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September 2002

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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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