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Lucidril (centrophenoxine)
- the
neuro-energizer
by James South MA
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order
Centrophenoxine, also
known as Lucidril® and meclofenoxate, is one of the older nootropic drugs- it
was developed in 1959 at the French National Scientific Research Center. (1) Centrophenoxine is a
compound of two other biochemicals- dimethyl-aminoethanol (DMAE) and
parachlorphenoxyacetic acid (PCPA). DMAE
is found naturally in some foods, especially fish, and is also, a natural
metabolite of choline in the human body. The
presence of high amounts of DMAE in fish may be the basis for the “folk
wisdom” that “fish is brain food.” PCPA
is a synthetic version of plant growth hormones called “auxins.” (1)
Centrophenoxine is well-absorbed orally, and after absorption a portion of the centrophenoxine
is broken down in the liver to yield DMAE and PCPA.
The DMAE is then converted to choline by the liver through adding a
methyl group to DMAE. Choline is simply trimethylaminoethanol, (2) and is used in
many biochemical processes in the body. The
remaining centrophenoxine then circulates through the bloodstream, eventually
entering especially the brain and heart. “Pharmacokinetic
studies of centrophenoxine revealed that … much higher levels of DMAE were
found in the brain after centrophenoxine treatment, as compared to DMAE alone,
since apparently the esterified form of DMAE with PCPA penetrates much easier
the blood-brain barrier.” (2)
CENTROPHENOXINE:
THE CLINICAL BENEFITS
“Beneficial
therapeutic effects of centrophenoxine have been observed in various human
disorders such as cerebral atrophy, brain injury, post apoplectic [post-stroke]
status, chronic alcoholism, [and] barbiturate intoxication.” (3) “Clinical trials with centrophenoxine in geriatric patients
with such symptoms as confusion, psychosomatic asthenia [extreme weakness], and
disturbances of memory and intellectual concentration revealed marked
improvement after several weeks of treatment …. Clinical studies in European
literature have reported a significant improvement of such symptoms as fatigue,
irritability, confusional states, and loss of memory in the geriatric patients
treated with centrophenoxine.” (1)
In
two small pilot studies of patients suffering from tardive dyskinesia, a
neurologic disorder characterized by “a variety of abnormal involuntary
movements of the mouth, tongue, jaw, neck and extremities,” and usually caused
by administration of antipsychotic drugs (such as Thorazine®), centrophenoxine
caused a drastic reduction (60-90%) of dyskinesic movements in about 2/3 of
patients. (4) In a double-blind
study of 50 elderly patients suffering “medium level dementia,” centrophenoxine
produced significantly greater memory improvement than placebo, based on 6
memory tests. The centrophenoxine-improved
patients also showed “improved health status according to the rating of the
medical doctor” checking the patients, while placebo patients showed no
general health improvements. (4A) A
double-blind geriatric study found that “… there is evidence from the
free-recall test to suggest that meclofenoxate [centrophenoxine] does improve
the ability to transfer new information into secondary memory …. the increase
in memory function measured by the free recall test was, in a number of cases,
accompanied by an improvement in the carrying out of day-to-day activities ….
Subjects who reported a beneficial effect of meclofenoxate consistently used
terms like ‘increased alertness’ and ‘feeling of well-being’ to describe
[their centrophenoxine-improved state]” (5)
CENTROPHENOXINE:
NEURO-ENERGIZER
Imre
Zs-Nagy, the world’s most prolific centrophenoxine researcher, has labeled centrophenoxine
a “brain metabolic stimulant” and a “neuroenergeticum” (Ed. Professor
Zs-Nagy describes centrophenoxine in his 2000 Monte Carlo Anti-Aging video) –
i.e. a neuro-energizer. Centrophenoxine
“stimulates glucose uptake, oxygen consumption, and carbon dioxide production
in vivo [in the living organism] and also in vitro in brain slices.” (2)
“The demonstration of [centrophenoxine’s] ability to enhance the
resistance of cerebral cells of rats, mice and rabbits to various forms of
oxygen deprivation, including cyanide intoxication …, reduced atmospheric
pressure, … and reduced oxygen tension … in the inspired air, provides
confirmation … that [centrophenoxine] operates through the enhancement of
alternative pathways of glucose metabolism.” (5)
“Experimentally, Nickel et al … observed by electroencephalography in
rats a sustained increase of cerebral metabolic activity even under conditions
of hypoxia [low brain oxygen].” (1) Roy
and Singh found in their studies with aged rats that centrophenoxine increased
the cortical electrical activity of both adult and old rats about 40%, and noted
that “It would thus appear that centrophenoxine can stimulate cerebral
electrical activity in the aging brain.”
(6) Since brain electrical
activity is a reflection of brain metabolic activity, this is further evidence
that centrophenoxine is indeed a “neuro-energizer.”
Some reports suggest that centrophenoxine has a stimulatory effect on the
brain reticular formation (6). The
chief function of the acetylcholine-using cells of the reticular formation is to
activate/energize the cerebral cortex into greater alertness/energy/focus, and
as the next section makes clear, centrophenoxine is an activator of
acetylcholine neurons.
CENTROPHENOXINE:
SUPERIOR CHOLINERGIC
As
mentioned previously, centrophenoxine can serve to generate choline in the
liver, and provide both DMAE and choline to the brain.
Choline, a B vitamin-like substance which is both derived from food and
made in the body, is essential for optimal brain function in several ways. Choline is the raw material for acetylcholine, one of the
most critical neurotransmitters for memory, learning and intellectual focus.
(7,8) Choline is also the essential raw material for
phosphatidylcholine and sphingomyelin, two key constituents of (brain) cell
membranes. (8)
While
the body can make some choline, normally a large portion of daily choline supply
comes from food. The main dietary
sources of choline are meat, eggs and organ meats.
Vegetarian and semi-synthetic/highly purified-processed “junk” foods
are very low in choline (8), and research with humans has shown such low-choline
diets to be inadequate for optimal health, as measured by liver function tests
and other variables. (9) Typical choline blood levels in fasting (between meals)
humans average 8 to 12 micromoles. (8) Choline
flows bi-directionally through the blood-brain barrier: the flow is from the
blood toward the brain when blood levels are 14 micromoles or greater, and from
the brain to the blood when choline blood levels are less than 14 micromoles.
(8) “Thus, under fasting
conditions, brain neurons derive choline [to make acetylcholine] largely from
auto-cannibalism of [choline-rich] membrane phospholipids ….
It is thought that prolonged choline insufficiency could lead to
continued auto-cannibalization, membrane disruption, and cell death.” (8)
Consumption
of choline-rich foods, choline lecithin supplements, DMAE or centrophenoxine can
raise plasma choline levels to 30 micro-molecules or higher, resulting in an
increase in brain choline and acetylcholine
levels. (8,10)
In this cholesterol-conscious age, most people will probably not consume
a high red meat/egg/organ meat choline-rich diet.
Choline supplements (e.g. choline chloride or bitartrate) are poorly
bioavailable, because about 60% of them are digested by intestinal bacteria to
trimethylamines, a fishy-smelling biochemical. (8) Lecithin is a dilute (13%) choline source, rich in phosphorus
and fat, which most modern people get too much of already from their diets.
Wood and Peloquin note that “[centrophenoxine] induced dramatic
elevations in CNS choline levels with a potency about twice that of Deanol®
[DMAE].” (10) Dormard et al note
that “It seems indispensable to esterify the DMAE to assure its normal passage
through the hemoencephalic barrier [blood-brain barrier].”
(11) Centrophenoxine is an
ester- i.e. an organic compound – of DMAE and PCPA.
Furthermore, the DMAE provided to neurons by centrophenoxine also
inhibits the enzyme choline dehydrogenase, thereby preventing choline from being
irreversibly oxidized to betaine (trimethylglycine), and keeping blood/brain
choline higher than they would otherwise be.
Thus centrophenoxine probably represents the most effective method of
elevating blood and brain choline/acetylcholine levels available today, while
simultaneously sparing brain neurons from the spectre of “choline
auto-cannibalization,” a phenomenon that has been linked with the genesis of
Alzheimer’s dementia. (8,12)
CENTROPHENOXINE: THE
ANTIOXIDANT NOOTROPIC
Imre
Zs-Nagy, the leading centrophenoxine researcher, believes that centrophenoxine
makes its greatest contribution to brain health through its antioxidant effects.
He notes that centrophenoxine is a more effective source for getting DMAE
into the brain, than DMAE itself. (2)
Once
inside brain cells, DMAE is converted into phosphatidyl choline. (2) Phosphatidyl DMAE is likewise incorporated into nerve cell
membranes, and “about 40% of it persists there even after 24 hr in place of
choline.” And unlike phosphatidyl
choline,
phosphatidyl DMAE is a powerful free radical scavenger – specifically it is a
highly effective hydroxyl radical scavenger. (2)
Hydroxyl radicals, formed through the interaction of superoxide radical
and hydrogen peroxide, are the most damaging of the free radicals/oxidants
common in living cells. Hydroxyl
radicals can oxidize the fatty acids that make up cell membranes, cross-link
proteins, and generally damage the various macromolecules that make up nerve
cell structures. (13,14)
Zs-Nagy
and other researchers have performed a variety of experiments on the deleterious
effects of hydroxyl
radicals on nerve cell membranes and proteins, and the benefits of centrophenoxine/phosphatidyl
DMAE in combating these effects. (2,14,15) For example, because of the hydroxyl
radical formation it promotes, iron overload in the cerebrospinal fluid is
extremely toxic, and at lower doses causes accelerated aging in young rats.
Synaptic membranes of rats were protected considerably by centrophenoxine
pre-treatment against this type of iron overload. (15)
When
membrane proteins from 2,12 and 24 month old rats were compared, there was an
increase in high molecular weight proteins, and a decrease in low molecular
weight proteins. This is caused by
an increase in cross-linking of proteins due to hydroxyl radicals attacks that
occur over a lifetime. Centrophenoxine
treatment for 2 months reversed this phenomenon in the old (24 month) rats, due
to the incorporation of phosphatidyl DMAE into neuronal membranes, which reduced
cross-linking of proteins. In
effect centrophenoxine “youthified” the synaptic membranes of the aged rats.
(16) If this seems a minor
technical achievement, it should be remembered that the two main “theories of
aging” are the “free radical theory of aging” and the “cross-linking
theory of aging.”
When
young, adult, and aged rats were treated with centrophenoxine for 40 days, there
was a significant increase in neuronal membrane fluidization in all three
groups. (17)
With
aging, neuronal membranes normally become less fluid and more rigid due to hydroxyl
radical-damaged fatty acids and cross-linked proteins.
The decreased membrane fluidity impairs the ability of neuronal membranes
to conduct electrical impulses. Since
membrane fluidity decreases as hydroxyl
radical-induced
membrane lipid peroxidation (“fat rancidification”)
increases, the results were interpreted as further evidence of centrophenoxine’s
anti-Hydroxyl
radical effect and
brain cell “youthifying” effect. (17)
Zs-Nagy
and Semsei gave centrophenoxine to 1.5,13, and 26 month old rats for 2 months. They had already measured a significant (50%) reduction in
total RNA and messenger RNA production in old (26 month) rats.
They found that centrophenoxine significantly increased the RNA synthesis
of the old rats almost to the levels of adult (13 month) rats. (3)
RNA is the biochemical that allows cells to receive “instructions”
from their nuclear genes and make new proteins to replace worn-out or Hydroxyl
radical-damaged proteins. Zs-Nagy and Semei note “If the membrane components are
relatively more protected against the cross-linking effect of free-radicals [by centrophenoxine],
the rate of their damage will be decreased
…. Therefore, … the
cytoplasm becomes rehydrated to a certain extent, and under such conditions the
chromatin [genes in the cell nucleus] becomes more decondensed again, resulting
in an increase of the rates of RNA synthesis, as shown by our present
experiments. If this causes an
increased turnover of the proteins, … the physiological properties of the cell
membrane can further improve, and this cycle may seriously reduce the
age-dependent damage of the nerve cells.” (3)
Hydroxyl
radicals represent a very serious difficulty for life, since no enzymatic
protection against them exists. SOD
is the enzyme that detoxifies superoxide radical, while catalase and glutathione
peroxidase protect cells from hydrogen peroxide. (18)
Thus it is hard to over-rate the importance of centrophenoxine’s
membrane-bound phosphatidyl DMAE anti-Hydroxyl radical effects.
Neuronal membranes are densely packed with proteins and polyunsaturated
fatty acids which are easily damaged by Hydroxyl radicals.
Maintaining
phosphatidyl DMAE-rich neuronal cell membranes through regular centrophenoxine
ingestion may actually be a primary brain anti-aging strategy, as well as a
means to allow some repair/regeneration of age/hydroxyl
radical-damaged cell membranes even late in life.
CENTROPHENOXINE:
LIPOFUSCIN REMOVER
Lipofuscin
is a “garbage residue” conglomerate of membrane fragments-damaged proteins
and fatty acids – that accumulates in cells over a lifetime. Hence it is sometimes called “age pigment.”
Various animal studies have shown centrophenoxine to reduce lipofuscin.
(1,15,18,19) Riga and Riga
treated old rats with centrophenoxine for 8 weeks.
They found lipofuscin
reductions in various brain areas ranging from 25 to 42%. (19) Nandy gave centrophenoxine to 12 month old mice for 3 months.
There was a roughly 25% reduction in lipofuscin
in hippocampus and a 45% reduction in cortex lipofuscin.
The centrophenoxine-treated mice also did better in learning tasks
compared to the non-centrophenoxine age-matched controls. (1)
Roy
and colleagues found reduction in lipofuscin
from 6 week centrophenoxine treatment in 6, 9, and 12 month old rats, as well as
significant increase in antioxidant enzymes in cortex, cerebellum and brain
stem. (18) Zs-Nagy points out that
“old cells do not display any specific biochemical reaction of ‘lipofuscinogenesis,’
they just have a lower (and progressively more and more insufficient) rate of
elimination of the damaged components [lipofuscin]
than do young [cells].” (15) Thus,
centrophenoxine reduces lipofuscin
simply by rejuvenating cellular “machinery,” especially the lysosomal
enzymes, whose job is to digest worn-out/damaged cell components.
CENTROPHENOXINE:
DOSAGE, SYNERGISTS, SIDE-EFFECTS
Centrophenoxine
is considered an extremely non-toxic drug (20), in part because its chief
metabolites which remain in the body – DMAE, phosphatidyl DMAE, and choline
– are natural food/body constituents normally found in significant levels in
both food and body. The PCPA component of centrophenoxine is rapidly excreted in
the urine after separation from the DMAE. (2)
Doses used in human clinical studies are typically 600-2000 mg/day, given
in 2 divided doses at breakfast and lunch. (4,5,20)
For those wishing to use centrophenoxine as a long-term anti-brain aging
treatment, or for general cognition enhancement where no
psychological/neurological disease exists, as little as 250 mg once or twice
daily with breakfast/lunch is a
generally safe and useful dose.
Centrophenoxine
is a natural synergist with piracetam.
Piracetam has shown synergistic learning/memory effects when combined
with choline or lecithin in both animal and human studies
Centrophenoxine is a “better cholinergic” than choline or lecithin,
as previously discussed.
For
those wishing to prevent Alzheimer’s type dementia, or treat it in early
stage, centrophenoxine may be usefully combined with deprenyl, which has shown
anti-Alzheimer’s effects in many human clinical trials. Although centrophenoxine
is generally safe and non-toxic, it can ironically cause problems precisely
because it is such a powerful cholinergic enhancer. Excessive brain/peripheral nervous system levels of
acetylcholine can lead to headaches, neck/jaw/shoulder muscle tension, insomnia,
irritability, agitation and depression. This
is NOT a toxicity reaction – it is simply too much of a good thing:
acetylcholine. If any of these
symptoms occur, simply discontinue centrophenoxine for several days and then try
a reduced dosage. Those especially
sensitive to centrophenoxine may need to take it only on alternate days to avoid
cholinergic excess. To avoid any
acetylcholine excess that may “creep up” unnoticed, it may be helpful to
skip centrophenoxine one or two days weekly.
Any persons suffering from major depression, mania, seizure disorders or
Parkinson’s disease should avoid centrophenoxine, as too much acetylcholine
may worsen these conditions. Also,
pregnant women should avoid centrophenoxine.
REFERENCES:
1.
Nandy, K. (1978) “Centrophenoxine: effects on aging mammalian brain” J Am
Ger Soc 26, 74-81.
2.
Zs-Nagy, I. (1994) “A survey of the available data on a new nootropic drug,
BCE-001” Ann NY Acad Sci 717, 102-14.
3.
Zs-Nagy, I. & Semsei, I. (1984) “Centrophenoxine increases the rates of
total and mRNA synthesis in the brain cortex of old rats: an explanation of its
action in terms of the membrane hypothesis of aging” Exp Gerontal 19, 171-78.
4.
Izumi, K. et al (1986) “Meclofenoxate therapy in tardive dyskinesia: a
preliminary report” Biol Psychiat 21, 151-60. 4A. Pek, G. (1989) “Gerontopsychological studies using NAI
… on patients with organic psychosyndrome… treated
with centrophenoxine….” Arch Gerontal Geriatr 9, 17-30.
5.
Marcer, D. & Hopkins, S. (1977) “The differential effects of meclofenoxate
on memory loss in the elderly” Age and Ageing 6, 123-31. 6. Roy, D. &
Singh, R. (1988) “Age-related change in the multiple unit activity of the rat
brain parietal cortex and the effect of centrophenoxine” Exp Gerontal 23,
161-74.
7.
Zeisel, S. (1992) “Choline: an important nutrient in brain development, liver
function and carcinogenesis” J Am Coll Nut 11, 478-81.
8.
Canty, B. & Zeisel, S. et al (n.d.) “Lecithin and Choline: research update
on health and nutrition” Ft. Wayne IN: Central Soya Co.
9.
Zeisel, S. et al (1991) “Choline , an essential nutrient for humans” FASEB J
5, 2093-98.
10.
Wood, P. & Peloquin, A. (1982) “Increases in choline levels in rat brain
elicited by meclofenoxate” Neuropharmacol 21, 349-55.
11.
Dormard, Y. et al (1975) “Pharmacokinetic study of … (Cyprodenate) and of
[DMAE] in animals” Arzneim Forsch/Drug Res 25, 194-201.
12.
Ehrenstein, G. et al (1997) “The choline-leakage hypothesis for the loss of
acetylcholine in Alzheimer’s disease” Biophys J 73, 1276-80.
13.
Bradford, R. & Allen, H. Oxidology, Chula Vista CA: R.W. Bradford
Foundation, 1997.
14.
Zs-Nagy, I. & Nagy, K. (1980) “On the role of cross-linking of cellular
proteins in aging” Mech Age Dev 14, 245-51.
15.
Zs-Nagy, I. (1989) “On the role of intracellular physicochemistry in
quantitive gene expression during aging and the effect of centrophenoxine”
Arch Gerontal Geriatr 9, 215-29.
16.
Nagy, K. & Zs-Nagy, I. (1984) “Alterations in the molecular weight
distribution of proteins in rat brain synaptosomes during aging and
centrophenoxine treatment of old rats” Mech Age Dev 28, 171-76.
17.
Wood, W. et al (1986) “Fluidizing effects of centrophenoxine in vitro on brain
and liver membranes from different age groups
of mice” Life Sci 39, 2089-95.
18.
Roy, D. et al (1983) “Effect of centrophenoxine on the antioxidative enzymes
in various regions of the aging rat brain” Exp Gerontal 18, 185-97.
19.
Riga, S. & Riga, D. (1974) “Effects of centrophenoxine on the lipofuscin
pigments in the nervous system of old rats” Brain Res 72, 265-75.
20.
Fulop, T. Jr. et al (1990) “Effects of centrophenoxine on body composition and
some biochemical parameters of demented elderly people…” Arch Gerontal
Geriatr 10, 239-51.
The above article is copyrighted and may
not be copied without the written permission of International Antiaging Systems,
Les Autelets Suite A, Sark GY9 0SF, Channel Islands, UK.
HOME
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