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Life Extension Magazine January 2011


Influence of phosphatidylserine on cognitive performance and cortical activity after induced stress.

The aim of this study was to investigate the effect of phosphatidylserine (PS) on cognition and cortical activity after mental stress. After familiarization, 16 healthy subjects completed cognitive tasks after induced stress in a test-re-test design (T1 and T2). Directly after T1, subjects were assigned double-blind to either PS or placebo groups followed by T2 after 42 days. At T1 and T2, cortical activity was measured at baseline and immediately after stress with cognitive tasks using electro-encephalography (EEG). EEG was recorded at 17 electrode positions and fast Fourier transforms (FFT) determined power at Theta, Alpha-1, Alpha-2, Beta-1 and Beta-2. Statistics were calculated using ANOVA (group x trial x time). The main finding of the study was that chronic supplementation of phosphatidylserine significantly decreases Beta-1 power in right hemispheric frontal brain regions (F8; P < 0.05) before and after induced stress. The results for Beta-1 power in the PS group were connected to a more relaxed state compared to the controls.

Nutr Neurosci. 2008 Jun;11(3):103-10

Omega-3 DHA and EPA for cognition, behavior, and mood: clinical findings and structural-functional synergies with cell membrane phospholipids.

The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are orthomolecular, conditionally essential nutrients that enhance quality of life and lower the risk of premature death. They function exclusively via cell membranes, in which they are anchored by phospholipid molecules. DHA is proven essential to pre- and postnatal brain development, whereas EPA seems more influential on behavior and mood. Both DHA and EPA generate neuroprotective metabolites. In double-blind, randomized, controlled trials, DHA and EPA combinations have been shown to benefit attention deficit/hyperactivity disorder (AD/HD), autism, dyspraxia, dyslexia, and aggression. For the affective disorders, meta-analyses confirm benefits in major depressive disorder (MDD) and bipolar disorder, with promising results in schizophrenia and initial benefit for borderline personality disorder. Accelerated cognitive decline and mild cognitive impairment (MCI) correlate with lowered tissue levels of DHA/EPA, and supplementation has improved cognitive function. Huntington disease has responded to EPA. Omega-3 phospholipid supplements that combine DHA/EPA and phospholipids into the same molecule have shown marked promise in early clinical trials. Phosphatidylserine with DHA/EPA attached (Omega-3 PS) has been shown to alleviate AD/HD symptoms. Krill omega-3 phospholipids, containing mostly phosphatidylcholine (PC) with DHA/EPA attached, markedly outperformed conventional fish oil DHA/EPA triglycerides in double-blind trials for premenstrual syndrome/dysmenorrhea and for normalizing blood lipid profiles. Krill omega-3 phospholipids demonstrated anti-inflammatory activity, lowering C-reactive protein (CRP) levels in a double-blind trial. Utilizing DHA and EPA together with phospholipids and membrane antioxidants to achieve a triple cell membrane synergy may further diversify their currently wide range of clinical applications.

Altern Med Rev. 2007 Sep;12(3):207-27

Cognition-enhancing properties of subchronic phosphatidylserine (PS) treatment in middle-aged rats: comparison of bovine cortex PS with egg PS and soybean PS.

There are various clinical and non-clinical studies that have indicated that phosphatidylserine (PS) treatment can improve cognitive functions in humans and other animals. However, treatment with PS derived from bovine cortex is not desirable because of possible transfer of infectious diseases. The present study investigated the cognition-enhancing properties of different types of PS in rats. Seventeen-month-old male Fischer 344 rats were treated daily with a dose of 15 mg/kg of PS derived from bovine cortex (BC-PS), soybean (S-PS), egg (E-PS), or vehicle (n = 9 for each group). The effects of treatment were evaluated in three different behavioral tests. An open field test was conducted to examine the effects of treatment on psychomotor behavior. Two other tests (Morris water escape task and two-way active avoidance) assessed treatment effects on the cognitive performance of rats. Treatment with the different forms of PS did not affect the psychomotor or spatial discrimination performance of the rats. In accordance with previous studies, the cognition-enhancing effects of BC-PS were observed in the two-way active avoidance task. It appeared that the cognition-enhancing effects of S-PS were not different from those of BC-PS. The performance of rats treated with E-PS did not deviate from that of vehicle-treated rats. On the basis of the present study, it was concluded that S-PS, but not E-PS, may have comparable effects on cognition when compared with BC-PS.

Nutrition. 1999 Oct;15(10):778-83

Cognitive decline in the elderly: a double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration.

This double-blind study assesses the therapeutic efficacy and the safety of oral treatment with phosphatidylserine (BC-PS) vs placebo (300 mg/day for 6 months) in a group of geriatric patients with cognitive impairment. A total of 494 elderly patients (age between 65 and 93 years), with moderate to severe cognitive decline, according to the Mini Mental State Examination and Global Deterioration Scale, were recruited in 23 Geriatric or General Medicine Units in Northeastern Italy. Sixty-nine patients dropped out within the 6-month trial period. Patients were examined just before starting therapy, and 3 and 6 months thereafter. The efficacy of treatment compared to placebo was measured on the basis of changes occurring in behavior and cognitive performance using the Plutchik Geriatric Rating Scale and the Buschke Selective Reminding Test. Statistically significant improvements in the phosphatidylserine-treated group compared to placebo were observed both in terms of behavioral and cognitive parameters. In addition, clinical evaluation and laboratory tests demonstrated that BC-PS was well tolerated. These results are clinically important since the patients were representative of the geriatric population commonly met in clinical practice.

Aging (Milano). 1993 Apr;5(2):123-33

Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials.

BACKGROUND: Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine) in delaying the conversion from MCI to Alzheimer disease or dementia. METHODS AND FINDINGS: The terms “donepezil”, “rivastigmine”, “galantamine”, and “mild cognitive impairment” and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO) and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and Published and unpublished studies were included if they were randomized clinical trials published (or described) in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine). Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y) to 25% (over 3 y) among treated patients, and from 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of conversion: 0.85 (95% confidence interval 0.64-1.12), and 0.84 (0.57-1.25). Statistically significant differences emerged for three secondary end points. However, when adjusting for multiple comparisons, only one difference remained significant (i.e., the rate of atrophy in the whole brain). CONCLUSIONS: The use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible. The uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity of these trials.

PLoS Med. 2007 Nov 27;4(11):e338

A role of GABA analogues in the treatment of neurological diseases.

Gamma-Amino butyric acid is an extremely important inhibitory neurotransmitter in the mammalian central nervous system and is essential for the overall balance between neuronal excitation and inhibition. It is well documented that GABA deficiency is associated with several important neurological disorders such as Huntington’s chorea, Parkinson’s and Alzheimer’s disease and other psychiatric disorders, like anxiety, depression, pain, panic, or mania. Although, it is known that increasing the brain concentration of GABA prevents convulsions, the high polarity and flexible structure of this compound are probably responsible for its inefficiency as an anticonvulsant when administered orally or intravenously. To resolve this problem, GABA analogues are being designed. Over recent years, there has been increasing interest in the synthesis and pharmacological effect of new GABA derivatives, which can be considered as potent drugs in the treatment of neurodegenerative disorders.

Curr Med Chem. 2010;17(22):2338-47

The cholinergic hypothesis of geriatric memory dysfunction.

Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.

Science. 1982 Jul 30;217(4558):408-14

Chronic L-alpha-glyceryl-phosphoryl-choline increases inositol phosphate formation in brain slices and neuronal cultures.

Repeated, but not single injections of L-alpha-glyceryl-phosphorylcholine (alpha GPC) significantly increased basal [3H]inositol monophosphate (InsP) formation in hippocampal, cortical, and striatal slices of male rats. The effect was dose-dependent and was accompanied by an increased incorporation of [3H]inositol into the phospholipid fraction. Incubation of brain slices with different neurotransmitter antagonists, such as atropine, prazosin, or L-2-amino-4-phosphonobutanoate (L-AP4) did not modify the increase in [3H]InsP formation produced by alpha GPC, suggesting that the effect is not mediated by an increased availability of a specific neurotransmitter. Similar results were obtained in cerebellar and cortico-striatal neurones in primary culture exposed to daily addition of alpha GPC since the second day of maturation in vitro. We suggest that alpha GPC treatment may result in an increased rate of phospholipid synthesis, including the phosphoinositides available for signal transduction at central nervous system level.

Pharmacol Toxicol. 1994 Feb;74(2):95-100

Long term choline alfoscerate treatment counters age-dependent microanatomical changes in rat brain.

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 6 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 fibres 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 fibres. 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

Cholinergic neurotransmission in the hippocampus of aged rats: influence of L-alpha-glycerylphosphorylcholine treatment.

The influence of aging and of L-alpha-glycerylphos-phorylcholine (GFC) treatment on the acetylcholine synthesizing and degradating enzymes choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) and on cholinergic muscarinic M-1 and M-2 receptors were assessed in the hippocampus using immunocytochemical, histochemical and radioligand binding techniques, respectively. The investigation was performed on male Wistar rats of 2 months (young), 12 months (adult), and 27 months (old). Oral GFC was given at the dose of 100 mg/Kg/day from the 21st to the 27th month of age. ChAT revealed the highest immunostaining in the hippocampus of adult rats followed by young and old animals. The highest expression of AChE reactivity was noticeable in the hippocampus of adult rats followed by old and young animals. Treatment with GFC restored in part ChAT immunoreactivity and AChE reactivity in the hippocampus of aged rats. Muscarinic M-1 and M-2 receptors were labeled with [3H]-pirenzepine and [3H]-AF-DX-116 respectively. The density of M-1 muscarinic receptors decreased with age, whereas M-2 muscarinic receptors did not change. GFC treatment countered in part the loss of M-1 receptors in old rats and was without effect on M-2 receptors.

Ann N Y Acad Sci. 1993 Sep 24;695:311-3

Oral choline alfoscerate counteracts age-dependent loss of mossy fibres in the rat hippocampus.

Mossy fibres 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 fibres 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 6 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 fibres, 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 fibres 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

Nerve growth factor receptor immunoreactivity in the cerebellar cortex of aged rats: effect of choline alfoscerate treatment.

The rat cerebellar cortex represents an interesting animal model for the analysis of age-dependent changes in brain microanatomy and function. Moreover, the cerebellar cortex contains detectable amounts of nerve growth factor (NGF) and express NGF receptors, which are sensitive to aging. Previous studies of our group have shown that treatment with choline alfoscerate (alpha-glyceryl-phosphorylcholine) countered the loss of nerve cells and fibers occurring with age in the cerebellar cortex. The present study was designed to assess whether treatment for 6 months with a daily dose of 100 mg/kg of choline alfoscerate has any effect on the expression of NGF receptor immunoreactivity in male Wistar rats of 24 months of age. Twelve-month-old rats were used as an adult reference group. NGF receptor immunoreactivity which was developed in the 3 layers of the cerebellar cortex in adult rats was decreased in the neuropil of the molecular layer and in the cytoplasm of Purkinje neurons of rats of 24 months. The number of NGF receptor immunoreactive Purkinje neurons was also lower in the oldest age group, whereas the NGF receptor immunoreactivity in the cytoplasm of granule neurons was unchanged. Treatment with choline alfoscerate increased NGF receptor immunoreactivity in the molecular layer and in the cytoplasm of Purkinje neurons as well as the number of immunoreactive Purkinje neurons but was without effect on NGF receptor immunoreactivity in the granule neurons. These results suggest that choline alfoscerate treatment may increase the expression of NGF receptors in the rat cerebellar cortex.

Mech Ageing Dev. 1993 Jun;69(1-2):119-27

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