LE Magazine September 2002
Page 1 of 4
Brain function-GPC
Oral choline alfoscerate counteracts
age-dependent loss of mossy fibers in the rat hippocampus.
Mossy fibers represent a major intrahippocampal associative
pathway. They consist of axons of granule cells of the dentate
gyrus and show an age-dependent loss as do the granule cells
of the dentate gyrus. The present study was designed to assess
whether long-term treatment of rats with choline alfoscerate
in their drinking water would be effective in countering the
loss of mossy fibers and of granule cells occurring with
aging. Choline alfoscerate is a precursor in the biosynthesis
of brain phospholipids and increases the bioavailability of
choline in nervous tissue. Male Sprague-Dawley rats of 18
months of age were divided into two groups. One group received
a daily dose of 100 mg/kg choline alfoscerate for six months;
the other group was used as an untreated control.
Twelve-month-old untreated animals were used as a reference
group. The area occupied by mossy fibers, as well as their
density, was significantly reduced in 24-month-old control
rats in comparison with 12-month-old rats. The same is true
for the density granule cells of the dentate gyrus, which was
decreased by about 20% in the oldest animals. In choline
alfoscerate-treated rats both the area occupied by mossy
fibers and their density were significantly higher than in
age-matched controls. Moreover, the number of granule neurons
of the hippocampus was higher by about 7% in choline
alfoscerate-treated than in control 24-month-old rats. The
above data suggest that choline alfoscerate treatment
counteracts some anatomical changes of the rat hippocampus
occurring in old age.
Mech Ageing Dev 1992;66(1):81-91
Long term choline alfoscerate
treatment counters age-dependent microanatomical changes in
rat brain.
1. The density of nerve cells and of silver-gold
impregnated fibres were evaluated in the hippocampus and in
the cerebellar cortex in adult (12-month-old) and old
(24-month-old) Sprague-Dawley rats. 2. The effects of
long-term choline alfoscerate (GFC) treatment (100 mg/kg/day
for six months) on the above parameters were investigated in
old rats. 3. The number of nerve cell profiles and the area
occupied by silver-gold impregnated fibers were decreased both
in the hippocampus and in the cerebellar cortex in old in
comparison with adult rats. 4. GFC treatment countered the
age-dependent reduction of nerve cells and silver-gold
impregnated fibers. The hippocampus was more sensitive than
the cerebellar cortex to the activity of GFC. 5. These results
suggest that GFC treatment is effective in slowing down the
expression of structural changes occurring in aging brain.
Prog Neuropsychopharmacol Biol
Psychiatry 1994 Sep;18(5):915-24
Effect of L-alpha
glycerylphosphorylcholine on muscarinic receptors and membrane
microviscosity of aged rat brain.
1. Old rats showed a significant decrease in the number of
muscarinic M(1) receptors and a significant increase in
membrane microviscosity in the striatum and hippocampus as
compared to young animals. In contrast, no significant changes
in the density of muscarinic M(2) receptors were observed with
aging. 2. Chronic treatment of aged rats with
L-alpha-glycerylphosphorylcholine (L-alpha-GPC) restored the
number of M(1) receptors to levels found in the striatum and
hippocampus from young animals. The same treatment to aged
rats partially restored membrane microviscosity in both
regions studied and hence increased membrane fluidity. 3. None
of the major metabolites of L-alpha-GPC (choline,
glycerophosphate or phosphorylcholine) was able to restore the
number of striatal and hippocampal M(1) sites and membrane
microviscosity of aged rats, neither did any of these
treatments (including treatment with L-alpha-GPC) modify the
level of M(1) receptors and microviscosity values in young
rats.
Prog Neuropsychopharmacol Biol
Psychiatry 1996 Feb;20(2):323-39
Alzheimer’s disease and senile
dementia: loss of neurons in the basal forebrain.
Recent evidence indicates that the nucleus basalis of
Meynert, a distinct population of basal forebrain neurons, is
a major source of cholinergic innervation of the cerebral
cortex. Postmortem studies have previously demonstrated
profound reduction in the presynaptic markers for cholinergic
neurons in the cortex of patients with Alzheimer’s
disease and senile dementia of the Alzheimer’s type. The
results of this study show that neurons of the nucleus basalis
of Meynert undergo a profound (greater than 75%) and selective
degeneration in these patients and provide a pathological
substrate of the cholinergic deficiency in their brains.
Demonstration of selective degeneration of such neurons
represents the first documentation of a loss of a
transmitter-specific neuronal population in a major disorder
of higher cortical function and, as such, points to a critical
subcortical lesion in Alzheimer’s patients.
Science 1982 Mar
5;215(4537):1237-9
Treatment of cognitive dysfunction
associated with Alzheimer’s disease with cholinergic
precursors. Ineffective treatments or inappropriate
approaches?
The observations of the loss of cholinergic function in
neocortex and hippocampus in Alzheimer’s disease (AD)
developed the hypothesis that replacement of cholinergic
function may be of therapeutic benefit to AD patients. The
different approaches proposed or tested included intervention
with acetylcholine (ACh) precursors, stimulation of ACh
release, use of muscarinic or nicotinic receptor agonists and
acetylcholinesterase (AChE) or cholinesterase (ChE)
inhibition. Inhibition of endogenous ACh degradation through
ChE inhibitors and precursor loading were treatments more
largely investigated in clinical trials. Of the numerous
compounds in development for the treatment of AD, AChE and ChE
inhibitors are the most clinically advanced, although clinical
trials conducted to date did not always confirm a significant
benefit of these drugs on all symptom domains of AD. The first
attempts in the treatment of AD with cholinergic precursors
did not confirm a clinical utility of this class of compounds
in well-controlled clinical trials. However, cholinergic
precursors most largely used, such as choline and
phosphatidylcholine (lecithin), were probably not suitable for
enhancing brain levels of ACh. Other phospholipids involved in
choline biosynthetic pathways, such as CDP-choline, choline
alphoscerate and phosphatidylserine clearly enhanced ACh
availability or release and provided a modest improvement of
cognitive dysfunction in AD, these effects being more
pronounced with choline alphoscerate. Although some positive
results cannot be generalized due to the small numbers of
patients studied, they probably would justify reconsideration
of the most promising molecules in larger carefully controlled
trials.
Mech Ageing Dev 2001
Nov;122(16):2025-40
Multicentre study of
l-alpha-glyceryl-phosphorylcholine vs ST200 among patients
with probable senile dementia of Alzheimer’s type.
A multicentre, 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 determinations.
Drugs Aging 1993
Mar-Apr;3(2):159-64
Alpha-glycerophosphocholine in the
mental recovery of cerebral ischemic attacks. An Italian
multicenter clinical trial.
The clinical efficacy and the tolerability of
alpha-glycerophosphocholine (alpha-GPC), a drug able to
provide high levels of choline for the nervous cells of the
brain and to protect their cell walls, have been tested in a
clinical open multicenter trial on 2,044 patients suffering
from recent stroke or transient ischemic attacks. alpha-GPC
was administered after the attack at the daily dose of 1000 mg
im for 28 days and orally at the dose of 400 mg tid during the
following five months after the first phase. The evaluation of
the efficacy on the psychic recovery was done by the Mathew
Scale (MS) during the period of im drug administration, and
using the Mini Mental State Test (MMST), the Crichton Rating
Scale (CRS) and the Global Deterioration Scale (GDS) during
the following period of oral administration. The MS mean
increased 15.9 points in 28 days in a statistically
significant way (p < 0.001) from 58.7 to 74.6. At the end
of the five month oral administration, the CRS mean
significantly decreased 4.3 points, from 20.2 to 15.9 (p <
0.001); the MMST mean significantly increased (p < 0.001)
from 21 to 24.3 at the end of the trial, reaching the
“normality” score at the 3rd month assessment. The
GDS score at the end of the trial corresponded to “no
cognitive decline” or “forgetfulness” in 71% of
the patients. Adverse events were complained of by 44 patients
(2.14%); in 14 (0.7%) the investigator preferred to
discontinue therapy. The most frequent complaints were
heartburn (0.7%), nausea-vomit (0.5%), insomnia-excitation
(0.4%), and headache (0.2%). The trial confirms the
therapeutic role of alpha-GPC on the cognitive recovery of
patients with acute stroke or TIA, and the low percentage of
adverse events confirms its excellent tolerability.
Ann N Y Acad Sci 1994 Jun
30;717:253-69
Choline alphoscerate in cognitive
decline and in acute cerebrovascular disease: an analysis of
published clinical data.
This paper has reviewed the documentation on the clinical
efficacy of choline alphoscerate, a cholinergic precursor,
considered as a centrally acting parasympathomimetic drug in
dementia disorders and in acute cerebrovascular disease.
Thirteen published clinical trials, examining in total 4,054
patients, have evaluated the use of choline alphoscerate in
various forms of dementia disorders of degenerative, vascular
or combined origin, such as senile dementia of the
Alzheimer’s type (SDAT) or vascular dementia (VaD) and in
acute cerebrovascular diseases, such as transitory ischemic
attack (TIA) and stroke. Analysis has assessed the design of
each study, in particular with respect to experimental design,
number of cases, duration of treatment and tests used to
evaluate drug clinical efficacy. Most of the 10 studies
performed in dementia disorders were controlled trials versus
a reference drug or placebo. Overall, 1,570 patients were
assessed in these studies, 854 of which in controlled trials.
As detected by validated and appropriate tests, such as Mini
Mental State Evaluation (MMSE) in SDAT and Sandoz Clinical
Assessment Geriatric (SCAG) in VaD, administration of choline
alphoscerate significantly improved patient clinical
condition. Clinical results obtained with choline alphoscerate
were superior or equivalent to those observed in control
groups under active treatment and superior to the results
observed in placebo groups. Analysis stresses the clear
internal consistency of clinical data gathered by different
experimental situations on the drug effect, especially with
regard to the cognitive symptoms (memory, attention)
characterizing the clinical picture of adult-onset dementia
disorders. The therapeutic usefulness of choline alphoscerate
in relieving cognitive symptoms of chronic cerebral
deterioration differentiates this drug from cholinergic
precursors used in the past, such as choline and lecithin.
Three uncontrolled trials were performed with choline
alphoscerate in acute cerebrovascular stroke and TIA, totaling
2,484 patients. The results of these trials suggest that this
drug might favor functional recovery of patients with cerebral
stroke and should be confirmed in future investigations aimed
at establishing the efficacy of the drug in achieving
functional recovery of patients with acute cerebrovascular
disease.
Mech Ageing Dev 2001
Nov;122(16):2041-55
Behavioral effects of
L-alpha-glycerylphosphorylcholine: influence on cognitive
mechanisms in the rat.
The phosphorylcholine precursor,
L-alpha-glycerylphosphorylcholine (alpha-GPC), was injected at
the dose of 100 mg/kg/day for 20 days to aged male rats of the
Sprague-Dawley strain, 24 months old, showing a deficit of
learning and memory capacity. The drug was also administered
to rats with amnesia induced pharmacologically with bilateral
injections of kainic acid into the nucleus basalis
magnocellularis (NBM). Learning and memory capacity of the
animals, studied with tests of active and passive avoidance
behavior, was improved after treatment with alpha-GPC in all
experimental groups. These results indicate that this drug
affects cognitive mechanisms in the rat through an involvement
of central neurotransmission.
Pharmacol Biochem Behav 1992
Feb;41(2):445-8
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