I'm gonna forward, one at a time, some articles I picked up off the WWW. This
one's about Deprenyl....
Deprenyl - A 1994 Update
The American Parkinson Disease Association
Summer 1994 Newsletter
Copyright 1994, Reproduced with Permission
EDITOR'S NOTE: In 1989 APDA published "Deprenyl Update" an educational
supplement authored by A. Lieberman, M.D., Chairman of the APDA Medical
Advisory Board. At that time Deprenyl had just been approved by the FDA for
use in this country.
A short time ago an article on Selegiline (Eldepryl-Deprenyl) authored by
E. Brunt, M.D., appeared in Parkinson Magazine highlighting the
presentations made at a June 1993 neurologists meeting in Budapest, the
city where Prof. Knoll developed this drug 30 years earlier.
APDA is grateful to both Dr. Brunt and to Parkinson Magazine for sharing
this article with our readers.
Originally developed as a "psychic energizer" selegiline, also known as
I-deprenyl or Eldepryl, appeared to be an irreversible inhibitor of the
MAO-B enzyme. The MAO-B enzyme constitutes the main degrading pathway for
dopamine, the transmitter which is deficient in the brain in Parkinson's
disease (PD). An important advantage of selegiline compared with other MAO
inhibitors was its lack of the "cheese effect". This effect is caused by
the uptake of a food constituent, tyramine, which is present in high
concentrations in cheese and Chianti wine, and causes the sudden, marked
elevation of blood pressure in patients treated with other, previously used
MAO inhibitors.
In the seventies, Prof. Birkmayer, Prof. Csanda and Dr. Lees were among the
first to apply, in the medical treatment of PD patients, the concept of
slowing down the dopamine degradation by selegiline. The addition of
selegiline to levodopa therapy appeared to be successful, as patients with
motor fluctuations showed improvement and levodopa dosage could be reduced.
In 1985 Birkmayer reported a nine year retrospective study from which
appeared that addition of selegiline to levodopa therapy in PD patients
also lengthened their lifetime. Thus, selegiline not only improved the
response to levodopa, but also appeared to have a protective action against
deterioration in PD. Support for a possible protective role of selegiline
came from studies on two animal models of PD. In the "MPTP model" and the
"6- hydroxy-dopa model", simultaneous administration of selegiline appeared
to prevent the development of parkinsonism. The MPTP animal model of PD
originates from the discovery that this substance,
methylphenytetrahydropyridine was responsible for the development of a
PD-like disease in users of a synthetic heroine-like drug in California in
the early eighties. MPTP was found to be oxidized in the brain by the MAO-B
enzyme into MPP+, which could destroy dopamine producing cells after being
taken up into these cells, causing a PD-like syndrome. In this model,
blocking of MAO-B enzyme prevents death of dopaminergic cells by MPTP.
In the 6-hydroxy-dopa model of PD, this substance is injected into the
brain of rodents in the tract formed by the dopamine nerve cell fibers
running from the brainstem to their target in the basal ganglia. After
being taken up into the nerve endings, 6-hydroxy-dopa also causes death of
these cells, again producing a PD-like syndrome. Also in this model,
selegiline prevents the damage, by blocking the uptake of the substance
into the nerve cells.
Thus in the second half of the previous decade, both human and animal
studies suggested a possible neuroprotective action of selegiline in PD.
To evaluate the results of previous open studies and to investigate the
supposed neuroprotective effect of selegiline, several controlled studies
have been performed by the groups of Dr. Langston, the Parkinson Study
Group in the United States, and by the groups of Dr. Myllyla in Finland and
Dr. Allain in France.
The largest and most important of these studies was a multicenter study
called "DATATOP" (deprenyl and tocopherol antioxidant therapy of
Parkinson). Over 800 newly diagnosed PD patients from 40 centers in the US
and Canada were included in this study and randomized to treatment with
selegiline, vitamin E (tocopherol) or placebo. This study showed a strongly
significant delay of the need to add levodopa therapy in the selegiline
treated group. However, the interpretation as to whether this effect was
due to a symptomatic or protective effect remained controversial. In other
words it could not be ascertained whether the delay was due to improvement
of PD symptoms, or to slowing down of the progression of the disease.
Critics argued that the one-month "wash-out" period following the
withdrawal of selegiline, after which the groups of patients had been
compared, was too short. Indeed, early this year, it was reported that the
difference in favor of the selegiline treated group was no longer obvious
after a prolonged wash-out period of 3 months.
As the time needed for the restoration of MAO-B in humans is now estimated
to be about 40 days, the current interpretation of the DATATOP study is
that selegiline does have a symptomatic effect, and possibly a protective
effect.
A comparable conclusion on the action of selegiline was drawn by Dr.
Myllyla in Finland from the interim analysis of a recently concluded study
on the effect of selegiline in newly treated PD patients. Also in this
study, the group treated with selegiline required introduction of levodopa
at a later date. In addition, in the following years patients in the
selegiline treated group needed less levodopa than those in the placebo
treated group. In a recent report on the French selegiline multicenter
trial, Dr. Allain also reported both an improvement of symptoms and a delay
in progression in the selegiline treated group.
As mentioned before, selegiline not only is being used in many countries in
the treatment of PD, but also has had a major impact upon the research on
PD and other neurodegenerative diseases. The exciting story of selegiline
includes study on the possible role of MAO-B enzyme in the pathogenesis of
PD and evidence for protective or even rescue effect of the drug upon
endangered and damaged nerve cells.
Investigations on the MAO enzymes have made clear that the two different
types, A and B. have their own distribution both outside and inside the
human brain, - and act upon different substances. The wide differences
found between individuals on the amounts of MAO-A and MAO-B present in skin
and blood may be important in the study of diseases such as PD.
Although preferably metabolized by MAO-B, dopamine is also degraded by
MAO-A and auto-oxidation. In the brain about 60% of MAO is of B type and
the amount of MAO-B increases after age 60.
After its production and excretion from the nerve cell to act upon the
receptors of other nerve cells, dopamine is re-uptaken and subsequently
degraded. This degradation takes place mainly outside the nerve cells,
possibly in the nearby support glial cells, which are known to contain the
highest concentration of MAO-B enzyme.
It appears that in the normal process of dopamine degradation by MAO
enzymes, toxic compounds such as hydrogen peroxide are formed, which may
react to form "free radicals". These "free radicals" are aggressive
oxidative substances which can impair the energy production or damage the
membrane of nerve cells, causing their death. At the Budapest meeting,
Profs. Olanow, Jenner and Youdim presented data suggesting that in dopamine
cells of PD patients the production of the oxidizing substances is
increased, while at the same time the defense mechanisms against this
"oxidative stress' is reduced. As selegiline reduces the turnover of
dopamine by impeding its degradation and increases one of the defending
enzymes, reduction of "oxidative stress" may be one way in which it may
protect nerve cells.
Evidence to support a protective role of selegiline was also provided by
Prof. Knoll. He has found a reduction of age related changes in the
dopamine nerve cells of the substantia nigra and increased longevity in
rats treated with selegiline.
Maybe the most exciting findings on the action of selegiline were discussed
at this meeting by Prof. Tatton.
Several experiments suggest an action of selegiline which differs from
MAO-inhibition or protection from oxidative free radicals.
The first example is the MPTP-mouse model in which low dose selegiline
given following MPTP administration at a time when lethal damage to neurons
has been completed, triples the number of surviving nerve cells. At this
dosage selegiline causes less than 50% inhibition of the MAO-B enzyme, so
this cannot explain the rescue. Another example is an experiment in which
one facial nerve is cut in rats of two weeks of age. At this age the cells
of the facial nerve are dependent on nurturing substances ('trophic" or
"growth" factors) from the muscles with which they are connected. These
trophic factors are transported via the nerve and cutting of the nerve
normally results in death for most of the nerve cells. Selegiline given to
these rats both in high and in low dosage, more than doubled the number of
surviving cells, apparently providing a substitute for the trophic factors.
The suggestion that selegiline provides a substitute for trophic factors is
also supported by the observation that in cultures of brain cells,
selegiline promotes the growth of these cells and increases the production
of growth factors.
These examples suggest that selegiline, used in low dosage, may have a
"rescue" effect, comparable to the effect of trophic factors. Several of
these neurotrophic factors have been identified and they play an important
role both in the growth and in maintenance of nerve cells, and they have
also been shown to be important in fetal cell transplantation.
It can be concluded that selegiline has proven to be a fascinating drug for
its use in the treatment of PD and for its inspiration of a vast area of
research on neurodegeneration. Actions of selegiline at different dosages
include; MAO-B inhibition, dopamine re-uptake inhibition, reinforcement of
defense against "oxidative stress", and substitution for trophic factors.
A symptomatic and levodopa sparing effect of selegiline in the treatment of
PD patients has become evident, supporting its use in patients already
treated with levodopa. A protective action in PD patients, by diminishing
the rate of progression of the disease, awaits further clinical proof.
Therefore, the decision to use selegiline as monotherapy in early stage PD
and during its further course is currently based upon the suggestion of
possible benefit rather than evidence. Its suggested rescue effect and
substitution of trophic factors for nerve cells opens most exciting
perspectives.
Selegiline has now taken a place in the treatment of PD and experimental
work has opened exciting perspectives. Whether these promises will become a
reality for the patients depends on clinical results. In the end only these
count. Much work needs to be done, but the hope for a better treatment of
this disease is a good reason for doing it.
