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Citicoline improves memory performance in elderly subjects
Abstract
Citicoline is a choline donor involved in the biosynthesis of brain phospholipids and acetylcholine extensively used in the treatment of neurodegenerative diseases. In this study we investigated the effects of the oral administration of citicoline alone (C1000:1000 mg/day; C500:500 mg/day) or in combination with nimodipine (C +NI:300 + 90 mg/day) during 4 weeks on memory performance in elderly subjects with memory deficits and without dementia (N = 24; age = 66.12 +/- 10.78 years; MMS score = 31.69 +/- 2.76). Results indicated that citicoline in comparison with placebo improves memory in free recall tasks, but not in recognition tests. A significant improvement in word recall (5.17 +/- 1.1 vs. 3.95 +/- 1.2 omissions; p < 0.005), immediate object recall (6.5 +/- 1.6 vs. 5.5 +/- 1.2 omission; p < 0.05) and delayed object recall (8.5 +/- 2.1 vs. 6.7 +/- 2.4 omissions; p < 0.005) was observed after citicoline treatment. Similar results were found in the three subgroups of treatment (8 subjects per group), suggesting that citicoline possesses memory-enhancing activity at doses of 300-1000 mg/day. A decrease in systolic blood pressure and minor changes in lymphocyte cell counting were also observed in old subjects after receiving citicoline. These effects are consistent with the vasoregulatory and neuroimmune actions of citicoline and suggest that this compound may improve memory by acting on mechanisms of brain neurotropism and cerebrovascular regulation. According to the present results, showing that citicoline improves memory performance in elderly subjects, we concluded that this molecule is suitable for the treatment of memory deficits in old people.
... Additionally, oral citicoline supplementation (1 g/d for 3 mo) improved logical memory score compared with placebo in men and women (n = 49/group, age 50-85 y) with relatively inefficient memory [i.e., scored below average of all recruited participants (17)]. Another openlabel clinical trial demonstrated a significant improvement in word and object recalls after citicoline supplementation (1 g/d) for 28 d (18). To date, no studies have investigated the effects of citicoline supplementation at 500 mg/d on memory in healthy elderly adults with age-associated memory impairment (AAMI). ...
... Although each cognitive test assessed distinct components of memory and tapped into different processes, composite score provides for a single outcome variable combining each cognitive test. Our observations are consistent with previous studies demonstrating beneficial effects of citicoline on memory (17,18). Episodic memory describes the ability to remember and recall specific events, paired with the content in which they occurred, such as identifying when and where an object was encountered (24). ...
Background
Supplementation of citicoline (CDP-choline), a naturally occurring mononucleotide, has shown beneficial effects on memory function and behavior in populations with a wide range of impairments. However, few studies have investigated its effect in healthy older populations.
Objective
The objective of this study was to investigate the effects of citicoline (Cognizin®), on memory in healthy elderly populations with age-associated memory impairment (AAMI).
Methods
A total of 100 healthy men and women aged between 50 and 85 y with AAMI participated in this randomized, double-blind, placebo-controlled trial. Participants were randomized to receive placebo (n = 51) or citicoline (n = 49; 500 mg/d) for 12 wk. Memory function was assessed at baseline and end of the intervention (12 wk) using computerized tests (Cambridge Brain Sciences, Ontario, Canada). Safety measurements included adverse events query, body weight, blood pressure, and hematology and metabolic panel. Intent-to-treat analysis was conducted using ANCOVA for the primary and secondary outcome variables with Bonferroni correction for multiple comparisons.
Results
A total of 99 out of 100 participants completed the study in its entirety. After the 12-wk intervention, participants supplemented with citicoline showed significantly greater improvements in secondary outcomes of episodic memory (assessed by the Paired Associate test), compared with those on placebo (mean: 0.15 vs. 0.06, respectively, P = 0.0025). Composite memory (secondary outcome), calculated using the scores of 4 memory tests, also significantly improved to a greater extent following citicoline supplementation (mean: 3.78) compared with placebo (mean: 0.72, P = 0.0052).
Conclusions
Dietary supplementation of citicoline for 12 wk improved overall memory performance, especially episodic memory, in healthy older males and females with AAMI. The findings suggest that regular consumption of citicoline may be safe and potentially beneficial against memory loss due to aging. This trial was registered at clinicaltrials.gov as NCT03369925.
... Based on these facts, many clinical trials have been conducted to assess the efficacy of citicoline in the treatment of cognitive disorders associated to brain aging, chronic cerebral vascular disease, and dementia [623]. Using magnetic resonance spectroscopy techniques, citicoline has been shown to stimulate phosphatidylcholine synthesis in the brain [624][625][626][627] and improves the energetic cerebral metabolism of elderly subjects [628], which is related to an improvement in their cognitive capacities [629], particularly memory [630][631][632] and reaction time [633]. In healthy volunteers, the administration of citicoline has been associated with improvement in attention [634,635], memory [636,637] and in some neurophysiological parameters [638][639][640][641]. ...
This review is based on the previous one published in 2016 (Secades JJ. Citicoline: pharmacological and clinical
review, 2016 update. Rev Neurol 2016; 63 (Supl 3): S1-S73), incorporating 176 new references, having all the information
available in the same document to facilitate the access to the information in one document. This review is focused on the
main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain
injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
... Based on these facts, many clinical trials have been conducted to assess the efficacy of citicoline in the treatment of cognitive disorders associated to brain aging, chronic cerebral vascular disease, and dementia [623]. Using magnetic resonance spectroscopy techniques, citicoline has been shown to stimulate phosphatidylcholine synthesis in the brain [624][625][626][627] and improves the energetic cerebral metabolism of elderly subjects [628], which is related to an improvement in their cognitive capacities [629], particularly memory [630][631][632] and reaction time [633]. In healthy volunteers, the administration of citicoline has been associated with improvement in attention [634,635], memory [636,637] and in some neurophysiological parameters [638][639][640][641]. ...
This review is based on the previous one published in 2016 (Secades JJ. Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol 2016; 63 (Supl 3): S1-S73), incorporating 176 new references, having all the information available in the same document to facilitate the access to the information in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
... In the second placebo-controlled, crossover study [46] the effects of oral citicoline (daily dose 500mg or 1,000mg) taken over 4 weeks by 24 elderly, nondemented subjects (18 male and 6 female, mean age 66.12 years, mean Mini-Mental Score 31.69) on memory performance were evaluated using neuropsychological tests assessing the following memory tasks: word recall, word recognition, immediate recall and delayed recall of objects, and recognition of objects. Prior to testing the effects of citicoline, the memory performance of the participants was compared to that of 24 younger persons (15 male and 9 females, mean age 29.20 years, mean Mini-Mental Score 34.41), and the memory of the older group was significantly less efficient in all 5 tests Aging and Disease • 8 (P<0.001, ...
Citicoline is the generic name of CDP-choline, a natural metabolite present in all living cells. Used in medicine as a drug since the 1980-s, citicoline was recently pronounced a food ingredient. When ingested, citicoline breaks down to cytidine and choline, which become incorporated into their respective normal metabolic pathways. Choline is a precursor of acetylcholine and phospholipids; these is a neurotransmitter pivotal for learning and memory and important constituents of neuronal membranes and myelin sheaths, respectively. Cytidine in humans is readily converted to uridine, which exerts a positive effect on synaptic function and supports the formation of synaptic membranes. Choline deficiency has been found to be correlated with memory dysfunction. Magnetic resonance spectroscopy studies showed that citicoline intake improves brain uptake of choline in older persons, suggestive of that it shall help in reversing early age-related cognitive changes. In randomized, placebo-controlled trials of cognitively normal middle-aged and elderly persons, positive effects of citicoline on memory efficacy were found. Similar effects of citicoline on memory indices were also found in patients suffering from mild cognitive impairment and some other neurological diseases. Altogether, the aforementioned data provide complex and unambiguous evidence supporting the claim that oral citicoline intake positively influences memory function in humans who encounter age-related memory impairment also in the absence of any detectable neurological or psychiatric disease.
... ЦДФ-холин улучшает показатели памяти у пожилых пациентов с нарушениями памяти, но без деменции (n=24; 66,12±10,78 года). На фоне применения ЦДФ-холина отмечено значительное улучшение запоминания слов (5,17±1,1 пропусков, контроль -3,95±1,2 пропусков; p<0,005), немедленного запоминания объекта (6,5±1,6 пропусков, контроль -5,5±1,2; p<0,05), отсроченного запоминания объекта (8,5±2,1, контроль -6,7±2,4, p<0,005) и также снижение систолического артериального давления [62]. ...
Objectives. To systematize publications on drugs based on cytidine diphosphocholine (CDP-choline). Materials and methods. Systematic computer analysis of all currently available publications on CDPcholine (1750 publications in PubMed) using topological analysis theory for big data. Results. CDP-choline is required for acetylcholine biosynthesis, phospholipid metabolism, and DNA methylation. This article sequentially considers the effects of CDP-choline on acetylcholinergic and other types of neurotransmission and the anti-inflammatory and neuroprotective effects of CDP-choline, as well as the influences of this molecule on fat metabolism and gene expression in the context of the postgenomic paradigm (particularly elevated expression of nicotinic and muscarinic acetylcholine receptors). Results from basic and clinical studies of CDP-choline in the treatment of cognitive impairments associated with cerebral ischemia and neurodegeneration are presented. Conclusions. The pharmacological effects of CDP-choline are realized via multiple molecular mechanisms contributing to the nootropic actions of this molecule.
... In laboratory animals, +Ch attenuates scopolamine-induced cognitive impairments, protects against the development of memory deficits in aging rats or rats raised in impoverished environments, facilitates the retention of learned behaviors in animals experiencing hypoxia, and attenuates cognitive deficits resulting from traumatic brain injury (Teather and Wurtman, 2005;Teather and Wurtman, 2003;Sigala et al., 1992;Guseva et al., 2008;Secades and Frontera, 1995). In humans, +Ch improves cognitive functioning following stroke and improves attention, verbal memory and memory efficiency in elderly individuals with poor memory, vascular dementia or Alzheimer's disease (Alvarez et al., 1997;Moreno, 2003;Garcia-Cobos et al., 2010;Clark et al., 1997). ...
Background
Choline supplementation (+Ch) improves cognitive function in impaired animals and humans. Chemotherapy-related cognitive deficits (CRCDs) occur in cancer patients, and these deficits persist following treatment, adversely impacting quality of life. To date, there are no approved treatments for this condition.
Aim
Because +Ch improves impaired memory, it was of interest to determine whether +Ch can attenuate spatial memory deficits induced by the chemotherapeutic agents doxorubicin (DOX) and cyclophosphamide (CYP).
Methods
Female BALB/C mice, 64 days of age, were trained in the Morris water maze and baseline performance determined on day 15. Following baseline assessment, mice were placed on +Ch diet (2.0% Ch) or remained on standard diet (0.12% Ch). Mice received intravenous injections of DOX (2.5 mg/kg) and CYP (25 mg/kg), or equivalent volumes of saline (0.9% NaCl), on days 16, 23, 30, and 37, and spatial memory was assessed weekly from day 22 to 71.
Results
DOX and CYP produced a prolonged impairment in spatial memory as indicated by an increased latency to the correct zone ( p < 0.05), and a decrease in time in the correct zone ( p < 0.05), % of total swim distance in the correct zone ( p < 0.05) and % entries to the correct zone ( p < 0.05). These effects were attenuated by +Ch.
Conclusion
Although it remains to be determined whether this effect extends to other cognitive domains and whether +Ch is prophylactic or therapeutic, these findings suggest that +Ch may be an effective intervention for CRCDs.
... ЦДФ-холин улучшает показатели памяти у пожилых пациентов с нарушениями памяти, но без деменции (n=24; 66,12±10,78 года). На фоне применения ЦДФ-холина отмечено значительное улучшение запоминания слов (5,17±1,1 пропусков, контроль -3,95±1,2 пропусков; p<0,005), немедленного запоминания объекта (6,5±1,6 пропусков, контроль -5,5±1,2; p<0,05), отсроченного запоминания объекта (8,5±2,1, контроль -6,7±2,4, p<0,005) и также снижение систолического артериального давления [62]. ...
Objective:
Systematization of the array of publications on cytidyldiphosphocholine (CDP-choline).
Material and methods:
Systematic computer analysis of all currently available publications on CDP-choline (1750 publications in PUBMED) using the topological theory of big data analysis.
Results:
CDP-choline is essential for acetylcholine biosynthesis, phospholipid metabolism, and DNA methylation. The article describes the effects of CDP-choline on acetylcholinergic and other types of neurotransmission, anti-inflammatory, neuroprotective and neurotrophic effects of CDP-choline. Also, the paper presents the effects of the molecule on lipid metabolism and gene expression within the post-genomic paradigm (in particular, an increase in the expression of nicotinic and muscarinic acetylcholine receptors). The results of fundamental and clinical studies of CDP-choline in the treatment of cognitive impairments associated with cerebral ischemia and neurodegeneration are presented.
Conclusion:
The pharmacological effects of CDP-choline are mediated through multiple molecular mechanisms that contribute to the nootropic action of this molecule.
Brain phosphatidylcholine (PC) levels are regulated by a balance between synthesis and hydrolysis. Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1α/β) activate phospholipase A2 (PLA2) and PC-phospholipase C (PC-PLC) to hydrolyze PC. PC hydrolysis by PLA2 releases free fatty acids including arachidonic acid, and lyso-PC, an inhibitor of CTP-phosphocholine cytidylyltransferase (CCT). Arachidonic acid metabolism by cyclooxygenases/lipoxygenases is a significant source of reactive oxygen species. CDP-choline might increase the PC levels by attenuating PLA2 stimulation and loss of CCT activity. TNF-α also stimulates proteolysis of CCT. TNF-α and IL-1β are induced in brain ischemia and may disrupt PC homeostasis by increasing its hydrolysis (increase PLA2 and PC-PLC activities) and inhibiting its synthesis (decrease CCT activity). The beneficial effects of CDP-choline may result by counteracting TNF-α and/or IL-1 mediated events, integrating cytokine biology and lipid metabolism. Re-evaluation of CDP-choline phase III stroke clinical trial data is encouraging and future trails are warranted. CDP-choline is non-xenobiotic, safe, well tolerated, and can be considered as one of the agents in multi-drug treatment of stroke.
Citicoline is an endogenous mononucleotide composed of ribose, cytosine, pyrophosphate, and choline, and an essential precursor for the synthesis of neuronal plasma membrane phospholipids, important as a rate-limiting step in phosphatidylcholine synthesis. Choline is a component of the diet and is produced in the brain, albeit in small amounts. The chapter discusses the broad spectrum of benefits in conditions associated with neurological disorders and dysfunctions that citicoline plays a role in, in addition to toxicological studies that lend support to its use as an oral dietary source.
Difference between citicoline and choline; bioavailability/pharmacokinetics; mechanism of action; clinical applications for its use in learning and memory, attention, Alzheimer's disease, and dementia, Parkinson's disease, stroke, and cerebral ischemia, traumatic head injuries; eye health and visual function, including amblyopia, glaucoma, ischemic optic neuropathy; substance abuse, infectious diseases, as well as, toxicology and safety, dosage, and drug interactions.
The major route of phosphatidylcholine (Ptd-choline) biosynthesis in mammalian cells is the CDP-choline pathway which involves stepwise conversion of choline to phosphocholine (P-choline), cytidine diphosphate choline (CDP-choline), and Ptd-choline. Our previous studies with electropermeabilized (EP) rat glioma (C6) cells have indicated that the intermediates of this pathway are not freely diffusible in the cell but are channeled toward synthesis of Ptd-choline (George, T.P., Morash, S.C., Cook, H.W., Byers, D.M., Palmer, F. B. St.C., and Spence, M.W. (1989) Biochim. Biophys. Acta 1004, 283-291). In this study, Ca(2+)-[ethylene-bis(oxyethylenenitrilo)]tetraacetic acid buffers were used to investigate the role of intracellular free Ca2+ levels in functional organization of this pathway in EP glioma cells. In EP cells reduction of free Ca2+ in the medium from 1.8 mM to less than 200 nM resulted in 2-3-fold stimulation of exogenous [3H]choline and [14C]P-choline incorporation into Ptd-choline whereas incorporation of exogenous CDP-[14C]choline was augmented 100-fold; there was no uptake or incorporation of labeled P-choline or CDP-choline in intact cells. In EP cells incubated at 1.8 mM Ca2+ the water-soluble products of choline metabolism (choline, P-choline, CDP-choline, and glycerophosphocholine) were retained at 37 degrees C; in contrast, in the presence of 100 nM Ca2+ there was uniform leakage of these metabolites. Experiments with hemicholinium-3, an inhibitor of choline transport, and EP cells at 100 nM Ca2+ show that linkage of choline transport and Ptd-choline biosynthesis is also dependent on Ca2+. These results suggest that channeling of intermediates in the CDP-choline pathway of Ptd-choline biosynthesis in glioma cells is mediated by intracellular Ca2+ levels that may coordinately regulate the steps involved in conversion of choline to Ptd-choline.
The phosphatidylcholine precursor, cytidine-diphosphocholine (CDP-choline), was injected intraperitoneally (IP) at the dose of 10 or 20 mg/kg/day for 20 days to 24-month-old male rats of the Sprague-Dawley strain that showed cognitive and motor deficits. The drug was also injected in animals with behavioral alterations induced pharmacologically with a single injection of the cholinergic receptor antagonist, scopolamine, with prenatal exposure to methylazoxymethanol (MAM rats), or 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 CDP-choline in all experimental groups. An improvement in motor performance and coordination in the rotorod and open field tests was also observed in aged rats. These results indicate that this drug affects central mechanisms involved in cognitive behaviors, probably through a cholinergic action.
The effects of cytidine (5') diphosphocholine (CDP-choline) on learning and memory were studied using conditioned reflex methods for passive avoidance and active avoidance with punishment reinforcement (step-through, step-down, shuttle box and maze), for active avoidance with alimentary reinforcement (staircase maze), and the Morris water maze. The majority of experiments involved comparative studies of the nootropic drugs meclofenoxate and/or piracetam. CDP-choline was administered orally, in some of the experiments also intraperitoneally, at doses of 10-500 mg/kg body weight once or twice daily for 5 or 7 days. In separate cases only single doses were administered. Trainings started one hour after the last dose of the drugs. Retention tests were given 3 h, 24 h, 7 days or 10 days after training. The results obtained with the different methods document CDP-choline's ability to improve learning and memory in rats and mice. No essential differences in the effects of CDP-choline were established upon oral and intraperitoneal administration of the drug. The learning- and memory-facilitating effects of CDP-choline were similar to those of meclofenoxate and piracetam. The results of the present study permit us to define CDP-choline as a substance capable of improving cognitive levels.
The basal and GH-releasing hormone-stimulated secretion of GH declines in the elderly. We tested the ability of cytidine 5'-diphosphocholine, a drug used in the treatment of stroke and Parkinson's disease, to alter GH secretion in 11 healthy elderly volunteers, aged 69-84. Each subject received an iv infusion of 2 g of cytidine 5'-diphosphocholine or normal saline. GHRH and TRH were also administered during cytidine 5'-diphosphocholine infusions. The infusion of cytidine 5'-diphosphocholine induced a 4-fold (p less than 0.05) increase in serum GH levels over basal values. A small increase in GH was seen after GHRH administration. However, the addition of GHRH to the cytidine 5'-diphosphocholine infusion resulted in a GH response which was significantly greater than that seen after GHRH alone; the integrated concentration of GH was more than 2-fold greater in the cytidine 5'-diphosphocholine treated group (706.85 +/- 185.1 vs 248.9 +/- 61.4 micrograms.l-1.(120 min)-1; p = 0.01). The PRL and TSH responses to TRH were not significantly affected by cytidine 5'-diphosphocholine infusion, indicating that dopaminergic mechanisms are not involved. These studies demonstrate that cytidine 5'-diphosphocholine can enhance basal and GHRH-stimulated GH release in the elderly, but the mechanism of action of the drug remains unclear.
Recent studies seem to indicate that the somatotropinergic system (STS) (GRF-SS-GH-SM axis) may be involved in the neuromodulation of higher activities of the central nervous system (CNS). In an attempt to demonstrate the influence of the STS on memory functions in humans, we have investigated the effects of acute administration of exogenous GRF vs. placebo on short-term memory (STM) in healthy young subjects. We gave GRF(1-29)NH2 (150 micrograms; i.v.) to a group of subjects (EG) (N = 17) and placebo (0.9% saline, 1 ml; i.v.) to a different group of subjects (CG) (N = 6). Prior to testing we presented a list of 20 neutral words (A1), and 2 hours after injection the same list (A2) and another list (B) of similar characteristics were presented in order to evaluate cognitive performance (CP). Basal CP (A1 list) was similar in EG and CG. Differences between EG and CG were found for both A2 (EG = 14.76 +/- 1.55 words vs. CG = 11.83 +/- 1.34 words, p less than 0.01) and B lists (EG = 12.17 +/- 1.68 words, p less than 0.005). According to the basal serum GH levels, EG subjects were divided into 2 subgroups: EG1 (N = 6), with high basal GH levels (11.57 +/- 4.47 ng/ml) and EG2 (N = 11), with low basal GH levels (1.55 +/- 1.71 ng/ml), similar to CG (1.3 +/- 1.53 ng/ml). GRF-induced GH response showed maxima 15 (28.15 +/- 11.71 ng/ml) and 30 min (28.09 +/- 17.07 ng/ml) after injection in EG1 and at 45 min (15.52 +/- 14.45 ng/ml) in EG2.(ABSTRACT TRUNCATED AT 250 WORDS)
Cold cytidine was intraventricularly administered into the brain of young rats, and its effect on CDP-choline, CDP-ethanolamine, and CMP pools followed for different time intervals and with various amounts of administered cytidine. The injected nucleoside produces a measureable increase of th concentrations of all three nucleotides. The increase produced by injecting 2.5 mumol of cytidine for brain does not essentially change with higher doses of injected nucleoside, except for CMP, whose increase reaches a maximum with 5 mumol of cytidine. A clear time dependence on cytidine administration was shown. The increases of the three nucleotide concentrations do not show a maximum till 60 min from administration into CMP and CDP-bases and measurably increases their endogenous brain pools. The compound is likely to enter metabolic events connected with phospholipid metabolism in brain.