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DEPRENYL- EXTENDING LIFESPAN
By James South MA
Deprenyl is a drug that was discovered
around 1964-65 by Dr. Joseph Knoll and colleagues. It was originally developed
as a psychic energizer, designed to integrate some amphetamine-like brain effects
with antidepressant effects. (1) Also known as L-deprenyl, (-)-deprenyl, and selegiline,
deprenyl (DPR) has been intensively researched over the past 36 years - many hundreds
of research papers on DPR have been published. Knoll has stated that DPR ...is
an exceptionally lucky modification of PEA [phenylethylamine], an endogenous ...
member of the family to which also the transmitters noradrenaline and dopamine
belong. (13) [See diagram.] DPR has shown a unique and exciting pharmacologic/clinical
profile. It is the only potent, selective MAO-B inhibitor in medical use. (1)
DPR is a catecholamine activity enhancer. (2) DPR has been shown to protect nerve
cells against a wide (and growing) number of neurotoxins. (3,4) DPR has also been
shown to be a neuroprotection/ neurorescue agent when nerve cells are exposed
to damaging or stressful conditions. (5)
DPR has become a standard treatment
for Parkinsons disease. (6) DPR is also useful in treating drug-resistant depression.
(8,9) In aged rats, DPR has proven to be a highly effective sexual rejuvenator.
(10) DPR also shows promise as a cognitive enhancement agent. (10) DPR has also
proven in four different rat studies and one dog study to be an effective life-extension
agent, even increasing the technical lifespan in Knolls rat experiments. (11,12)
and these are just some of DPRs reported benefits.
DEPRENYL:
MAO-B INHIBITOR EXTRAORDINAIRE
By 1971 Knoll had shown that DPR was
a unique kind of MAO inhibitor - a selective MAO-B inhibitor, without the cheese
effect. To fully appreciate what this means, some technical background is necessary.
Some of the most important neurotransmitters in the brain are the monoamine
(MA) transmitters: serotonin, dopamine and noradrenalin. After being secreted
into the synaptic gap, where one neuron connects to another, many to the transmitter
molecules are reabsorbed by the secreting neuron and then disposed of by enzymes
called monoamine oxidases (MAO). This prevents excessive levels of transmitters
from accumulating in the synaptic gap and over-amping the brain. However, with
aging MAO activity significantly increases in the human brain, often to the point
of severely depressing necessary levels of MA transmitters. (1) In the 1950s the
first antidepressant drugs to be developed were MAO inhibitors (MAOI). By the
1960s however, MAOIs began to drop out of medical use due to a dangerous side-effect
- the so-called cheese effect. When most MOIs are used in people consuming a diet
rich in a substance called tyramine, a dangerous, even fatal, high blood pressure
crisis can be triggered. Tyramine is found in many foods, including aged cheeses,
some wines, beans, yeast products, chicken liver and pickled herring, to name
just a few. (23)
By 1968, further research had shown that there were
two types of MAO-A and B. It is primarily intestinal MAO-A that digests incoming
tyramine. Most of the MAOIs that have been used clinically inhibit both MAO-A
and MAO-B, thus setting up the danger of the cheese effect by inhibiting intestinal
and brain MAO-A, allowing toxic tyramine levels to accumulate. DPR is unique among
clinically used MAO-Is. At normally used clinical dosages (10-15 mg/day), DPR
is a selective MAO-B inhibitor, so it doesnt prevent intestinal MAO-A from digesting
dietary tyramine.(1) In addition, DPR has the unique ability to prevent tyramine
from getting into noradrenalin-using nerve calls, and its only when tyramine enters
noradrenalin nerve cells that control arterial blood pressure that it triggers
the cheese effect. (1) DPR thus has a dual safety lock in preventing the cheese
effect, making it far safer than other MAOIs. At doses over 20-30 mg/day, however,
DPR does start to significantly inhibit MAO-A , so there is some risk of the cheese
effect at these higher (rarely clinically used) doses. (1)
MAO-A enzymes
break down serotonin (5-HT) and noradrenalin (NA), and to a lesser extent dopamine
(DA). MAO-B breaks down DA and the traceamine phenylethylamine (PEA). At doses
of 5-10 mg per day DPR will inhibit MAO-B about 90%. (1) It was initially presumed
that DPR would increase synaptic levels of DA in DA-using neurons, and this lead
to its use to treat Parkinsons disease in the late 1970s, Alzheimers disease in
the 1980s-90s, and depression starting in the late 1970s. In his 1983 paper on
the history of DPRs clinical benefits to its unique MAO-B effects. (1)
Yet many experts have questioned whether DPRs MAO-B inhibition can significantly
increase synaptic DA levels. (14,15) This is due to the fact that MAO-B is found
only in glial cells in the human brain, non-nerve cells that support, surround
and feed the brains billions of neurons. (1) And whether there is any exchange
of DA between these glial cells and the DA-using neurons is still an unanswered
question. It is commonly believed that it is MAO-A in DA neurons that breaks DA
down. By the 1990s Knoll believed he had discovered the real basis of DPRs being
a MAO-B inhibitor. (2)
Yet as will be made clear shortly, even if DPRs
originally hypothesized mode of action - directly increasing synaptic DA levels
through MAO-B inhibition - is false, DPRs MAO-B inhibition still provides part
of its benefit.
DEPRENYL: CATECHOLAMINE ACTIVITY ENHANCER
During the
1990s Knolls DPR research took a new direction. Working with rat brain stems,
rabbit pulmonary and ear arteries, frog hearts and rats in shuttle boxes, Knoll
discovered a new mode of action of DPR that he believes explains its widespread
clinical utility. (2,16) Knoll discovered that DPR (and its cousin, PEA) are catecholamine
activity enhancers (CAE). (Ed. - Dr Knoll explains this on his 2000 Monte Carlo
Anti-Aging Conference Audio Cassette).
Catecholamines (CA) refers to
the inter-related neurotransmitters dopamine (DA), noradrenalin (NA) and adrenalin.
CAs are the transmitters for key activating brain circuits - the mesolimbic-cortical
circuit (MLC) and the locus coeruleus (LC). The neurons of the MLC and LC project
from the brain stem, through the mid-brain, to the cerebral cortex. They help
to maintain focus, concentration, alertness and effortful attention. (17) DA is
also the transmitter for a brainstem circuit - the nigrostriatal tract - which
connects the substantia nigra and the striatum, a nerve tract that helps control
bodily movement and which partially dies off and malfunctions in Parkinsons disease.
(1)
When an electrical impulse travels down the length of a neuron -
from the receiving dendrite, through the cell body, and down the transmitting
axon - it triggers the release of packets of neurotransmitters into the synaptic
gap. These transmitters hook onto receptors of the next neuron, triggering an
electrical impulse which then travels down that neuron, causing yet another transmitter
release. What Knoll and colleagues discovered through their highly technical experiments
is that DPR and PEA act to more efficiently couple the release of neurotransmitters
to the electrical impulse that triggers their release. (2,16)
In other
words, DPR (and PEA) cause a larger release of transmitters in response to a given
electrical impulse. Its like turning up the volume on CA nerve cell activity.
And this may be clinically very useful in various contexts - such as Parkinsons
disease and Alzheimers disease, where the nigrostriatal tract (PD) and MLC circuits
(AD) under-function (1,17), as well as in depression, where they may be under-activity
of both DA and NA neurons. (18,19)
Knolls research also indicates that
after sexual maturity the activity of the CA nervous system gradually declines,
and that the rate of decline determines the rate at which a person or animal ages.
(10,20) Knoll therefore believes that DPRs CAE effect explains its anti-aging
benefit. (10,20) Knoll also believes that DPRs CAE activity is independent of
its MAO-B inhibition effect, because in rats he has shown CAE effect at doses
considerably lower than that needed to achieve MAO-B inhibition.
Knolls
work indicates that PEA is also a CAE substance. (16) PEA is a trace amine made
in the brain that modulates (enhances) the activity of DA/NA neurons. (16,21)
Autopsy studies have shown that while DPR increases DA levels in Parkinson patient
brains by only 40-70%, DPR increases PEA levels 1300 - 3500%! (14,22) PEA is the
preferred substrate for MAO-B, the MAO that DPR inhibits. Paterson and colleagues
have shown that PEA has an extremely rapid turnover due to its rapid and continuous
breakdown by MAO-B. (21) Thus DPRs CAE activity has a dual mode of action. At
low, non-MAO-B inhibiting doses, DPR has a direct CAE activity.
At higher,
MAO-B inhibiting doses, DPR creates an additional CAE effect, due to the huge
increases in brain PEA levels that DPR causes, PEA also being a CAE substance.
Many authors have pointed out the probable DA neuron activity enhancing effect
of PEA in Parkinson patients taking DPR. (14, 15, 22)
Knolls discovery
of PEAs CAE effect now explains this PEA DA-enhancing effect.
DEPRENYL:
THE NEUROPROTECTOR
DPR has been shown to protect nerve cells from
an ever-growing list of neurotoxins. Some of these neurotoxins can actually be
produced within the brain under certain conditions, while others come from the
environment or diet.
MPTP is a chemical first identified as a contaminant
in synthetic heroin. In the 1980s young men using synthetic heroin suddenly developed
a Parkinson-like disease. It was then discovered that the MPTP was taken up by
glial cells surrounding nigrostriatal neurons, where it was converted by glial
MAO-B enzymes into the real toxin, MPP+. The nigral neurons then absorbed MPP+
into their mitochondria, where MPP+ poisoned the mitochondria, killing the DA-using
neurons.(15) The MAO-B inhibiting dose of DPR (10 mg/day) has been shown to prevent
MPTP from being converted to the neurotoxin MPP+.(4) And as Lange and colleagues
note, Compounds with a chemical structure similar to MPTP include both natural
and synthetic products (e.g. paraquat) that are used in agriculture! (15)
6-hydroxydopamine (6-OHDA) is a potent neurotoxin that can spontaneously
form from DA in DA-using neurons. (11,13) 6-OHDA may then further auto-oxidize
to generate toxic superoxide and hydroxyl free radicals and hydrogen peroxide.
(11,13) Knolls research has shown that pre-treatment of striatal DA-neurons with
DPR can completely protect them from 6-OHDA toxicity. (4,11,13) Even in those
not suffering from Parkinsons disease, the nigrostriatal neurons are the fastest
aging neuron population in the human brain - an average 13% loss every decade
from the 40s on. (1,13) Knoll and others believe that 6-OHDA neurotoxicity is
a key cause of this normal nigral death, and that DPR may be just what the doctor
ordered to retard this debilitating downhill neural slide.
DSP-4 is a synthetic
NA-nerve toxin. In rodents DPR has been shown to prevent the depletion of NA in
NA-using neurons and NA-nerve degeneration that DSP-4 causes. (4) AF64A is a cholinergic
toxin - it damages brain cells that use acetylcholine. DPR pre-treatment has been
shown to protect cholinergic neurons from AF64A toxicity. (4)
DPR has
also protected human nerve cells from peroxynitrite and nitric oxide toxicity.
Peroxynitrite is formed naturally in the brain when nitric oxide reacts with superoxide
radical. Peroxynitrite causes apoptosis, a programmed suicide cell death that
can be triggered in neurons by various agents. DPR was found to inhibit peroxynitrite-caused
apoptosis, even after the DPR was washed from DPR pre-treated cells. (3)
Methyl-salsolinol is another MAO-B produced endogenous neurotoxin. Salsolinol
is a tetra-hydroisoquinoline produced from the interaction of DA and acetaldehyde,
the first-stage breakdown product of alcohol.
Once formed, salsolinol can
then be further modified by MAO-B to generate methyl-salsolinol. DPRs MAO-B inhibiting
activity can prevent the DNA damage caused by this toxin. (3,4)
By inhibiting
MAO-B, DPR reduces the toxic load on the brain that is routinely produced through
the normal operation of MAO-B. MAO-B digests not just DA and PEA, but also tryptamine,
tyramine and various other secondary and tertiary amines. (15)
As noted
earlier, PEA is the substance MAO-B is most efficient at digesting, so that the
half-life of PEA is estimated at only 0.4 minutes. (21)
This continuous
high level breakdown of PEA (and other amines) produces aldehydes, hydrogen peroxide
and ammonia as automatic MAO-B reaction products, and they are all toxins. (4)
Thus by reducing age-elevated MAO-B activity, DPR reduces the toxin burden on
DA/NA neurons (where PEA is primarily produced).
...L-deprenyl provides
neuroprotection against growth factor withdrawal in PC12 cells, oxidative stress
in mesencepahalic neurons, and the genotoxic compound, Ara C, in cerebellar granule
neurons, and against axotomy-induced motoneuronal degeneration and delayed neuronal
death in hippocampus after global ischaemia. (24) And these are just some of the
many reports in the scientific literature on DPRs versatile neuroprotection.
DEPRENYL: PARKINSONS DISEASE
Parkinsons
disease (PD) is one of the two major neurodegenerative diseases of the modern
world - Alzheimers disease is the other. PD affects up to 1% of those over 70,
a lesser percent of those 40-70, and rarely anyone below 40. (23) PD is caused
by a severe loss of DA-using nigrostriatal neurons, with symptoms manifesting
after 70% neuronal loss, and death usually ensuing after 90% loss. (23)
The physiologic role of the nigral neurons is the continuous inhibition of the
firing rate of the cholinergic interneurons in the striatum. (13) When the nigral
neurons fail in this negative feedback control, voluntary movement and motor control
is scrambled, leading to the typical PD symptoms: shuffling gait, stooped posture,
difficulty initiating movement, freezing in mid-movement, and the shaking palsy.
By the late 1960s the standard treatment for PD was the amino-acid precursor of
DA, L-dopa. The L-dopa increased the DA levels in the few remaining nigrostriatal
neurons in PD patients (80% of brain DA is normally located in nigral neurons(11),
thus at least partially restoring normal movement and motor control.
However by 1980 A. Barbeau, after analyzing results of 1052 PD patients treated
over 12 years, wrote 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. (1)
DPR became a standard therapy
to treat PD by the late 1970s. In 1985 Birkmayer, Knoll and colleagues published
a paper summarizing the results of long term (9 years) treatment with L-dopa alone
or combined with DPR in PD. (25) They found a typical 1 to 2 year life extension
over the average 10 years from L-dopa onset until death in the L-Dopa/DPR group.
The 1996 DATATOP study found that To the extent that it is desirable to delay
levodopa therapy, deprenyl remains a rational therapeutic option for patients
with early PD. (26) In a 1992 paper Lieberman cited 17 studies supporting the
claim that ... with levodopa-treated patients with moderate or advanced PD...
the addition of selegiline [DPR] is beneficial. (6) Thus by the 1980s-1990s DPR
had become a standard PD therapy, used either to delay L-dopa use, or in combination
with L-dopa. Yet in 1995 a report published in the British Medical Journal seriously
questioned the use of DPR in combination with L-dopa to treat PD. (27)
The UK-PD Research Group study followed 520 PD patients for 5-6 years. Several
hundred patients initially received 375 mg L-dopa, while several hundred others
received 375 mg L-dopa plus 10 mg DPR daily. After 5-6 years, the mortality rate
in the L-Dopa/DPR group was almost 60% higher than in the L-dopa only group. The
study authors therefore recommended DPR not be used in PD treatment. Yet the UK-PD
study is the only one ever to find increased mortality with DPR use in PD, and
the study has been severely criticized on multiple grounds by various PD experts.
In response to the study, the BMJ published 8 letters in 1996 criticizing the
study on various methodological and statistical grounds. (28) And a 1996 Annals
of Neurology article by 4 PD experts provided an exhaustive analysis of the BMJ
study, raising many questions and criticisms. (29) One key criticism is that the
UK-PD study was open label and patients could be reassigned to treatment groups
during the study. 52% of the L-dopa group and 45% of the L-Dopa/DPR group changed
treatment groups, yet the allocation of end points (deaths) was based on patients
original drug assignment, regardless of which drugs the patient was actually taking
at time of death! When the death rate was compared only between those remaining
on their original drug assignment, there was no statistically significant difference
in mortality between the L-dopa and DPR/L-Dopa groups.
Another criticism
levelled against the UK study is based on the dosage of L-dopa. It is generally
accepted that DPR reduces L-dopa need by about 40%. (14) Thus, to achieve bio-equivalent
L-dopa doses, the DPR/L-Dopa group should have only received 225 mg L-dopa, compared
to 375 mg in the L-dopa only group. As evidence that the initial L-dopa dose was
too high in the DPR/L-Dopa group, after 4-5 years the median L-dopa dose remained
at 375 mg in the DPR group, while it had increased to 625 mg in the L-dopa only
group. And a growing body of evidence has shown L-dopa to be neurotoxic in PD
patients. In a 1996 review paper, S. Fahn briefly reviews 20 in vitro and 17 in
vivo studies showing L-dopa to be toxic, especially in neurologically compromised,
oxidant-stressed individuals, such as PD patients. (30) Thus if there were any
real increased mortality in the DPR/L-Dopa group in the UK study, it is more likely
due to L-dopa toxicity than DPR. This is further borne out by a 1991 study by
Rinne and colleagues, who studied 25 autopsied PD brains. (31) When they compared
the substantia nigra of 10 patients who had received L-dopa plus DPR with 15 patients
who had received L-dopa only, they discovered that there were significantly more
nigral neurons remaining in the DPR/L-Dopa brains, i.e. the DPR had actually acted
to preserve nigral neurons from L-dopa toxicity. Olanow and co-authors conclude
their paper reviewing the UK study: It is our opinion that the evidence in support
of discontinuing selegiline [DPR] in levodopa-treated patients, because of fears
of early mortality, is not persuasive. Accordingly, we do not recommend that selegiline
be withheld in PD patients based solely on the results of the UK study. (29)
DEPRENYL: ALZHEIMERS DISEASE
Alzheimers disease
(AD) is the most widespread neurodenerative disease of modern times, affecting
several million people in the U.S. alone. AD is characterized not only by severe
memory loss, but by verbal dysfunction, learning disability and behavioral difficulties
- even hallucinations. AD is known to involve damage to the cholinergic neurons
of the hippocampus, but In [AD], in addition to the reduction of acetylcholine,
alterations have been observed in the activities of other neurotransmitters. More
specifically, the deterioration of the dopaminergic [DA] and noradrenergic [NA]
systems... seems particularly relevant to the cognitive manifestations.... cerebral
depletion of dopamine (DA) can easily lead to memory and attention deficits. In
[AD] there is significant increase in type-B cerebral and platelet monoamine oxidases
(MAO-Bs).... [Therefore] pharmacological inhibition of MAO-B could result in an
improvement in the cognitive functions normally mediated by the catecholaminergic
systems. (17)
Thus, with its combined MAO-B inhibition effects and catecholamine
activity enhancing effects, DPR would seem tailor-made to treat AD. And indeed
that is the conclusion of a 1996 review paper on AD and DPR.
Tolbert and
Fuller reviewed 4 single-blind and 2 open label DPR trials in AD, as well as 11
double-blind DPR/AD studies. (7) They noted that all 6 single-blind/open label
studies reported positive results, while 8 of the 11 double-blind studies reported
favorable results, typically with a 10 mg DPR/day dosage. In 3 of the single-blind
studies DPR was compared to 3 nootropics - oxiracetam, phosphatidylserine and
acetyl-L-carnitine - and was superior to all 3. Tolbert and Fuller were so impressed
with DPR that they concluded ...in our opinion, selegiline is useful as initial
therapy in patients with mild-to-moderate Alzheimer disease to manage cognitive
behavioral symptoms. In patients with moderate-to-severe Alzheimer disease, selegilines
efficacy has not been adequately assessed; however, given the lack of standard
treatment, selegiline should be considered among the various treatment options.
(7)
DEPRENYL: DEPRESSION
DPR has been used
experimentally as a treatment for depression since the late 1970s. While the causes
of depression are diverse and still under investigation, it is by now accepted
that dysfunction of DA and NA neural systems is a frequent biochemical cause of
depression. (18,19)
In addition the research of A. Sabelli and colleagues
has established that a brain PEA deficiency also seems to be strongly implicated
in many cases of depression. (32) Given that DPR is a catecholamine (DA and NA)
activity enhancer, and that DPR strongly increases brain PEA through MAO-B inhibition,
DPR would seem a rational treatment for depression.
Studies with atypical
depressives (33), treatment-resistant depressives (34), and major depressives
(35) have shown DPR to be an effective, low side-effect depression treatment.
However, such studies have often required DPR dosages in the 20-30, even 60 mg
range. While these dosages caused little problem in short-term studies, it is
dubious to consider using such high, non-selective MAO-B inhibition doses for
long term (months - years) treatment. Three studies have shown antidepressant
promise at selective, MAO-B inhibiting doses.
In 1978 Mendelwicz and Youdim
treated 14 depressed patients with 5 mg DPR plus 300 mg 5-HTP 3 times daily for
32 days. (1) DPR potentiated the antidepressant effect of 5-HTP in 10/14 patients.
5-HTP enhances brain serotonin metabolism, which is frequently a problem in depression
(37), while DPR enhances DA/NA activity. Under-activity of brain DA, NA and serotonin
neural systems are the most frequently cited biochemical causes of depression
(18,19,37), so DPR plus 5-HTP would seem a natural antidepressant combination.
In 1984 Birkmayer, Knoll and colleagues published their successful results
in 155 unipolar depressed patients who were extremely treatment-resistant. (8)
Patients were given 5-10 mg DPR plus 250 mg phenylalanine daily. Approximately
70% of their patients achieved full remission, typically within 1-3 weeks. Some
patients were continued up to 2 years on treatment without loss of antidepressant
action. The combination of DPR plus phenylalanine enhances brain PEA activity,
while both DPR and PEA enhance brain catecholamine activity. Thus DPR plus phenylalanine
is also a natural antidepressant combination.
In 1991 H. Sabelli reported
successful results treating 6 of 10 drug-resistant major depressive disorder patients.
(9) Sabelli used 5 mg DPR daily, 100 mg vitamin B6 daily, and 1-3 grams phenylalanine
twice daily as treatment. 6 of 10 patients viewed their depressive episodes terminated
within 2-3 days! Global Assessment Scale scores confirmed the patients subjective
experiences. Vitamin B6 activates the enzyme that converts phenylalanine to PEA,
so the combination of low-dose DPR, B6, and phenylalanine is a bio-logical way
to enhance both PEA and catecholamine brain function, and thus to diminish depression.
DEPRENYL: THE ANTI-AGING DRUG
4 series of
rat experiments, as well as an experiment with beagle dogs, have shown that DPR
can extend lifespan significantly, even beyond the technical lifespan of a species.
Knoll reported that 132 Wistar-Logan rats were treated from the end of their second
year of life with either saline injections or 0.25 mg/kg DPR injection 3 times
weekly until death. (11)
In the saline-treated group the oldest rat
reached 164 weeks of age, and the average lifespan of the group was 147 weeks.
In the DPR group, the average lifespan was 192 weeks, with the shortest-living
rat dying at 171 weeks, and the longest-lived rat reaching 226 weeks.
In a second series of experiments Knoll treated a group of 94 low-performing (LP)
sexually inactive male rats with either saline or DPR injections (0.25 mg/kg)
from their eighth month of life until death. (11) Knoll had already established
a general correlation between sexual activity status and longevity in the rats.
The saline-treated LP rats lived an average 135 weeks, while the DPR-treated LP
rats averaged 153 weeks of life. The saline treated HP rats lived an average 151
weeks of life, while the DPR -treated HP rats averaged 185 weeks of life, with
17/50 HP-DPR rats exceeding their estimated technical lifespan of 182 weeks. (20)
Knolls experiments were partially replicated by Milgram and co-workers
and Kitani and colleagues. (11) Milgrams group used shorter-living Fischer 344
rats, while still starting DPR treatment at 2 years of age - in effect later in
their lives - and found a marginally significant 16% lifespan extension. The Kitani
group, also using the shorter-lived Fischer rats, started their DPR treatment
at 1.5 years of age, and found a 34% life increase.(11)
Ruehl and colleagues
performed an experiment with beagle dogs and DPR, administered at 1 mg/kg orally
per day, for up to 2 years 10 weeks. In a subset of the oldest dogs tested (10-15
years of age), 12 of 15 DPR-treated dogs survived to the conclusion of the study,
while only 7 of 18 placebo-treated dogs survived. By the time the first DPR-treated
dog died on day 427 of the study, 5 placebo-treated dogs had already died, the
first at day 295. (12) Ruehl et al note that dogs provide an excellent model of
human aging, so their study takes on added significance.
Knoll has repeatedly
emphasized that the nigrostriatal tract, the tiny DA-using nerve cluster in the
basal ganglia (old brain), typically dies off at an average rate of 13% per decade
starting around age 45 in humans.
This fact literally sets the human technical
lifespan (maximum obtainable by a member of a species) at about 115 years, since
by that age the nigral neuron population would have dropped below 10% of its original
number, at which time death ensues even if in all other respects the organism
were healthy. (23) Based on the sum total of the animal DPR literature, as well
as the 1985 study showing life-extension in DPR-treated PD patients (25) Knoll
has suggested that if DPR were used from the 40s on, and only modestly lowered
the nigrostriatal neuron death rate - i.e. from 13% to 10% per decade - then the
average human lifespan might increase 15 years, and the human technical lifespan
would increase to roughly 145 years. (23)
After 45 years of research,
Knoll has concluded that ...the regulation of lifespan must be located in the
brain, (20) His research has further convinced him that ... it is the role of
the catecholaminergic neurones to keep the higher brain centres in a continually
active state, the intensity of which is dynamically changed within broad limits
according to need. (20) Knolls research has shown that catecholaminergic nerve
activity reaches a maximum at sexual maturity, and then begins a long, gradual
downhill slide thereafter. Knolls animal research has shown catecholaminergic
activity, learning ability, sexual activity and longevity to be inextricably interlinked.
(11,20)
Knoll argues that the quality and duration of life is a function
of the inborn efficiency of the catecholaminergic brain machinery, i.e. a high
performing longer living individual has a more active, more slowly deteriorating
catecholaminergic system than [his/her] low performing, shorter living peer.(20)
And his key conclusion is that ... as the activity of the catecholaminergic system
can be improved at any time during life, it must be essentially feasible to ...
[transform] a lower performing, shorter living individual to a better performing,
longer living one. (20)
It is on this basis that Knoll consistently,
throughout his DPR papers (11,20,23), recommends the use of 10 - 15 mg oral DPR/week,
starting in the 40s, to help achieve this goal in humans. Knolls research clearly
convinces him that DPR is both a safe and effective preserver of the nigrostriatal
tract, as well as a catecholamine activity enhancer. DPR may not be the ultimate
anti-aging drug, but it is one that is safe and effective, well validated theoretically
and experimentally, and its available now.
DEPRENYL: DOSAGE &
SIDE-EFFECTS
Both Dr. Joseph Knoll and the Life Extension Foundation
(37) recommend a 10-15 mg weekly (i.e. 1.5 - 2 mg/day) oral DPR dosage for humans,
starting around age 40, possibly even in the 30s. 10 mg/day is a relatively standard
DPR dose for treatment of PD and AD, but this higher dose should only be used
with medical supervision. Some DPR experts believe this dosage is excessive, and
that with long term DPR use lower doses may still be effective and safer. (22)
Knoll has noted that the human MAO-B inhibiting DPR dose ranges from
0.05 to 0.20 mg/kg of bodyweight. (1) Thus, even in those wishing to use DPR at
an effective MAO-B inhibiting dose, it should not be necessary to use more than
3-5 mg/day. Because DPR is a potent and irreversible MAO-B inhibitor, it may even
turn out in many individuals that the suggested 1.5-2 mg/day life extension DPR
dose may achieve MAO-B inhibition with long term use.
DPR is reported
in most human studies to be well tolerated. (7) Typically, no abnormalities are
noted in blood pressure, laboratory valves, ECG or EEG. (7) The most common side
effects reported for DPR are gastrointestinal symptoms, such as nausea, heartburn,
upset stomach, etc. (7) Some studies have found side effects such as irritability,
hyper-excitability, psychomotor agitation, and insomnia, (7,8) These effects are
probably due to DPRs catecholamine-enhancing effect, over-activating DA/NA neural
systems at the expense of calming/sleep-inducing serotonergic systems, so taking
magnesium and tryptophan or 5-HTP may suffice to counter these psychic effects.
REFERENCES
1. Knoll, J. (1983) Deprenyl (selegeline):the history of its development and pharmacological
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