 |
 |
 |
|
What is Cerebra GPC?
Cerebra-GPC is 100% Purified PhosChol with the fatty acids
removed. It is a simple formulation of
purified GPC and water, which comes together as a clear, concentrated, sweet
tasting solution that is easy to administer to adults and children.
GPC is a safe, stable, and rapidly absorbed source of free
choline, which easily enters the brain and has many functions in the body. It is important for the structural integrity
of cell membranes, cholinergic neurotransmission, transmembrane signalling,
methyl metabolism, and lipid-cholesterol transport and metabolism. Choline is a
precursor for phosphatidylcholine, sphingomyelin, platelet-activating factor,
betaine, and other phospholipids.
GPC is a nutrient
present in all
mammalian cells and other life forms. It is a rapidly absorbed source of choline, which easily enters the
brain and
has many functions in
the body.
Choline is
important for the structural integrity of cell membranes, cholinergic
neurotransmission, transmembrane signalling, methyl metabolism, and
lipid-cholesterol transport and metabolism [1]. Choline is a precursor for
phosphatidylcholine, sphingomyelin, platelet-activating factor, betaine, and
other phospholipids (Food and Nutrition Board (FNB) 1998). Choline speeds the
synthesis and release of acetylcholine, an important neurotransmitter involved
in numerous important functions in the body. Choline is an essential nutrient
since the
de novo synthesis of
choline is not always sufficient to meet human requirements for choline.
The FNB
established various Adequate Intake levels (AI) for choline based on gender/age
groups. Table 1 lists the AI levels established by the Food and Nutritional Board.
The Adequate Intake for pregnancy
and lactation was established as 450 mg/day and 550 mg/day,
respectively (FNB, 1998).
Table 1 shows that the
Adequate Intake of choline is about 550 mg/day for men and 425 mg/day
for women. Choline in the diet is available as free choline or is bound as
esters such as phosphocholine, GPC, sphingomyelin, or phosphatidylcholine.
It should
be noted that foods that are good sources of choline and choline esters are typically
higher in fat and/or cholesterol. Many Americans, in view of recommendations
from various private and government public health organizations, are decreasing
fat, saturated fat, and cholesterol in their diet. The consumption of less fat,
saturated fat, and cholesterol will lead to a concomitant decrease in choline
intake.
The de facto intake of choline and choline
compounds were examined during the Framingham Offspring Study in several
thousand men and women and showed that the general dietary intake of choline as
free form and as compounds is about 312 mg/day for men and 314 mg/day
for women [2]. Total choline intake was calculated as the sum of intake from
free choline, phosphocholine, glycerophosphocholine, phosphatidylcholine and
lecithin. Thus, the addition of choline and choline precursors to certain foods
may compensate for a possible deficit in choline.
Choline is a
vitamin-like, essential nutrient. But free choline is poorly bioavailable and
unstable in the water phase. GPC is a physiological form of choline in the
body. Figure 2 shows the metabolic pathway of choline and GPC.
Figure 2: Metabolic pathway of
GPC [3].
Cerebra GPC is water
soluble and able to efficiently increase choline levels in the blood and the
brain.
Cerebra GPC
is recommended at 500mg to 1000mg of pure GPC per day, which is equivalent to 200
- 400 mg free choline.
Safety
of GPC
GPC is a choline
precursor like lecithin and choline salts. Commercial lecithin, phosphatidylcholine,
choline bitartrate, and choline chloride are also precursors of choline and are
all generally recognized as safe (GRAS) (21 CFR - 182,184).
GPC is a naturally
occurring food component. Table
2 lists the content of free choline, GPC, and other
naturally present choline esters in common foods (mg choline moiety per 100 g
food) [6].
Table 2: Choline concentrations
in common food in mg choline moiety/100 g food [6].
|
food
|
Choline
|
GPC
|
Phospho-
choline
|
Phosphatidyl-
choline
|
Total
choline
|
|
2 % milk
|
2.82
|
9.98
|
1.58
|
1.15
|
16.40
|
|
Cheese half & half
|
3.92
|
8.48
|
1.17
|
1.71
|
16.82
|
|
Sour cream
|
4.73
|
8.08
|
1.26
|
3.51
|
20.33
|
|
Yoghurt, plain
|
2.32
|
9.10
|
1.65
|
1.04
|
15.20
|
|
Olive oil
|
0.02
|
0.28
|
ND
|
ND
|
0.29
|
|
Bananas
|
3.20
|
5.60
|
0.51
|
0.44
|
9.76
|
|
Fin fish - Atlantic cod
|
17.73
|
30.04
|
1.57
|
32.90
|
83.63
|
|
Oat bran, raw
|
4.41
|
33.25
|
0.68
|
20.23
|
58.57
|
|
Beef liver
|
56.67
|
77.93
|
11.77
|
247.75
|
418.22
|
Table 2 shows that GPC
is the predominant choline component in foods such as milk, dairy products (e.g.,
cheese), olive oil, oat bran, and bananas. The average intake of GPC in the subjects
participating in the Framingham Offspring Study was 54+/-21 mg/day [2].
Additional GPC is formed in the body by hydrolysis of phosphatidylcholine from
food by phospholipase A in the gut mucosa. GPC is also an important component
in human milk, with a concentration of 362+/-70 u-mol/l as derived by the
mean of 16 women [3].
The bioavailability of
choline and choline esters from milk was studied in a rat-pup model [7].
15-day-old rat pups were fed infant formula, labeled with approximately
15,725 Bq of either
14C-choline, 14C-phosphocholine,
14C-GPC, or 14C-phosphatidylcholine. Stomach content,
blood, and tissues were analyzed for the different choline species at different
time points.
The disappearance of
the radiolabel in the stomach was similar for choline, phosphocholine and GPC.
There was a 3-fold decrease in all labels at 30 min post incubation. At 4 h
post incubation there was essentially no label present in the stomach contents.
Disappearance of phosphatidylcholine-derived label in stomach contents was
slower than for the other three labels. It took 8 h before a 3-fold
decrease was observed and more than 12 h before this label disappeared
from the stomach contents. In the GI tract, choline, GPC, and phosphocholine derived
labels were similar, and the total area under the curves were significantly
different from the phosphatidylcholine-derived label.
The labeled choline
compounds were absorbed and distributed to the GI tract, liver, blood, and
brain of the rat pups. The appearance and disappearance of choline, GPC, and phosphatidylcholine-derived
labels were similar. In the liver, phosphocholine appeared and disappeared more
rapidly than did the other labels. Labels from all of the water-soluble forms
of choline reached maximum levels within 4 h; phosphocholine label did so
by 1 h. Phosphatidylcholine appeared much more slowly than did the other
labels and was still accumulating at 24 h post dose. In the liver, the
total area under the curve was significantly different for each label over the
time periods studied. Different choline containing compounds were formed in
liver from choline, phosphocholine, GPC, and phosphatidylcholine-radio
labeled infant formula. In liver at 4 h post treatment, choline (Table 3),
phosphocholine, and GPC derived label were present in the greatest amount as
betaine, with phosphocholine being the next most common metabolite formed.
Phosphatidylcholine derived label was principally associated with phosphatidylcholine
in liver.
Table 3: Percentages of labelled
choline and choline metabolites formed in liver of 15-day-old rat pups at
4 h post treatment [7].
|
Metabolites formed
|
Treatments
|
|
14C-Choline
[%]
|
14C-Phosphocholine
[%]
|
14C-GPC
[%]
|
14C-Phosphatidylcholine
[%]
|
|
Betaine
|
48.3
|
43.4
|
42.5
|
10.7
|
|
Choline
|
2.1
|
7.5
|
16.5
|
0.0
|
|
Phosphocholine
|
22.4
|
20.9
|
22.5
|
4.3
|
|
GPC
|
12.3
|
13.2
|
3.5
|
0.0
|
|
Phosphatidlycholine
|
14.9
|
14.9
|
14.5
|
84.8
|
By 24 h in liver
(Table 4), choline and phosphocholine label was mainly present as betaine, with
a small amount of phosphatidylcholine formed. No choline- and
phosphocholine-derived label was present as choline, GPC, or phosphocholine. GPC-derived
label was present as betaine, with some choline, GPC and phosphatidylcholine
also being formed. Phosphatidylcholine-derived label was present mainly as phosphatidylcholine
in liver with some betaine and phosphocholine formed.
Table 4: Percentages of labelled
choline and choline metabolites formed in liver of 15-day-old rat pups at 24 h
post treatment [7].
|
Metabolites formed
|
Treatments
|
|
14C-Choline
[%]
|
14C-Phosphocholine
[%]
|
14C-GPC
[%]
|
14C-Phosphatidylcholine
[%]
|
|
Betaine
|
85.0
|
85.0
|
53.7
|
13.0
|
|
Choline
|
0.0
|
0.0
|
18.3
|
0.0
|
|
Phosphocholine
|
0.0
|
0.0
|
10.7
|
2.0
|
|
GPC
|
0.0
|
0.0
|
2.4
|
0.0
|
|
Phosphatidlycholine
|
14.9
|
14.9
|
14.6
|
84.7
|
These data indicate
that in liver GPC was metabolized differently than free choline and phosphatidylcholine.
GPC seems to offer a sustained liberation of choline for further metabolism.
The absorption,
distribution, and excretion after single doses of radio labeled GPC ([
14G]-GPC,
labeled in the glycerol part of the molecule, and [
14C]-GPC, labeled
in the choline part of the molecule) were also extensively studied in rats [8].
The blood and plasma kinetics and the excretion and tissue distribution of GPC were
investigated after oral (100-300 mg GPC/kg) and i.v. (10 mg GPC/kg)
uptake.
The blood and plasma
concentration of [
14G] GPC reached a maximum between 2-4 h
after oral intake of 100 mg/kg. For [
14C]-GPC, the peak
concentration was obtained after 24 h. The GPC concentrations for both
labeled forms stayed above the baseline during the 72 h of investigation.
The tissue
distribution of radioactivity was examined 3 h and 72 h after oral
administration.
After 3 h the radioactivity
of [
14G]-GPC peaked in the gut, corresponding to 18-20 % of the
administered dose. The concentration in liver and kidney were respectively
about twice the concentration of the blood levels, equivalent to 2-6 % of
the dose.
Furthermore, 3 h
after oral intake of [
14C]-GPC, the liver contained the highest
level of radioactivity (5-11 % of the dose). Other tissues with
radioactivity levels higher than blood were the kidneys (1-1.5% of the dose),
spleen and lung. The total radioactivity in the gut was 2-3 % of the administered
dose. Brain radioactivity was about half that found in blood.
After 72 h the
total remaining radioactivity for both labeled GPC-forms was spread over most
tissues and organs, but values higher than blood levels were found in liver,
kidneys, lung, and spleen.
The brain-to-blood
distribution of radioactivity was also measured time-dependently. After [
14G]-GPC,
the time courses of blood and brain concentrations were almost parallel within
32 h of dosing. For [
14C]-GPC, brain radioactivity increased
slowly up 24 h and then remained constant up to the end of the experiment.
Within this plateau it amounted about 50 % of blood radioactivity.
Another experiment,
with 300 mg/kg GPC orally administrated showed that the radioactivity was
registered in the brain as phosphatidylcholine. This suggests that choline from
GPC enters the brain and is reused for biosynthesis of phospholipids.
The excretion of
labeled GPC during 72 h was also investigated. Renal and fecal excretion
was comparable to the G- and C-labeled compounds, but low (10 % of the
dose).
By far the largest
part of the administered radioactivity was exhaled as
14CO2,
in accordance with established catabolic pathways of glycerol and choline
degradation.
This study showed that
in the rat, GPC is hydrolyzed to choline and glycerol-3-phosphate.
Some metabolic studies
in men from the literature will be described:
A comparative study of
free plasma choline levels following intramuscular administration of
l-alpha-glycerylphosphorylcholine and
citicoline in normal volunteers [9]
l-alpha-glycerylphosphorylcholine
(alpha-GPC) is a recently developed cognitive enhancer whose mode of action is
considered to involve the release of free choline, which is then utilized for
acetylcholine and phosphatidylcholine biosynthesis in the brain. The purpose of
this study was to evaluate the profile of free plasma choline levels following
a single i.m. dose of alpha-GPC in 12 normal volunteers. Citicoline (CTC),
which also acts as a choline precursor, was included for comparison purposes.
Each subject was studied on three randomized occasions, (i) on a control day in
the absence of drug administration (to evaluate the plasma level profile of
endogenous choline); (ii) after i.m. alpha-GPC (1,000 mg); and (iii) after
i.m. CTC (1,000 mg), respectively, with a washout period of at least
1-week between sessions. Blood samples for plasma choline HPLC determinations
were collected at regular intervals over a 6-h period. In the control session,
plasma choline levels remained stable during the sampling period. The
administration of alpha-GPC was associated with a rapid rise in plasma choline,
peak levels being usually observed at the first (0.25 h) or second (0.5 h)
sampling time after the injection. Thereafter, the concentration of choline
declined gradually and returned to near baseline values at the end of the observation
period. After the administration of CTC, plasma choline levels showed a similar
time course, but were considerably lower than those observed after the
administration of alpha-GPC.
Pharmacokinetics of
choline alfoscerate in the healthy volunteer [10]
This was a
pharmacokinetic study of i.m., i.v., and oral dosing with GPC. Four healthy
volunteers aged 19-24 years received GPC 1000 mg i.v., then subsequently
i.m., then by mouth, then received a placebo by mouth, in four separate
sessions separated by 1-week washouts. During each session blood was sampled
periodically over 10 hours. With i.v. administration of GPC, plasma total
choline peaked at 5 minutes
and returned to baseline by 4 hours. With i.m. administration, plasma total
choline peaked at 0.5 hours and returned to baseline by 6 hours. With oral GPC,
plasma total choline peaked at 3
hours, at a concentration slightly less than half that reached by i.m.
administration. But with oral GPC, the plasma total choline remained above
baseline at 10 hours. The
investigators concluded that i.v. and i.m. GPC both delivered virtually
identical total plasma doses (AUC, area under the curve), and that oral
administration delivered about half this amount.
Several clinical
studies showed that the tolerability of GPC was very good, even when administered
in very high doses for a long term.
Numerous clinical
studies have described the effects of high oral or parenteral doses of GPC on
several neuronal disorders:
Multi-center study of l-alpha-glyceryl-phosphorylcholine vs.
ST200 among patients with probable senile dementia of Alzheimer's type [11]
A multi-center,
randomized, controlled study compared the efficacy of
l-alpha-glyceryl-phosphorylcholine (alpha-GPC) and ST200
(acetyl-
l-carnitine) among 126
patients with probable senile dementia of Alzheimer's type (SDAT) of mild to
moderate degree. Efficacy was evaluated by means of behavioural scales and
psychometric tests. The results showed significant improvements in most
neuropsychological parameters in the alpha-GPC recipients. Improvements also
occurred in the ST200 recipients, but to a lesser extent. Tolerability was good
in both groups. These positive findings require replication in larger,
double-blind, longitudinal studies coupling clinical and biological evaluations.
Multi-center clinical study of
efficacy and tolerability of choline alfoscerate in patients with deficits in
higher mental function arising after an acute ischemic cerebrovascular attack
[12]
A total of 320
patients suffering mental decline after a cerebral ischemic attack received GPC
1000 mg i.m. once daily for 28 days, then 1200 mg by mouth for another 20
weeks. GPC significantly improved neurologic measures by week 4 (p<0.0001).
By week 24, the various cognitive and global clinical assessment scales showed
a "large improvement" of the mental status of the patients.
Clinical study of the
therapeutic effectiveness and tolerability of choline alfoscerate in 15
subjects with compromised cognitive functions subsequent to acute focal cerebral
ischemia [13]
This was a
small open trial that followed the usual GPC stroke protocol. Eleven patients
of average age 74 years received GPC 1000 mg i.m. once daily for 28 days, then
1200 mg orally daily for at least another 20 weeks. On various rating scales
(Mathew, MMSE, SCAG, the Psychic Evaluation Scale), GPC significantly improved results
with regard to memory, anxiety, emotional lability, sociability, spatial
orientation, aspects of language, eye deviation, confusion, vigilance, and
general mental sharpness. Two patients complained of slight, transitory heartburn
but did not withdraw from the trial. At 6 months the physicians judged 10/11 of
the patients as showing results excellent to fairly good, while 10/10 patients
judged themselves as having excellent to fairly good. Thus, in 5 open trials
completed with 2,972 patients variously afflicted by stroke, a regimen of 1
month of intramuscular GPC followed by 5 months of oral intake produced
clinically remarkable improvement. Given that the patients were generally too
ill to be given placebos, the degrees of clinical improvement over the 6-month
trial periods were well above those predictable as placebo effects. Many
patients showed accelerated improvement within the first 2-4 weeks and
continued to improve over the remaining 5 months. The physicians as well as the
patients uniformly judged GPC to be very well tolerated.
Effect of l-alpha-glyceryl-phosphorylcholine on
amnesia caused by scopolamine [14]
The present
study was carried out to test the effects of
l-alpha-glycerylphosphorylcholine
(
l-alpha-GFC) on memory impairment
induced by scopolamine in human subjects. Thirty-two healthy young volunteers
were randomly allocated to four different groups. They were given a ten-day pre-treatment
with either
l-alpha-GFC or
placebo, p.o., and on the eleventh day either scopolamine or placebo, i.m.
Before and 0.5, 1, 2, 3, and 6 h after
injection, the subjects were given attention and mnemonic tests. The findings
of this study indicate that the drug is able to antagonize impairment of
attention and memory induced by scopolamine.
Changes in the interaction
between CNS cholinergic and dopaminergic neurons induced by
l-alpha-glycerylphosphorylcholine, a
cholinomimetic drug [15]
The present
study investigates the cholinomimetic properties of the drug
l-alpha-glycerylphosphorylcholine
(alpha-GPC) at the CNS level. Experiments using tritium-labelled alpha-GPC
indicate that the drug reaches the brain after i.p. and p.o. administration. In
order to study the cholinomimetic properties of this drug, an indirect
functional index of cholinergic activation was used. In fact cholinergic
agonists induce an activation of striatal dopaminergic output. Administration
of alpha-GPC, both i.p. and p.o., increased striatal dihydroxyphenylacetic acid
(DOPAC) content. In addition, the
in
vitro
K+-stimulated dopamine release was increased in rats
treated
in vivo with alpha-GPC. Since
alpha-GPC has a weak displacing activity in QNB binding, the
in vivo cholinergic activity might be
due to the fact that this drug may increase the availability of choline for
acetylcholine synthesis leading to increased acetylcholine production. This
activity may be useful in those situations such as aging in which cholinergic
activity is deficient.
Choline alfoscerate in the
treatment of mental disorder after acute cerebrovascular accident [16]
An Italian multi-center
trial involved 425 patients aged 45-85 years, who were recruited from 44
centers distributed throughout the country. All the patients had suffered
cerebral ischemic attacks (stroke, TIA, or acute cerebral ischemia) within the
previous 10 days. It was another open trial, since the patients were too
severely afflicted to be subjected to placebo treatment. Patients who scored 35
or below on the Mathew Scale were eligible for the trial, but comatose patients
were not, nor were those not expected to live or judged unable to comply over
the 6-month period of the trial. As per the typical GPC stroke protocol,
treatment proceeded in two phases, first by giving GPC 1000 mg i.m.
in-hospital daily for 28 days, then switching to GPC 1200 mg by mouth for
5 more months (400 mg 3 times per day). Upon completion of the GPC i.m.
phase, there was an average improvement on the Mathew Scale of 18.56 %
(11.5 points, from 62.02 to 73.53). This was statistically highly significant over
baseline. A 20 % or greater improvement was seen in 168 (39.5 %) of
the patients. By this measure the more impaired, older patients (65-85 years)
were more likely to benefit than were the younger patients 45-64 years). During
the second phase, after discharge (GPC oral, for 5 months), evaluation was
based on clinical interviews and three assessment scales were used. On the MMSE
for cognitive functions, there was a 12.3 % improvement (from 21.53 at week 5 to 24.19 at 6 months). A 20 % or greater
improvement was seen in 126 patients (29.7 %). On the Global Deterioration
Scale, there was an average 20.2 % improvement. A 20 % or greater
improvement was seen in 180 patients (42.3 %). On the Crichton Geriatric
Rating Scale, which assesses mainly behavioural functioning, there was an
average 19.5 % improvement. A 20 % or greater improvement was seen in
166 patients (39.1 %). The researchers judged GPC to be effective and well
tolerated both parenterally and orally. They noted that despite the many drugs
with which GPC was co-administered, no single GPC-drug interaction was observed
clinically or in laboratory tests. GPC's benefits were consistent, and spanned functional
state as well as performance and social behavior. With the possible exception
of the MMSE (at 12.3 %), the degrees of improvement from GPC on the various
scales were well above that expected from a placebo, namely 12 % in at
least 20 % of such patients.
Glycerophosphocholine
is a natural, physiological, water-soluble and stable precursor of choline. It
is part of the daily nutrition and its levels are reduced on account of changed
dietary composition. The fortification of different foods with GPC can supply GPC
and choline as readily absorbed nutrients for enhancing cholinergenic metabolic
functions such as neurological and mental performance.
[1]Canty
D.J., Zeisel S.H., Jolitz A.J., Lecithin and Choline - Research Update on
Health and Nutrition.
[2]Cho
E., Zeisel S.H., Jaques P., Selhub J., Dougherty L., Colditz G.A., Dietary
choline and betaine assessed by food-frequency questionnaire in relation to plasma
total homocysteine concentration in the Framingham Offspring Study, Am. J.
Clin. Nutr. 2006, 83: 905-911.
[3]Holmes-McNary
M.Q., Cheng W.-L., Nar M.-H., Fussell S., Zeisel S.H., Choline and choline
esters in human and rat milk and in infant formulas. Am. J. Clin. Nutr. 1996,
64: 572-576.
[4]Howe
J.C., Williams J.R., Holden J.M., Zeisel S.H., Mar M.-H., USDA Database for the
Choline Content of Common Foods, March 2004.
[5]Koc
H., Mar M.-H., Ranasinghe A., Swenberg J.A., Zeisel S.H., Quantitation of Choline
and Its Metabolites in Tissues and Foods by Liquid Chromatography(Electrospray Ionization-Isotope
Dilution Mass Spectrometry, Analytical Chemistry 2002, 74(18): 4734-4740.
[6]Zeisel
S.H., Mar M.-H., Hove J.C., Holden J.M.,
Concentrations of Choline-Containing Compounds and Betaine in Common Foods. Human
Nutrition and Metabolism 2003: 1302-1307.
[7]Cheng
W.-L., Holmes-McNary M.Q., Mar M.-H., Lien E.L. Zeisel S.H., Bioavailability of
choline and choline esters from milk in rat pups, Nutritional Biochemistry
1996, 7: 457-464.
[8]Abbiati
G., Fossati T., Lachmann G., Bergamaschi M., Castiglioni C., Absorption, tissue
distribution and excretion of radiolabeled compounds in rats after
administration of
[14C]-l-a-glycerylohosphorylcholine, Euro. J.
Drug Metabol. Pharma 1993, 18(2): 173-180.
[9]Gatti
J. et al., A comparative study of free plasma choline levels following
intramuscular administration of L-alpha-glycerylphosphorylcholine and
citicoline in normal volunteers, Int. J. Clin. Pharmacol. Ther. Toxicol. 1992, 30(9):
331-335.
[10]De
Moliner et al., Pharmacokinetics of choline alsphscerate in the healthy volunteer,
Le Basi Raz. Ter. 1993, 23, Suppl. 3, 75.
[11]Parnetti
L,. Avate G., Bartorelli L., Cucinotta D., Cuzzupoli M., Maggioni M.,
Villardita C., Senin U., Multicenter Study of
l-a-Glyceryl-Phosphorylcholine vs ST200
among Patients with Probable Senile Dementia of Alzheimer's Type, Drugs &
Aging 1993, 3(2): 159-164.
[12]Gambi
D., Onofrj M., Multicenter clinical study of efficacy and tolerability of
choline alfoscerate in patients with deficits in higher mental function arising
after an acute ischemic cerebrovascular attack, Geriatrica 1994, 6:91.
[13]Tomasina
C. et al., Clinical study of the therapeutic effectiveness and tolerability of
choline alfoscerate in 15 subjects with compromised cognitive functions
subsequent to acute focal cerebral ischemia, Rivista Neuropsi. Sci. Affini.
1996, 3(7): 21.
[14]Canal
et al., Effect of L-alpha-glycerylphosphorylcholine on amnesia caused by scopolamine.
Int. J. Clin. Pharmacol. Ther. Toxico. 1991, 29(3): 103-107.
[15]Trabucchi
et al., Changes in the interaction between CNS cholinergic and dopaminergic
neurons induced by
l-alpha-glycerylphosphorylcholine,
a cholinomimetic drug, Farmaco. Sci. 1986, 41(4): 325-334.
[16]Aguglia
E. et al.,
Choline alfoscerate
in the treatment of mental pathology following acute cerebrovascular accident.
Funct. Neurol. 1993; 8 (Suppl):5.
|
|
|
 |
|
 |
|
|
|
 |
|
 |
|
GPC is a nutrient
present in all
mammalian cells and other life forms. It is a rapidly absorbed source of choline, which easily enters the
brain and
has many functions in
the body.
Choline is
important for the structural integrity of cell membranes, cholinergic
neurotransmission, transmembrane signalling, methyl metabolism, and
lipid-cholesterol transport and metabolism [1]. Choline is a precursor for
phosphatidylcholine, sphingomyelin, platelet-activating factor, betaine, and
other phospholipids (Food and Nutrition Board (FNB) 1998). Choline speeds the
synthesis and release of acetylcholine, an important neurotransmitter involved
in numerous important functions in the body. Choline is an essential nutrient
since the
de novo synthesis of
choline is not always sufficient to meet human requirements for choline.
The FNB
established various Adequate Intake levels (AI) for choline based on gender/age
groups. Table 1 lists the AI levels established by the Food and Nutritional Board.
The Adequate Intake for pregnancy
and lactation was established as 450 mg/day and 550 mg/day,
respectively (FNB, 1998).
Table 1 shows that the
Adequate Intake of choline is about 550 mg/day for men and 425 mg/day
for women. Choline in the diet is available as free choline or is bound as
esters such as phosphocholine, GPC, sphingomyelin, or phosphatidylcholine.
It should
be noted that foods that are good sources of choline and choline esters are typically
higher in fat and/or cholesterol. Many Americans, in view of recommendations
from various private and government public health organizations, are decreasing
fat, saturated fat, and cholesterol in their diet. The consumption of less fat,
saturated fat, and cholesterol will lead to a concomitant decrease in choline
intake.
The de facto intake of choline and choline
compounds were examined during the Framingham Offspring Study in several
thousand men and women and showed that the general dietary intake of choline as
free form and as compounds is about 312 mg/day for men and 314 mg/day
for women [2]. Total choline intake was calculated as the sum of intake from
free choline, phosphocholine, glycerophosphocholine, phosphatidylcholine and
lecithin. Thus, the addition of choline and choline precursors to certain foods
may compensate for a possible deficit in choline.
Choline is a
vitamin-like, essential nutrient. But free choline is poorly bioavailable and
unstable in the water phase. GPC is a physiological form of choline in the
body. Figure 2 shows the metabolic pathway of choline and GPC.
Figure 2: Metabolic pathway of
GPC [3].
Cerebra GPC is water
soluble and able to efficiently increase choline levels in the blood and the
brain.
Cerebra GPC
is recommended at 500mg to 1000mg of pure GPC per day, which is equivalent to 200
- 400 mg free choline.
Safety
of GPC
GPC is a choline
precursor like lecithin and choline salts. Commercial lecithin, phosphatidylcholine,
choline bitartrate, and choline chloride are also precursors of choline and are
all generally recognized as safe (GRAS) (21 CFR - 182,184).
GPC is a naturally
occurring food component. Table
2 lists the content of free choline, GPC, and other
naturally present choline esters in common foods (mg choline moiety per 100 g
food) [6].
Table 2: Choline concentrations
in common food in mg choline moiety/100 g food [6].
|
food
|
Choline
|
GPC
|
Phospho-
choline
|
Phosphatidyl-
choline
|
Total
choline
|
|
2 % milk
|
2.82
|
9.98
|
1.58
|
1.15
|
16.40
|
|
Cheese half & half
|
3.92
|
8.48
|
1.17
|
1.71
|
16.82
|
|
Sour cream
|
4.73
|
8.08
|
1.26
|
3.51
|
20.33
|
|
Yoghurt, plain
|
2.32
|
9.10
|
1.65
|
1.04
|
15.20
|
|
Olive oil
|
0.02
|
0.28
|
ND
|
ND
|
0.29
|
|
Bananas
|
3.20
|
5.60
|
0.51
|
0.44
|
9.76
|
|
Fin fish - Atlantic cod
|
17.73
|
30.04
|
1.57
|
32.90
|
83.63
|
|
Oat bran, raw
|
4.41
|
33.25
|
0.68
|
20.23
|
58.57
|
|
Beef liver
|
56.67
|
77.93
|
11.77
|
247.75
|
418.22
|
Table 2 shows that GPC
is the predominant choline component in foods such as milk, dairy products (e.g.,
cheese), olive oil, oat bran, and bananas. The average intake of GPC in the subjects
participating in the Framingham Offspring Study was 54+/-21 mg/day [2].
Additional GPC is formed in the body by hydrolysis of phosphatidylcholine from
food by phospholipase A in the gut mucosa. GPC is also an important component
in human milk, with a concentration of 362+/-70 u-mol/l as derived by the
mean of 16 women [3].
The bioavailability of
choline and choline esters from milk was studied in a rat-pup model [7].
15-day-old rat pups were fed infant formula, labeled with approximately
15,725 Bq of either
14C-choline, 14C-phosphocholine,
14C-GPC, or 14C-phosphatidylcholine. Stomach content,
blood, and tissues were analyzed for the different choline species at different
time points.
The disappearance of
the radiolabel in the stomach was similar for choline, phosphocholine and GPC.
There was a 3-fold decrease in all labels at 30 min post incubation. At 4 h
post incubation there was essentially no label present in the stomach contents.
Disappearance of phosphatidylcholine-derived label in stomach contents was
slower than for the other three labels. It took 8 h before a 3-fold
decrease was observed and more than 12 h before this label disappeared
from the stomach contents. In the GI tract, choline, GPC, and phosphocholine derived
labels were similar, and the total area under the curves were significantly
different from the phosphatidylcholine-derived label.
The labeled choline
compounds were absorbed and distributed to the GI tract, liver, blood, and
brain of the rat pups. The appearance and disappearance of choline, GPC, and phosphatidylcholine-derived
labels were similar. In the liver, phosphocholine appeared and disappeared more
rapidly than did the other labels. Labels from all of the water-soluble forms
of choline reached maximum levels within 4 h; phosphocholine label did so
by 1 h. Phosphatidylcholine appeared much more slowly than did the other
labels and was still accumulating at 24 h post dose. In the liver, the
total area under the curve was significantly different for each label over the
time periods studied. Different choline containing compounds were formed in
liver from choline, phosphocholine, GPC, and phosphatidylcholine-radio
labeled infant formula. In liver at 4 h post treatment, choline (Table 3),
phosphocholine, and GPC derived label were present in the greatest amount as
betaine, with phosphocholine being the next most common metabolite formed.
Phosphatidylcholine derived label was principally associated with phosphatidylcholine
in liver.
Table 3: Percentages of labelled
choline and choline metabolites formed in liver of 15-day-old rat pups at
4 h post treatment [7].
|
Metabolites formed
|
Treatments
|
|
14C-Choline
[%]
|
14C-Phosphocholine
[%]
|
14C-GPC
[%]
|
14C-Phosphatidylcholine
[%]
|
|
Betaine
|
48.3
|
43.4
|
42.5
|
10.7
|
|
Choline
|
2.1
|
7.5
|
16.5
|
0.0
|
|
Phosphocholine
|
22.4
|
20.9
|
22.5
|
4.3
|
|
GPC
|
12.3
|
13.2
|
3.5
|
0.0
|
|
Phosphatidlycholine
|
14.9
|
14.9
|
14.5
|
84.8
|
By 24 h in liver
(Table 4), choline and phosphocholine label was mainly present as betaine, with
a small amount of phosphatidylcholine formed. No choline- and
phosphocholine-derived label was present as choline, GPC, or phosphocholine. GPC-derived
label was present as betaine, with some choline, GPC and phosphatidylcholine
also being formed. Phosphatidylcholine-derived label was present mainly as phosphatidylcholine
in liver with some betaine and phosphocholine formed.
Table 4: Percentages of labelled
choline and choline metabolites formed in liver of 15-day-old rat pups at 24 h
post treatment [7].
|
Metabolites formed
|
Treatments
|
|
14C-Choline
[%]
|
14C-Phosphocholine
[%]
|
14C-GPC
[%]
|
14C-Phosphatidylcholine
[%]
|
|
Betaine
|
85.0
|
85.0
|
53.7
|
13.0
|
|
Choline
|
0.0
|
0.0
|
18.3
|
0.0
|
|
Phosphocholine
|
0.0
|
0.0
|
10.7
|
2.0
|
|
GPC
|
0.0
|
0.0
|
2.4
|
0.0
|
|
Phosphatidlycholine
|
14.9
|
14.9
|
14.6
|
84.7
|
These data indicate
that in liver GPC was metabolized differently than free choline and phosphatidylcholine.
GPC seems to offer a sustained liberation of choline for further metabolism.
The absorption,
distribution, and excretion after single doses of radio labeled GPC ([
14G]-GPC,
labeled in the glycerol part of the molecule, and [
14C]-GPC, labeled
in the choline part of the molecule) were also extensively studied in rats [8].
The blood and plasma kinetics and the excretion and tissue distribution of GPC were
investigated after oral (100-300 mg GPC/kg) and i.v. (10 mg GPC/kg)
uptake.
The blood and plasma
concentration of [
14G] GPC reached a maximum between 2-4 h
after oral intake of 100 mg/kg. For [
14C]-GPC, the peak
concentration was obtained after 24 h. The GPC concentrations for both
labeled forms stayed above the baseline during the 72 h of investigation.
The tissue
distribution of radioactivity was examined 3 h and 72 h after oral
administration.
After 3 h the radioactivity
of [
14G]-GPC peaked in the gut, corresponding to 18-20 % of the
administered dose. The concentration in liver and kidney were respectively
about twice the concentration of the blood levels, equivalent to 2-6 % of
the dose.
Furthermore, 3 h
after oral intake of [
14C]-GPC, the liver contained the highest
level of radioactivity (5-11 % of the dose). Other tissues with
radioactivity levels higher than blood were the kidneys (1-1.5% of the dose),
spleen and lung. The total radioactivity in the gut was 2-3 % of the administered
dose. Brain radioactivity was about half that found in blood.
After 72 h the
total remaining radioactivity for both labeled GPC-forms was spread over most
tissues and organs, but values higher than blood levels were found in liver,
kidneys, lung, and spleen.
The brain-to-blood
distribution of radioactivity was also measured time-dependently. After [
14G]-GPC,
the time courses of blood and brain concentrations were almost parallel within
32 h of dosing. For [
14C]-GPC, brain radioactivity increased
slowly up 24 h and then remained constant up to the end of the experiment.
Within this plateau it amounted about 50 % of blood radioactivity.
Another experiment,
with 300 mg/kg GPC orally administrated showed that the radioactivity was
registered in the brain as phosphatidylcholine. This suggests that choline from
GPC enters the brain and is reused for biosynthesis of phospholipids.
The excretion of
labeled GPC during 72 h was also investigated. Renal and fecal excretion
was comparable to the G- and C-labeled compounds, but low (10 % of the
dose).
By far the largest
part of the administered radioactivity was exhaled as
14CO2,
in accordance with established catabolic pathways of glycerol and choline
degradation.
This study showed that
in the rat, GPC is hydrolyzed to choline and glycerol-3-phosphate.
Some metabolic studies
in men from the literature will be described:
A comparative study of
free plasma choline levels following intramuscular administration of
l-alpha-glycerylphosphorylcholine and
citicoline in normal volunteers [9]
l-alpha-glycerylphosphorylcholine
(alpha-GPC) is a recently developed cognitive enhancer whose mode of action is
considered to involve the release of free choline, which is then utilized for
acetylcholine and phosphatidylcholine biosynthesis in the brain. The purpose of
this study was to evaluate the profile of free plasma choline levels following
a single i.m. dose of alpha-GPC in 12 normal volunteers. Citicoline (CTC),
which also acts as a choline precursor, was included for comparison purposes.
Each subject was studied on three randomized occasions, (i) on a control day in
the absence of drug administration (to evaluate the plasma level profile of
endogenous choline); (ii) after i.m. alpha-GPC (1,000 mg); and (iii) after
i.m. CTC (1,000 mg), respectively, with a washout period of at least
1-week between sessions. Blood samples for plasma choline HPLC determinations
were collected at regular intervals over a 6-h period. In the control session,
plasma choline levels remained stable during the sampling period. The
administration of alpha-GPC was associated with a rapid rise in plasma choline,
peak levels being usually observed at the first (0.25 h) or second (0.5 h)
sampling time after the injection. Thereafter, the concentration of choline
declined gradually and returned to near baseline values at the end of the observation
period. After the administration of CTC, plasma choline levels showed a similar
time course, but were considerably lower than those observed after the
administration of alpha-GPC.
Pharmacokinetics of
choline alfoscerate in the healthy volunteer [10]
This was a
pharmacokinetic study of i.m., i.v., and oral dosing with GPC. Four healthy
volunteers aged 19-24 years received GPC 1000 mg i.v., then subsequently
i.m., then by mouth, then received a placebo by mouth, in four separate
sessions separated by 1-week washouts. During each session blood was sampled
periodically over 10 hours. With i.v. administration of GPC, plasma total
choline peaked at 5 minutes
and returned to baseline by 4 hours. With i.m. administration, plasma total
choline peaked at 0.5 hours and returned to baseline by 6 hours. With oral GPC,
plasma total choline peaked at 3
hours, at a concentration slightly less than half that reached by i.m.
administration. But with oral GPC, the plasma total choline remained above
baseline at 10 hours. The
investigators concluded that i.v. and i.m. GPC both delivered virtually
identical total plasma doses (AUC, area under the curve), and that oral
administration delivered about half this amount.
Several clinical
studies showed that the tolerability of GPC was very good, even when administered
in very high doses for a long term.
Numerous clinical
studies have described the effects of high oral or parenteral doses of GPC on
several neuronal disorders:
Multi-center study of l-alpha-glyceryl-phosphorylcholine vs.
ST200 among patients with probable senile dementia of Alzheimer's type [11]
A multi-center,
randomized, controlled study compared the efficacy of
l-alpha-glyceryl-phosphorylcholine (alpha-GPC) and ST200
(acetyl-
l-carnitine) among 126
patients with probable senile dementia of Alzheimer's type (SDAT) of mild to
moderate degree. Efficacy was evaluated by means of behavioural scales and
psychometric tests. The results showed significant improvements in most
neuropsychological parameters in the alpha-GPC recipients. Improvements also
occurred in the ST200 recipients, but to a lesser extent. Tolerability was good
in both groups. These positive findings require replication in larger,
double-blind, longitudinal studies coupling clinical and biological evaluations.
Multi-center clinical study of
efficacy and tolerability of choline alfoscerate in patients with deficits in
higher mental function arising after an acute ischemic cerebrovascular attack
[12]
A total of 320
patients suffering mental decline after a cerebral ischemic attack received GPC
1000 mg i.m. once daily for 28 days, then 1200 mg by mouth for another 20
weeks. GPC significantly improved neurologic measures by week 4 (p<0.0001).
By week 24, the various cognitive and global clinical assessment scales showed
a "large improvement" of the mental status of the patients.
Clinical study of the
therapeutic effectiveness and tolerability of choline alfoscerate in 15
subjects with compromised cognitive functions subsequent to acute focal cerebral
ischemia [13]
This was a
small open trial that followed the usual GPC stroke protocol. Eleven patients
of average age 74 years received GPC 1000 mg i.m. once daily for 28 days, then
1200 mg orally daily for at least another 20 weeks. On various rating scales
(Mathew, MMSE, SCAG, the Psychic Evaluation Scale), GPC significantly improved results
with regard to memory, anxiety, emotional lability, sociability, spatial
orientation, aspects of language, eye deviation, confusion, vigilance, and
general mental sharpness. Two patients complained of slight, transitory heartburn
but did not withdraw from the trial. At 6 months the physicians judged 10/11 of
the patients as showing results excellent to fairly good, while 10/10 patients
judged themselves as having excellent to fairly good. Thus, in 5 open trials
completed with 2,972 patients variously afflicted by stroke, a regimen of 1
month of intramuscular GPC followed by 5 months of oral intake produced
clinically remarkable improvement. Given that the patients were generally too
ill to be given placebos, the degrees of clinical improvement over the 6-month
trial periods were well above those predictable as placebo effects. Many
patients showed accelerated improvement within the first 2-4 weeks and
continued to improve over the remaining 5 months. The physicians as well as the
patients uniformly judged GPC to be very well tolerated.
Effect of l-alpha-glyceryl-phosphorylcholine on
amnesia caused by scopolamine [14]
The present
study was carried out to test the effects of
l-alpha-glycerylphosphorylcholine
(
l-alpha-GFC) on memory impairment
induced by scopolamine in human subjects. Thirty-two healthy young volunteers
were randomly allocated to four different groups. They were given a ten-day pre-treatment
with either
l-alpha-GFC or
placebo, p.o., and on the eleventh day either scopolamine or placebo, i.m.
Before and 0.5, 1, 2, 3, and 6 h after
injection, the subjects were given attention and mnemonic tests. The findings
of this study indicate that the drug is able to antagonize impairment of
attention and memory induced by scopolamine.
Changes in the interaction
between CNS cholinergic and dopaminergic neurons induced by
l-alpha-glycerylphosphorylcholine, a
cholinomimetic drug [15]
The present
study investigates the cholinomimetic properties of the drug
l-alpha-glycerylphosphorylcholine
(alpha-GPC) at the CNS level. Experiments using tritium-labelled alpha-GPC
indicate that the drug reaches the brain after i.p. and p.o. administration. In
order to study the cholinomimetic properties of this drug, an indirect
functional index of cholinergic activation was used. In fact cholinergic
agonists induce an activation of striatal dopaminergic output. Administration
of alpha-GPC, both i.p. and p.o., increased striatal dihydroxyphenylacetic acid
(DOPAC) content. In addition, the
in
vitro
K+-stimulated dopamine release was increased in rats
treated
in vivo with alpha-GPC. Since
alpha-GPC has a weak displacing activity in QNB binding, the
in vivo cholinergic activity might be
due to the fact that this drug may increase the availability of choline for
acetylcholine synthesis leading to increased acetylcholine production. This
activity may be useful in those situations such as aging in which cholinergic
activity is deficient.
Choline alfoscerate in the
treatment of mental disorder after acute cerebrovascular accident [16]
An Italian multi-center
trial involved 425 patients aged 45-85 years, who were recruited from 44
centers distributed throughout the country. All the patients had suffered
cerebral ischemic attacks (stroke, TIA, or acute cerebral ischemia) within the
previous 10 days. It was another open trial, since the patients were too
severely afflicted to be subjected to placebo treatment. Patients who scored 35
or below on the Mathew Scale were eligible for the trial, but comatose patients
were not, nor were those not expected to live or judged unable to comply over
the 6-month period of the trial. As per the typical GPC stroke protocol,
treatment proceeded in two phases, first by giving GPC 1000 mg i.m.
in-hospital daily for 28 days, then switching to GPC 1200 mg by mouth for
5 more months (400 mg 3 times per day). Upon completion of the GPC i.m.
phase, there was an average improvement on the Mathew Scale of 18.56 %
(11.5 points, from 62.02 to 73.53). This was statistically highly significant over
baseline. A 20 % or greater improvement was seen in 168 (39.5 %) of
the patients. By this measure the more impaired, older patients (65-85 years)
were more likely to benefit than were the younger patients 45-64 years). During
the second phase, after discharge (GPC oral, for 5 months), evaluation was
based on clinical interviews and three assessment scales were used. On the MMSE
for cognitive functions, there was a 12.3 % improvement (from 21.53 at week 5 to 24.19 at 6 months). A 20 % or greater
improvement was seen in 126 patients (29.7 %). On the Global Deterioration
Scale, there was an average 20.2 % improvement. A 20 % or greater
improvement was seen in 180 patients (42.3 %). On the Crichton Geriatric
Rating Scale, which assesses mainly behavioural functioning, there was an
average 19.5 % improvement. A 20 % or greater improvement was seen in
166 patients (39.1 %). The researchers judged GPC to be effective and well
tolerated both parenterally and orally. They noted that despite the many drugs
with which GPC was co-administered, no single GPC-drug interaction was observed
clinically or in laboratory tests. GPC's benefits were consistent, and spanned functional
state as well as performance and social behavior. With the possible exception
of the MMSE (at 12.3 %), the degrees of improvement from GPC on the various
scales were well above that expected from a placebo, namely 12 % in at
least 20 % of such patients.
Glycerophosphocholine
is a natural, physiological, water-soluble and stable precursor of choline. It
is part of the daily nutrition and its levels are reduced on account of changed
dietary composition. The fortification of different foods with GPC can supply GPC
and choline as readily absorbed nutrients for enhancing cholinergenic metabolic
functions such as neurological and mental performance.
|
|
|
|
|
|
|