervene,
it is usually highly responsive to treatment
with either tricyclic antidepressants or MA0
inhibitors. Thus, it seems possible that age-
related and progressive reduction in dopa-
minergic tone does play a decisive role in the
proneness of the elderly to depression.
Male sexual activity and ageing. Sexual ac-
tivity in the human male is known to be in-
fluenced by a number of factors, such as
good health, stable marriage, satisfactory
sexual partner(s), adequate financial and
social status, etc. But even in males who meet
all the requirements for retention and
maintenance of sexual functioning, there is
an age-related decrease in sexual vigour, the
reason for which still remains obscure.
Martin (1977) (100) studied coital activity
as a function of age, interviewing 628 in-
dividuals who took part in the Baltimore
Longitudinal Study of Aging. The subjects
were white, married, urban residents in good
health, living in the Washington-Baltimore
area, their age ranging from 20-95 years.
According to this study, median coital acti-
vity was highest (2.1 events per week) between
the ages of 30 and 34 and decreased pro-
gressively with increasing age, falling to 0.2
per week in the age-group 65-69.
The data in Martin’s study reveal enor-
mous individual variations in sexual vigour.
The mean frequency of total sexual activity
in 159 males was found to be 520 sexual
events per 5 years in the age group 20 to 39,
ranging from young males performing less
than 100 sexual events per 5 years to those
with frequencies of total sexual activity
greater than 1,OOO sexual events per 5 years.
In the age group 65-79, the mean frequency
of total sexual activity decreased to 75 sexual
events per 5 years, but even in this group, sub-
jects performing 400-700 sexual acts per 5
years were recorded.
It is known from animal experiments that
13
J. Knoll
the dopaminergic system facilitates and the
serotonergic system inhibits coital activity in
males. There are many data supporting the
conclusion that the same is true for human
males. The age-related decrease of sexual ac-
tivity in man is probably not unrelated to the
decline of brain DA in the ageing brain. In-
dividual differences in the activity of the
dopaminergic system might explain the con-
siderable variations in sexual performance
observed between males in the same age
group. Individuals in the age range 20-39,
with high rates of performance (over 800 sex-
ual events per 4 years) might possess a more
active dopaminergic system than poor per-
formers (less than 200 sexual events per 5
years). Such individual differences might also
explain why a number of males in the age-
group 65-79 maintain remarkable sexual
vigour, a few being even better performers
than the average in the age group 20-39,
despite an unavoidable age-related decrease
in the activity of the dopaminergic system.
Parkinsonian symptoms and ageing. As
has been previously mentioned, the DA con-
tent of the human caudate nucleus decreases
by 13 To per decade over the age of 45.
Parkinson’s disease seems to be a kind of
selective, highly accelerated ’premature age-
ing’ of the nigrostriatal dopaminergic system,
and the DA content of this neuron system
shrinks within a short time to less than 10 To
of the normal level in the premorbid state.
Clinical studies have revealed that parkin-
sonian symptoms appear if the striatum loses
more than 70 To of its DA content. The age-
related decrease in the DA content of the
basal ganglia explains the usual appearance
of Parkinson’s disease in advanced age.
In answer to the question as to why all
elderly persons do not exhibit parkinsonian
symptoms, we might once more mention the
importance of individual variation in dopa-
minergic activity. It seems likely that in-
dividuals with relatively high dopaminergic
activity in early life maintain during their
latter decades a higher dopaminergic tone
and, despite an age-related decrease in the
DA content of the basal ganglia, the activity
74
of the system remains above the critical
threshold for parkinsonian symptoms. How-
ever, proneness to the disease evidently in-
creases with age and different aetiological
factors are then capable of provoking the
disorder. The relationship between parkinso-
nian symptoms, dopaminergic activity and
age is likely to be similar to that between
depression with late onset, catecholaminergic
tone and age.
The potential benefits of using deprenyl in
the elderly
We may well be able to counter the conse-
quences of the age-related decrease in brain
DA by facilitating the response of the
dopaminergic system to physiological and
pharmacological influences or by continuous
stimulation of postsynaptic DA receptors. As
such medication must, of necessity, be con-
tinued for decades, the latter possibility, i.e.
continuous administration of a DA receptor
agonist, is probably contraindicated. Modern
parkinsonian therapy has taught us that both
an abundant supply of exogenous DA to the
brain, by oral administration of levodopa,
the precursor of this amine which penetrates
the blood-brain barrier, or continuous
stimulation of postsynaptic DA receptors by
an agonist such as 2-bromocryptine, have too
many side-effects; in addition, their efficacy
seems likely to decrease substantially during
long-term administration.
A drug which facilitates dopaminergic
modulation in the brain without acting on
the postsynaptic DA receptor, which remains
efficient during many years of administration
and which is reasonably free from side-
effects has a potentially greater chance of
being adopted as a special medicament for
counteracting the consequences of age-
related decreases in brain DA concentration.
Up to the present time, deprenyl seems to
be the only drug which is close to fulfilling
these requirements. It has a characteristic
spectrum of pharmacological activity,
enhances dopaminergic tone in the brain
without affecting postsynaptic DA receptors
and is a safe drug in man, being reasonably
 Pharmacology of deprenyl (selegiline)

free from side-effects even after many years

of daily administration.
We have sought a suitable experimental
model to illustrate how the age-dependent
decline of a physiological function can be
countered by deprenyl medication. Sexual
performance in male rats represents a quan-
tifiablel function decreasing with age. As an
experimental model, it may well possess good
predictive value for man, for the similarities
in the decline of sexual vigour with increasing
age in both male rats and man are striking.
Table IX demonstrates the significant dif-
ference between the sexual performance of
male rats aged less than 6 months and those
aged more than 12 months. Continuous ad-
ministration of low doses of deprenyl
significantly increased the sexual vigour of
older male rats. Fig. 1 shows an example. Out
of the 76 males of the 'old group', selected ac-
cording to their "sluggish" sexual behaviour
in the first four consecutive weekly mating
tests (see Table IX), 20 were injected sub-
cutaneously with 0.25 mg/kg of deprenyl and
10 with saline, 3 times a week. Their sexual
activity was then tested weekly during a
period of 10 weeks. The data in Fig. 1 clearly
demonstrate that no change in the sexual per-
formance of saline-treated rats was to be
observed during this long-lasting experiment.
Deprenyl, however, enhanced sexual activity
greatly.
Our working hypothesis that deprenyl
medication might be useful for counteracting
impairment of dopamine-dependent func-
tions receives substantial support from the
previously quoted recent clinical evaluation
of the consequences of long-term deprenyl
treatment in parkinsonian patients (67). Up
to the present time only Birkmayer and his
group have treated very large numbers of pa-
tients for 2-8 years with deprenyl. Evalu-
ation of the accumulated data revealed that c -
03
deprenyl significantly prolonged the duration d .5
of Parkinson's disease, i.e. the life span of the 2 9
deprenyl-treated patients was substantially
extended, as shown in Fig. 2. This effect of
deprenyl is unique. None of the other anti-
parkinsonian drugs, including levodopa, in-
fluences the duration of the disease.
Putting experimental data and theoretical

75
J Knoll

considerations together, it seems likely that
those unavoidable age-related morphological
and biochemical changes which lead to a pro-
gressive decline of dopaminergic activity in
the elderly have serious functional conse-
quences. It is now open to medical science to
devise an appropriate long-term treatment
strategy aimed at preventing or at least par-
tially countering the problems caused by DA
deficiency in the ageing brain. Thus, our
work with deprenyl may possibly be regarded
as the first exploratory step towards the ob-
jective of improving the quality of life in
senescence.

.
;. 0.80.

O I
.s 0.40..
4 '50.00.
5c E.-. 1.60-
C
Ig 1.20.
2.2
+ 0.80..
0
.-
o, 0.40.

0 0.00
. . - . . . . .. J weekly
1 3 5 7 9 11 13 1 3 5 7 9 11 13 mating
tests
injections 3 times a week injections 3 times a week
p < 0.05 ** p < 0.01; *** p< 0.001 Control (-IDeprenyl

Fig. 1. The true aphrodisiac effect of repeated administration of 0.25 mg/kg S.C.deprenyl for 10 weeks
in sexually sluggish male rats.
Male CFY rats (LATI, Godc316, Hungary) weighing 650-750 g, which showed at least one intromission
without any ejaculatory pattern were chosen for the experiment. Copulatory tests were performed once
a week. N = 20 in the deprenyl-treated group and N = 10 in the control group.

Outpatients Deceased patients

Madopar Madopar Madopar Madopar
Dep;enyl DeGenyl
N =323 N =284 N =150 N=96
9.0 f 2.7 12.0 * 3.9' 8.4 2.1 *
11.9 3.5f

iool n
-
v)
4d

:so.
.-
70. -
gw
u-

$: @
10 --@a 0
0 Number of patients p < O.oOO5
Based on data of Birkmayer et al. 1983
Duration of the
disease (years)

Fig. 2. Comparison of the duration of Parkinson's disease in patients treated with Madopar or with
Madopar and concurrent administration of deprenyl for 2-8 years. Note that deprenyl prolonged the
duration of the disease from 9 to 12 years in the still living group of outpatients and from 8.4 to 11.9 years
in the deceased group. Based on data of Birkmayer et al., 1983 (67).

76

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Address:
J. Knoll, M.D.
Department of Pharmacology
Semmelweis University of Medicine
Budapest
Hungary