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Citicoline: A Superior Form of Choline?

Authors:
  • Mossakowski Medical Research Center, Polish Academy of Sciences
Article

Citicoline: A Superior Form of Choline?

Abstract

Medicines containing citicoline (cytidine-diphosphocholine) as an active principle have been marketed since the 1970s as nootropic and psychostimulant drugs available on prescription. Recently, the inner salt variant of this substance was pronounced a food ingredient in the major world markets. However, in the EU no nutrition or health claim has been authorized for use in commercial communications concerning its properties. Citicoline is considered a dietetic source of choline and cytidine. Cytidine does not have any health claim authorized either, but there are claims authorized for choline, concerning its contribution to normal lipid metabolism, maintenance of normal liver function, and normal homocysteine metabolism. The applicability of these claims to citicoline is discussed, leading to the conclusion that the issue is not a trivial one. Intriguing data, showing that on a molar mass basis citicoline is significantly less toxic than choline, are also analyzed. It is hypothesized that, compared to choline moiety in other dietary sources such as phosphatidylcholine, choline in citicoline is less prone to conversion to trimethylamine (TMA) and its putative atherogenic N-oxide (TMAO). Epidemiological studies have suggested that choline supplementation may improve cognitive performance, and for this application citicoline may be safer and more efficacious.
nutrients
Discussion
Citicoline: A Superior Form of Choline?
Kamil Synoradzki and Paweł Grieb *
Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of
Sciences, 5 Pawinskiego Street, 02-106 Warsaw, Poland
*Correspondence: pgrieb@imdik.pan.pl
Received: 11 June 2019; Accepted: 10 July 2019; Published: 12 July 2019


Abstract:
Medicines containing citicoline (cytidine-diphosphocholine) as an active principle have
been marketed since the 1970s as nootropic and psychostimulant drugs available on prescription.
Recently, the inner salt variant of this substance was pronounced a food ingredient in the major world
markets. However, in the EU no nutrition or health claim has been authorized for use in commercial
communications concerning its properties. Citicoline is considered a dietetic source of choline and
cytidine. Cytidine does not have any health claim authorized either, but there are claims authorized
for choline, concerning its contribution to normal lipid metabolism, maintenance of normal liver
function, and normal homocysteine metabolism. The applicability of these claims to citicoline is
discussed, leading to the conclusion that the issue is not a trivial one. Intriguing data, showing
that on a molar mass basis citicoline is significantly less toxic than choline, are also analyzed. It is
hypothesized that, compared to choline moiety in other dietary sources such as phosphatidylcholine,
choline in citicoline is less prone to conversion to trimethylamine (TMA) and its putative atherogenic
N-oxide (TMAO). Epidemiological studies have suggested that choline supplementation may improve
cognitive performance, and for this application citicoline may be safer and more ecacious.
Keywords: citicoline; choline; health claims; toxicity; trimethylamine oxide; procognitive eects
1. Introduction
Citicoline is the international nonproprietary name (INN) for cytidine-diphosphocholine
(CDP-Cho). The substance is commercially available in two forms, sodium salt and inner salt.
Citicoline sodium salt, classified as a nootropic and psychostimulant [
1
], is an active principle of a
variety of prescription drugs, either injectables or oral formulations. In 2009 in the USA, citicoline
(inner salt) was self-armed by the Japanese company Kyowa-Hakko as GRAS (generally regarded as
safe) [
2
], and in 2014 it was announced as a novel food ingredient by the appropriate Implementing
Decision of the Commission of the European Union [3].
The aforementioned EU Implementing Decision states that citicoline may be placed on the EU
market, where it is intended to be used in food supplements aimed at a target population of middle-aged
to elderly adults at a maximum level of 500 mg/day, and in dietary foods for special medical purposes
with a maximum dose of 250 mg per serving and with a maximum daily consumption level of 1000 mg
from these types of foods.
2. Citicoline in Food Supplements: The Issue of Health Claims
Classifying citicoline as a food ingredient suitable for food supplements should make it widely
available, but in the highly regulated market of the European Union its marketing is problematic.
According to the EU Regulation EC No 1924/2006 [
4
], all nutrition and health claims made in
commercial communications concerning food supplements must be formally authorized following
scientific assessment performed by the European Food Safety Agency (EFSA). Citicoline does not
Nutrients 2019,11, 1569; doi:10.3390/nu11071569 www.mdpi.com/journal/nutrients
Nutrients 2019,11, 1569 2 of 8
have any nutrition or health claim authorized up to date. Moreover, application for authorization of a
health claim (related to citicoline and maintenance of normal vision) was turned down by the EFSA
because it was concluded that a cause and eect relationship has not been established between the
consumption of citicoline and the maintenance of normal vision [
5
]. Does this mean that, although it is
legal to introduce citicoline to the EU market in a food supplement, information provided about this
supplement should not contain any information about its specific nutritional and/or functional value?
Looking through the positive EFSA Scientific Opinion on citicoline issued prior to the
aforementioned implementing decision [
6
], we find the reference to the observation that, both
in humans and in rats, upon ingestion citicoline undergoes quick hydrolysis, breaking down to
choline and cytidine [
7
], which then undergo further metabolism and incorporation into normal
pathways of metabolism [
8
]. Cytidine, a pyrimidine nucleoside which in humans interconverts with
uridine [
9
], undergoes intracellular phosphorylations to cytidine triphosphate (CTP), which participates
in phospholipids synthesis via the Kennedy pathway, and may also be incorporated into nucleic acids.
Choline is either phosphorylated to phosphocholine and participates in phosphatidylcholine synthesis,
or oxidized to betaine, which serves as a methyl donor in the betaine-homocysteine methyltransferase
reaction. Also, in cholinergic neurons, choline is acetylated to form the neurotransmitter acetylcholine.
We may, therefore, consider citicoline as a source of choline and cytidine. Whereas there is no
nutrition or health claim authorized for cytidine either, there are three such claims authorized for
choline. These are so-called functional claims relating to the beneficial eects of a nutrient on certain
normal bodily functions. The first two state that choline contributes to normal lipid metabolism
and to the maintenance of normal liver function. These claims were accepted because they were
substantiated by observations that choline deficiency is associated with signs of liver damage (elevated
serum alanine aminotransferase activity) and the development of fatty liver (hepatosteatosis) in
humans fed choline-free total parenteral nutrition solutions, whose eects can be reversed by the
administration of dietary choline [
10
,
11
]. The third claim, stating that choline contributes to normal
homocysteine metabolism, was substantiated by the observations that choline-depleted diets tend to
increase plasma concentrations of homocysteine [
12
], whereas human observational [
13
,
14
] as well
as intervention [
15
] studies supported the inverse association between dietary choline and blood
concentrations of homocysteine. Of note is that in the aforementioned intervention study, choline was
supplied orally in the form of phosphatidylcholine (lecithin).
At the same time, health claims stating that choline contributes to the maintenance of normal
neurological function and normal cognitive function were rejected by the EFSA because cause and
eect relationships have not been established between the consumption of choline and the claimed
eects [
16
]. One of the reasons was that some references that presented support for the claimed eects
described studies that did not evaluate choline, but, for example, citicoline. A possible explanation of
this paradox is that at the date of issuing scientific opinion on the health claims concerning choline (i.e.,
year 2011), citicoline was not yet appreciated by EFSA experts as the dietary source of choline. Indeed,
natural foods do not contain any significant amount of this substance.
There is no direct proof that citicoline intake can reverse either elevated serum alanine
aminotransferase activity or the development of fatty liver in people who are choline-deficient.
There is also no direct proof that citicoline intake may lower homocysteine in blood. On the contrary,
single oral administration of a high dose of citicoline (1 g/kg b.w.) to rats resulted in a transient increase
of plasma homocysteine, but when a lower dose was supplemented in the diet for two months, plasma
homocysteine remained unchanged [
17
]. At the same time there is no reasonable doubt that oral intake
of citicoline is a safe and ecient method of delivery of choline to the human body.
It might perhaps be concluded that the issue of the applicability to citicoline of health claims
pertaining to choline (and apparently also to some of its derivatives, such as phosphatidylcholine)
is merely a legal problem that shall be settled accordingly by the appropriate authorities. On the
other hand, a health claim authorized almost a decade ago may not be supported in its entirety by the
contemporary scientific data. Current guidelines for the management of fatty liver do not mention
Nutrients 2019,11, 1569 3 of 8
supplementation with choline or its derivatives [
18
]. Likewise, folic acid, vitamin B
6
, vitamin B
12
, and
betaine, but not cholines, are listed among nutrients that may counteract hyperhomocysteinemia [
19
].
3. Citicoline as a Source of Choline: The Issue of Acute Toxicity
It is well established that following ingestion citicoline is fully absorbed and catabolized to
cytidine and choline, which enter their respective metabolic pools in the body [
20
22
]. However,
the particulars of its absorption, hydrolysis, and dephosphorylation(s) are a bit unclear. Citicoline
contains equimolar amounts of choline and cytidine. Following citicoline ingestion in rats, the increase
in both plasma cytidine and choline occurred quickly, but the molar increase in plasma choline was
markedly smaller [
23
]. In a human study [
24
], oral citicoline resulted in increases in plasma choline
and uridine that were similar in timing and magnitude, but in the other human study, the increase in
plasma choline following citicoline ingestion was biphasic and delayed [
25
]. It has been suggested
that citicoline is absorbed intact and its hydrolysis occurs in the liver and is coupled with a selective
withdrawal of choline from blood [
26
]. Following oral citicoline intake in humans, the quantitative
transformation of cytidine to uridine occurring in the intestine or liver was also postulated [24].
Absorption of intact citicoline molecules from the intestine to blood could also be helpful for
explaining dierences of acute toxicity of citicoline versus choline upon dierent routes of administration
(Figure 1).
Nutrients 2019, 11, x FOR PEER REVIEW 3 of 8
supplementation with choline or its derivatives [18]. Likewise, folic acid, vitamin B6, vitamin B12, and
betaine, but not cholines, are listed among nutrients that may counteract hyperhomocysteinemia [19].
3. Citicoline as a Source of Choline: The Issue of Acute Toxicity
It is well established that following ingestion citicoline is fully absorbed and catabolized to
cytidine and choline, which enter their respective metabolic pools in the body [20–22]. However, the
particulars of its absorption, hydrolysis, and dephosphorylation(s) are a bit unclear. Citicoline
contains equimolar amounts of choline and cytidine. Following citicoline ingestion in rats, the
increase in both plasma cytidine and choline occurred quickly, but the molar increase in plasma
choline was markedly smaller [23]. In a human study [24], oral citicoline resulted in increases in
plasma choline and uridine that were similar in timing and magnitude, but in the other human study,
the increase in plasma choline following citicoline ingestion was biphasic and delayed [25]. It has
been suggested that citicoline is absorbed intact and its hydrolysis occurs in the liver and is coupled
with a selective withdrawal of choline from blood [26]. Following oral citicoline intake in humans,
the quantitative transformation of cytidine to uridine occurring in the intestine or liver was also
postulated [24].
Absorption of intact citicoline molecules from the intestine to blood could also be helpful for
explaining differences of acute toxicity of citicoline versus choline upon different routes of
administration (Figure 1).
Figure 1. Median lethal dose of choline chloride and citicoline in mice (A,B) and rats (C,D) expressed
in milligrams (A,C) or in millimoles (B,D) per kilogram body weight, depending on the route
administration. Data compiled from refs. [27–31]. Abbreviations used: i.v., intravenous; i.p.,
intraperitoneal; ND, no data available.
The classical measure of acute toxicity is LD50, the median lethal dose of the tested compound
expressed in milligrams per kilogram body weight. The lower the LD50 value, the more toxic the
substance. For any route of administration (oral, intraperitoneal, intravenous), the LD50 of citicoline
Figure 1.
Median lethal dose of choline chloride and citicoline in mice (
A
,
B
) and rats (
C
,
D
) expressed
in milligrams (
A
,
C
) or in millimoles (
B
,
D
) per kilogram body weight, depending on the route
administration. Data compiled from refs. [
27
31
]. Abbreviations used: i.v., intravenous; i.p.,
intraperitoneal; ND, no data available.
The classical measure of acute toxicity is LD
50
, the median lethal dose of the tested compound
expressed in milligrams per kilogram body weight. The lower the LD
50
value, the more toxic the
substance. For any route of administration (oral, intraperitoneal, intravenous), the LD
50
of citicoline
is higher than the corresponding LD
50
of choline, indicating that citicoline is much less toxic than
Nutrients 2019,11, 1569 4 of 8
choline. This dierence is certainly not unexpected when we consider that the molecular weight of
choline moiety (MW =104) contributes less than 30% to the molecular weight of citicoline (
MW =489
),
whereas the acute toxicity of cytidine is probably lower than that of choline. However, when we
express the aforementioned LD
50
values on a molar basis, citicoline is still substantially less toxic than
choline. The dierence in molar toxicity between citicoline and choline is more than 20-fold when
the substances are applied intravenously. Apparently intact citicoline molecules do not evoke acute
cholinergic toxicity, probably because they are not substrates for acetylcholine synthesis.
When the compounds are given per os, the dierence in toxicity is several times lower, but it still
is quite significant. Two possible explanations can be proposed for the aforementioned dierences.
One could be that when cytidine appears in blood concomitantly with choline, it somehow attenuates
acute choline toxicity. The other, which seems more plausible, could be that upon oral application
choline is not liberated from citicoline in the intestinal lumen, preventing its conversion to TMA.
Compared with phosphatidylcholine and other choline derivatives encountered in food (e.g., carnitine,
glycerophosphocholine), citicoline may be less prone to enzymatic hydrolysis inside the intestinal
lumen because it is the only compound containing pyrophosphate group (it should, however, be
noted that according to one study [
32
], the distribution of radioactivity in tissues, urine, and expired
air following oral and intravenous administration of methyl-
14
C-labeled citicoline in rats showed
metabolic dierences which suggested that the compound is, at least partially, metabolized to TMA
prior to its gastrointestinal absorption).
4. Does Resistance to Hydrolysis in the Intestine Make Citicoline a Safer Choline Supplement?
The issue of hypothetical citicoline resistance to intraintestinal hydrolysis is of importance when we
consider that the intestinal microbiome metabolizes a significant fraction of choline and its derivatives
to trimethylamine (TMA), a gaseous metabolite readily taken up and oxidized in the liver to its
N-oxide, TMAO.
TMAO has been implicated in the etiology of various diseases, such as kidney failure, diabetes,
and cancer [
33
]. There is a large and growing amount of literature on the atherogenicity of TMAO
resulting in increased incidence of myocardial infarction, stroke, or death [
34
]. A meta-analysis
published recently led to the conclusion that higher plasma TMAO correlates with a 23% increase
in risk for cardiovascular events and a 55% increase in all-cause mortality [
35
]. Two recent reports
showed that higher TMAO levels were associated with increased risk of first ischemic stroke and
worse neurological deficit [
36
], and that patients suering from atrial fibrillation who developed
cardiogenic stroke displayed approx. 4 times higher TMAO levels in plasma than patients with atrial
fibrillation who did not develop stroke [
37
]. Another recent report suggested a link between TMAO
and Alzheimer’s disease [
38
]. It has even been suggested that supplementation with choline esters
prone to be metabolized to TMA and TMAO, such as phosphatidylcholine, may be dangerous to
human health [39].
On the other hand, several observations cast doubt on the pivotal role of TMAO in atherosclerosis.
First of all, nutritional intakes of TMAO and its precursors do not always correlate with cardiovascular
disease risk. For example, high fish intake increases TMA/TMAO while being cardioprotective. Some
hypotheses have been proposed recently to resolve this paradox, employing inter alia a phenomenon
of reverse causality, a possible role of insulin resistance and diabetes mellitus in activating N-oxidation
of TMA, etc. [40].
Nonetheless, many authors still take it as having been proven that TMAO is a causative factor in
the development of atherosclerosis and cardiovascular diseases. For example, in a recent review on
TMAO and stroke [
41
], several reports are quoted that show the importance of TMAO as a risk factor
and prognostic marker for this disease, and indicate the pathomechanisms involved. These include
increased TMAO generation promoting atherosclerosis, platelet activation, and inflammation. The
author concludes that TMAO may be a central molecule in the relationship of diet, genetics, the gut
microbiota, and cardiovascular disease.
Nutrients 2019,11, 1569 5 of 8
It may be concluded that until the place of TMAO in the chain of events leading to cardiovascular
diseases and mortality is ultimately clarified, citicoline could be a more reasonable choice than other
choline compounds, when choline supplementation is indicated.
5. Citicoline: A “Procognitive” Form of Choline
In two population studies, significant associations were found between choline intake or free
choline level in blood and the cognitive performance of adult and elderly people. In a community-based
population of non-demented individuals (1391 subjects, mean age 60.9 years), higher concurrent choline
intake was related to better cognitive performance [
42
] (Figure 2). In another cross-sectional study
(2195 subjects aged 70–74 years), low plasma free choline concentrations were associated with poor
cognitive performance [
43
]. A possible explanation for the eect of choline intake on cognition in
adults has been sought in its function as a precursor of phosphatidylcholine (PC), a major constituent
of all biological membranes, and acetylcholine, a neurotransmitter involved in cognition [44].
Nutrients 2019, 11, x FOR PEER REVIEW 5 of 8
It may be concluded that until the place of TMAO in the chain of events leading to cardiovascular
diseases and mortality is ultimately clarified, citicoline could be a more reasonable choice than other
choline compounds, when choline supplementation is indicated.
5. Citicoline: A “Procognitive” Form of Choline
In two population studies, significant associations were found between choline intake or free
choline level in blood and the cognitive performance of adult and elderly people. In a community-
based population of non-demented individuals (1391 subjects, mean age 60.9 years), higher
concurrent choline intake was related to better cognitive performance [42] (Figure 2). In another cross-
sectional study (2195 subjects aged 70–74 years), low plasma free choline concentrations were
associated with poor cognitive performance [43]. A possible explanation for the effect of choline
intake on cognition in adults has been sought in its function as a precursor of phosphatidylcholine
(PC), a major constituent of all biological membranes, and acetylcholine, a neurotransmitter involved
in cognition [44].
Figure 2. Dose–response relationship between the average daily choline intake and verbal and visual
memory performance in non-demented adults. Black lines indicate the mean score and red lines
indicate 95% confidence interval. Figure reproduced from [44].
Therefore, it might be expected that supplementation with choline will improve cognitive
performance. However, trials in which the effects of oral supplementation of humans with choline or
Figure 2.
Dose–response relationship between the average daily choline intake and verbal and visual
memory performance in non-demented adults. Black lines indicate the mean score and red lines
indicate 95% confidence interval. Figure reproduced from [44].
Therefore, it might be expected that supplementation with choline will improve cognitive
performance. However, trials in which the eects of oral supplementation of humans with choline or
Nutrients 2019,11, 1569 6 of 8
phosphatidylcholine on cognition were investigated yielded mixed, mostly negative results (see [
45
] and
references cited therein). On the other hand, in a recent small placebo-controlled study, adolescent males
treated with citicoline showed improved attention and psychomotor speed and reduced impulsivity [
46
].
In other recent controlled studies, citicoline seemed to be ecacious in adult patients suering from
cognitive impairments, especially of vascular origin [
47
]. These newer studies corroborated results
obtained previously when citicoline as a prescription drug had been tested in several placebo-controlled
trials for cognitive impairment due to chronic cerebral disorders in the elderly. The review of those
early trials led to the conclusion that there was some evidence of a positive eect of citicoline on
memory and behavior in at least the short to medium term [
48
]. Moreover, it was recently shown
that in patients suering from dementia concomitant oral intake of citicoline improved the ecacy of
cholinesterase inhibitors [49,50].
6. Conclusions
Altogether, whereas the jury may still be out on the issue whether, or to what extent, citicoline
taken orally is metabolized to TMA and TMAO, there are reasons to believe that procognitive eects of
citicoline supplementation are superior over those of choline or phosphatidylcholine.
Author Contributions: P.G. and K.S. wrote the paper.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
... [5]. More recently, one of its variants (citicoline inner salt) was pronounced a food constituent in the major world markets (USA, European Union) [6]. Therefore, citicoline became freely available over the counter as a food supplement that is considered a memory enhancer [7]. ...
... Choline derivatives from ingested food may have different accessibility for the gut microbes due to their different moieties and intestinal absorption rates. It has been suggested that citicoline is a potentially safer form of choline because it may resist hydrolysis inside the intestinal lumen, possibly due to its pyrophosphate group [6]. ...
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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.
... The bioavailability of CDP-choline administrated upon oral and intravenous routes is similar [75]. After injection, CDP-choline is rapidly metabolized to its cholinergic and pyrimidinergic catabolites, being probably even safer and a more "procognitive" form of choline supplement [76][77][78][79][80][81]. Nevertheless, there are still a lot of open questions regarding the place and particular mechanisms of CDP-choline catabolism and its precise mode of action as well its involvement in some kinases activation and trimethylamine N-oxide (TMAO) formation [58,76]. ...
... After injection, CDP-choline is rapidly metabolized to its cholinergic and pyrimidinergic catabolites, being probably even safer and a more "procognitive" form of choline supplement [76][77][78][79][80][81]. Nevertheless, there are still a lot of open questions regarding the place and particular mechanisms of CDP-choline catabolism and its precise mode of action as well its involvement in some kinases activation and trimethylamine N-oxide (TMAO) formation [58,76]. The best way to prove the efficacy of CDP-choline should be to investigate the lowest dose of the drug that still possesses its regenerative efficacy. ...
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Inflammatory attacks and demyelination in the central nervous system (CNS) are the key factors responsible for the damage of neurons in multiple sclerosis (MS). Remyelination is the natural regenerating process after demyelination that also provides neuroprotection but is often incomplete or fails in MS. Currently available therapeutics are affecting the immune system, but there is no substance that might enhance remyelination. Cytidine-S-diphosphate choline (CDP-choline), a precursor of the biomembrane component phospholipid phosphatidylcholine was shown to improve remyelination in two animal models of demyelination. However, the doses used in previous animal studies were high (500 mg/kg), and it is not clear if lower doses, which could be applied in human trials, might exert the same beneficial effect on remyelination. The aim of this study was to confirm previous results and to determine the potential regenerative effects of lower doses of CDP-choline (100 and 50 mg/kg). The effects of CDP-choline were investigated in the toxic cuprizone-induced mouse model of de- and remyelination. We found that even low doses of CDP-choline effectively enhanced early remyelination. The beneficial effects on myelin regeneration were accompanied by higher numbers of oligodendrocytes. In conclusion, CDP-choline could become a promising regenerative substance for patients with multiple sclerosis and should be tested in a clinical trial.
... 28 Findings from a systematic review of dexamethasone combination therapy with thalidomide (twelve studies, including 451 patients with multiple myeloma) indicated that dexamethasone could significantly reduce peripheral neuropathy. 29 Numerous studies have been implied that citicoline demonstrated its neuroprotective properties through increasing Sirtuin-1 30, 31 , acetylcholine 32,33 , and serotonin 34 , decreasing glutamate levels 17 , anti-inflammation activity via blocking phospholipase A2, and diminish reactive oxygen species (ROS) generation. 14 Besides, in an experiment by Bagdas et al., they used the Randall-Sellito test to evaluate the pain threshold, which citicoline significantly elevated the pain threshold through central opioid receptors in a neuropathic pain rat model. ...
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INTRODUCTION: Given the rising prevalence of Cisplatin-induced peripheral neuropathy (CisIPN), investigations for alleviating its adverse effects are required. Oxidative stress and free radical development are essential pathways of CisIPN. Specifically, dexamethasone and citicoline are characterized by anti-inflammatory and antioxidant activities that might reduce CisIPN incidence and severity. The current study assessed the possible impacts of novel interventions, dexamethasone, and citicoline, on CisIPN. METHODS: Seventy-two male mice were randomly allocated into nine groups (n=8/each group). Different doses of dexamethasone (7.5, 15, 30 mg/kg, i.p.), citicoline (10, 20, 40 mg/kg, i.p.) and the combined (dexamethasone 7.5 mg/kg + citicoline 10 mg/kg, i.p.) were injected in the first three days and one day before receiving cisplatin (2 mg/kg, i.p.). The tail-flick method was used for the assessment of nociception. Besides, malondialdehyde (MDA), interleukin-1beta (IL-1β), tumor necrosis factor-α (TNF-α), total antioxidant capacity (TAC), and mice weight differences (∆W) were measured. RESULTS: Different doses of dexamethasone and citicoline enhanced latency time (P<0.05). Moreover, dexamethasone 15 mg/kg diminished the level of MDA and increased TAC (P<0.05), and in 30 mg/kg, MDA was reduced (P<0.05). Besides, 20 and 40 mg/kg of citicoline reduced MDA and elevated TAC (P<0.05), and 10 mg/kg merely reduced MDA (P<0.05). Dexamethasone in all doses declined IL-1β and TNF-α levels, and citicoline only at 40 mg/kg lessened their levels (P<0.05). Interestingly, ∆W declined more in the dexamethasone and citicoline groups than the Cisplatin group (P<0.05). CONCLUSION: Dexamethasone and citicoline attenuate CisIPN through anti-inflammatory, improving antioxidant capacity, and inhibiting lipid peroxidation.
... Citicoline has been hypothesized as a superior form of choline, due to its choline content and its lower susceptibility to being transformed into trimethylamine, a compound that may later undergo hepatic oxidization to trimethylamine N-oxide, a suspected factor in various chronic diseases [130]. Thus, the effects of citicoline on cognitive function have been investigated in various populations. ...
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Background and aim: Brain health is becoming more important to the average person as the number of people with cognitive impairments, such as Alzheimer's disease (AD), is rising significantly. The current Food and Drug Administration-approved pharmacotherapeutics for dementia neither cure nor halt cognitive decline; they just delay the worsening cognitive impairment. This narrative review summarizes the effects of nutrients and phytonutrients on cognitive function. Methods: A comprehensive literature search of PubMed was performed to find clinical trials in humans that assessed the effects of nutrients and phytonutrients on cognitive function published in English between 2000 and 2021. Six independent reviewers evaluated the articles for inclusion in this review. Results: Ninety-six articles were summarized in this narrative review. In total 21 categories of nutrients and phytonutrients were included, i.e., α-lipoic acid, Bacopa monnieri, B vitamins, cholinergic precursors, vitamin D, vitamin E, Ginkgo biloba, ginseng, lion's mane mushroom, N-acetyl cysteine, omega-3 fatty acids, aloe polysaccharides, Rhodiola rosea, rosemary, saffron, tart cherries, turmeric, wild yam, Withania somnifera, xanthines, and zinc. Particular noteworthy effects on cognition included memory, recollection, attention, intelligence, vocabulary, recognition, response inhibition, arousal, performance enhancement, planning, creative thinking, reaction time, vigilance, task switching, orientation to time, place, and person, reading, writing, comprehension, accuracy, learning, information processing speed, executive function, mental flexibility, daily functioning, decrease in mental fatigue, and freedom from distractibility. Some nutrients and phytonutrients also improved mood and contentedness and reduced anxiety and the need for caregiving. These effects are not completely consistent or ubiquitous across all patient populations or health statuses. Adverse effects were minimal or nonexistent. Conclusion: Due to the growing population of people with cognitive impairment and the lack of effective pharmacotherapeutics, it is prudent for those afflicted or their caregivers to find alternative treatments. Our narrative review shows that many of these nutrients and phytonutrients may be promising for treating some aspects of cognitive impairment, especially for people afflicted with AD. Relevance for patients: As demonstrated in a number of clinical trials, healthy adults and patients with various health challenges (e.g., AD, mild cognitive impairment, multiple sclerosis, and Parkinson's disease) exhibiting a wide range of severity in cognitive defects would be best served to consider multiple nutrients and phytonutrients to improve aspects of their cognitive function.
... In the present study, citicoline contributed to cardiac recovery when administered to MPTP-treated rats. The citicoline functions improved the mitochondrial dysfunctions and mitophagy by ameliorating UCP2, AMPK-a2 transcriptions (42). Several studies introduced valuable evidence on citicoline's protective effect upon myocardial dysfunction during the rats' heart reperfusion (25). ...
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The autonomic nervous system controls cardiovascular function. Autonomic dysfunction or dysautonomia is commonly encountered in several diseases like Parkinson's disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a chemical that changes into the neurotoxin MPP+, which causes catecholamine depletion. We aimed to study the effects of citicoline on cardiovascular function in MPTP-treated albino rats. Twenty-four male albino rats were divided into four groups (6 rats/group): negative control received intraperitoneal (i.p.) saline injection for five consecutive days, a positive control (Citicoline group) received citicoline (250 mg/kg) by oral gavage for consecutive 20 days, MPTP treated with MPTP-HCL (30 mg/kg, i.p.) for five consecutive days, MPTP + citicoline treated with MPTP-HCL (30 mg/kg, i.p.) for five consecutive days followed by treatment with oral doses of citicoline (250 mg/kg) for 20 days. Cardiovascular functions evaluated through recording electrocardiogram (ECG), echocardiography, measuring arterial blood pressure and assessment of aortic rings vascular reactivity. Biochemical measurements on cardiac tissue for tyrosine hydroxylase, norepinephrine, glucose transporter 1 (GLUT1), insulin receptor substrate 1 (IRS1), peroxisome proliferator-activated receptor γ co-activator-1 (PPAR-γ co-activator-1) (PGC-1), phosphatase and tensin homolog-induced kinase 1 (PINK1), carnitine palmitoyltransferase I (CPT1), uncoupling protein 2 (UCP2) and adenosine monophosphate-activated protein kinase alpha 2 (AMPKα2). Citicoline increased cardiac norepinephrine and tyrosine hydroxylase and improved markers related to ROS scavenger, mitochondrial permeability, calcium homeostasis on the cellular level, metabolic homeostasis, and mitochondrial biogenesis. We conclude that citicoline improved cardiovascular dysautonomia and that was reflected on cardiac contractility, electrical activity, blood pressure, and vascular reactivity.
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The high hydrophilicity of citicoline and its rapid metabolism are the two main obstacles hindering intact molecules from passing the blood-brain barrier. This study aimed to formulate citicoline-loaded niosomes (CTC-NSMs) for efficient brain delivery via the intranasal route to improve management of epilepsy. CTC-NSMs were formulated via thin-film hydration method, optimized using D-optimal design, and characterized for entrapment efficiency, vesicle size, drug release, and cumulative amount permeated. The entrapment efficiency ranged from 19.44 to 61.98% with sustained drug release, and the vesicle size ranged from 125.4 to 542.5 nm with enhanced drug permeation. Cholesterol: Span ratio of 1:1.19 and cholesterol amount of 20 mg were predicted to produce optimal characteristics. Subsequently, the optimized formulation permeation confirmed a high nasal penetration using confocal laser scanning microscopy (CLSM). Afterward, the optimized CTC-NSM formulation was integrated into in situ gel to boost the residence time in the nasal cavity. Additionally, Computed Tomography (CT) was performed by labeling the optimized formulation with gold nanoparticles (GNPs) to assess brain uptake and cellular translocation after intranasal administration of CTC. Furthermore, the protection against pentylenetetrazole-induced generalized seizures and mortality were determined in rats and compared with the oral drug solution at the exact dosage. The in vivo results revealed that a low dose of CTC-NSM in situ gel had a powerful protective effect with delayed the latency for the start of convulsions. Collectively, NSM in situ gel is a potentially valuable intranasal drug delivery system that can boost the efficacy of CTC in epilepsy management.
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Introduction The present article reports an overview of the studies about combination treatment with citicoline of Alzheimer’s (AD) and mixed dementia (MD). Methods A Medline search was carried out by using the keywords Alzheimer’s dementia, mixed dementia, older people, treatment with citicoline, memantine, and acetylcholinesterase inhibitors (AchEIs). Results Six studies were found to match the combination treatment of citicoline with AcheIs and/or memantine. The CITIRIVAD and CITICHOLINAGE studies were the first to report the potential benefits of adding citicoline to acetylcholinesterase inhibitors (AchEIs). Then, we added citicoline to memantine in the CITIMEM study, and finally, we demonstrated benefits in terms of delay in cognitive worsening with the triple therapy (citicoline + AchEIs + memantine). Other authors also reinforced our hypothesis through two further studies. Conclusions Open, prospective studies are advised to confirm the utility of combination therapy with citicoline for the treatment of AD and MD.
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A new 2019 coronavirus disease has been spreading worldwide for more than a year, with a high risk of infection and death. Various sequelae and complications can develop in COVID-19 survivors, lasting from several weeks to several months after initial recovery, affecting different organs and systems. Various sequelae and complications can occur in COVID-19 survivors not only in adults and the elderly, but also in young people. A wide range of neurological manifestations of COVID-19 are now described in the available literature. The incidence of selected neurological symptoms, syndromes and nosological forms in individuals both in the acute period of COVID-19 disease and in the short- and long-term follow-up of these patients is presented. In this article, cognitive impairments occurring in individuals who have had coronavirus disease are discussed in depth. Data on the prevalence of cognitive impairment in different regions and at different periods of the disease are presented. The main possible pathophysiological processes and risk factors for the development of cognitive impairment in COVID-19 are described. Possible ways of drug and non-drug rehabilitation of patients with cognitive impairment in coronavirus infection that is a new problem of modern medicine are considered. Attention is also paid to neuroprotection as one of the therapy areas.
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Trimethylamine N-oxide (TMAO) is produced when trimethylamine, a waste product of gut microbes, is converted via hepatic flavin monooxygenases. As TMAO is a potential causative factor in various cardiovascular diseases (CVDs) considerable research interest has arisen on its use as a biomarker. Higher TMAO levels are associated with future risk of both incident CVD in the general population and established CVD, including stroke. The addition of TMAO into models with traditional risk factors significantly improved the prediction of future CVD risk. TMAO promotes atherosclerosis and is associated with platelet hyperreactivity and inflammation, which are in turn associated with the development of stroke and its secondary consequences. Additionally, TMAO may play a key mediator role in the relationship between the diet, gut microbiota, and CVD development. Compelling evidence suggesting that TMAO is both a risk factor and prognostic marker of stroke and CVD. Potential therapeutic strategy of diet and drugs in reducing TMAO levels have emerged. Thus, TMAO is a novel biomarker and target in stroke and CVD prevention.
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Objective: Accumulating evidence suggests that Trimethylamine-N-oxide (TMAO), a gut microbial metabolite, is implicated in the pathogenesis of many cardiovascular diseases. The aim of the present study was to investigate the serum levels of TMAO in Chinese patients with ischemic stroke. Method: In the present study, 255 consecutive patients with first-ever acute ischemic stroke and 255 age and gender-matched healthy volunteers were included for testing serum TMAO. Stroke severity was determined by the NIH Stroke Scale (NIHSS). The stroke severity was dichotomized as minor (NIHSS ≤ 5) and moderate-to-high clinical severity (NIHSS > 6). Results: The serum levels of TMAO in stroke ranged from 0.5 to 18.3 μM, with a median value of 5.8 (interquartile range (IQR), 3.3–10.0) μM, which was higher than in those controls (3.9; IQR, 2.6–6.1 μM). The median level of TMAO in those patients was significantly lower than in those moderate-to-high stroke patients (4.1 μM [IQR, 2.8–6.2] vs. 9.1 μM [5.1–11.0]; P<0.001). In univariate and multivariable models, the unadjusted risk of moderate-to-high stroke was increased by 31% (odds ratio (OR) = 1.31 [95% confidence interval (CI): 1.21–1.42], P<0.001) and 22% (OR = 1.22; 95% CI = 1.08–1.32; P<0.001), when TMAO was increased each by 1 μM. Based on the receiver operating characteristic (ROC) curve, the optimal cut-off value of serum level of TMAO as an indicator for screening of moderate-to-high stroke was estimated to be 6.6 μM, which yielded a sensitivity of 69.3 % and a specificity of 79.0%, with the area under the curve at 0.750 (95% CI, 0.687–0.812). Conclusions: Higher TMAO levels were associated with increased risk of first ischemic stroke and worse neurological deficit in Chinese patients.
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Hyperhomocysteinemia is recognized as a risk factor for several diseases, including cardiovascular and neurological conditions. Homocysteine (HCys) is a key metabolite involved in the biosynthesis and metabolism of methionine (Met), which plays a pivotal role in the physiological cell's life cycle. The biochemistry of Met is finely regulated by several enzymes that control HCys concentration. Indeed, balanced activity among the enzymes is essential for the cell's well-being, while its malfunction could raise HCys concentration which can lead to the onset of several pathological conditions. The HCys concentration increase seems to be caused mainly by the widely diffused polymorphisms of several enzymes. Nowadays, a blood test can easily detect elevated concentrations of HCys, referred to as Hyperhomocysteinemia (HHCys). Prolonged exposure to this condition can lead to the onset of cardiovascular disease and can lead to the development of atherosclerosis, stroke, inflammatory syndromes like osteoporosis and rheumatism, as well as neuronal pathologies including Alzheimer's and Parkinson's diseases. In this review, we analyzed the literature of several pathological conditions in which the molecular pathways of HHCys are involved. Interestingly, several observations indicate that the calibrated assumption of correct doses of vitamins such as folic acid, vitamin B6, vitamin B12, and betaine may control HHCys-related conditions.
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Background Trimethylamine N-oxide (TMAO), a small molecule produced by the metaorganismal metabolism of dietary choline, has been implicated in human disease pathogenesis, including known risk factors for Alzheimer’s disease (AD), such as metabolic, cardiovascular, and cerebrovascular disease. Methods In this study, we tested whether TMAO is linked to AD by examining TMAO levels in cerebrospinal fluid (CSF) collected from a large sample (n = 410) of individuals with Alzheimer’s clinical syndrome (n = 40), individuals with mild cognitive impairment (MCI) (n = 35), and cognitively-unimpaired individuals (n = 335). Linear regression analyses were used to determine differences in CSF TMAO between groups (controlling for age, sex, and APOE ε4 genotype), as well as to determine relationships between CSF TMAO and CSF biomarkers of AD (phosphorylated tau and beta-amyloid) and neuronal degeneration (total tau, neurogranin, and neurofilament light chain protein). Results CSF TMAO is higher in individuals with MCI and AD dementia compared to cognitively-unimpaired individuals, and elevated CSF TMAO is associated with biomarkers of AD pathology (phosphorylated tau and phosphorylated tau/Aβ42) and neuronal degeneration (total tau and neurofilament light chain protein). Conclusions These findings provide additional insight into gut microbial involvement in AD and add to the growing understanding of the gut–brain axis. Electronic supplementary material The online version of this article (10.1186/s13195-018-0451-2) contains supplementary material, which is available to authorized users.
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The current epidemic of non-alcoholic fatty liver disease (NAFLD) is reshaping the field of hepatology all around the world. The widespread diffusion of metabolic risk factors such as obesity, type2-diabetes mellitus, and dyslipidemia has led to a worldwide diffusion of NAFLD. In parallel to the increased availability of effective anti-viral agents, NAFLD is rapidly becoming the most common cause of chronic liver disease in Western Countries, and a similar trend is expected in Eastern Countries in the next years. This epidemic and its consequences have prompted experts from all over the word in identifying effective strategies for the diagnosis, management, and treatment of NAFLD. Different scientific societies from Europe, America, and Asia-Pacific regions have proposed guidelines based on the most recent evidence about NAFLD. These guidelines are consistent with the key elements in the management of NAFLD, but still, show significant difference about some critical points. We reviewed the current literature in English language to identify the most recent scientific guidelines about NAFLD with the aim to find and critically analyse the main differences. We distinguished guidelines from 5 different scientific societies whose reputation is worldwide recognised and who are representative of the clinical practice in different geographical regions. Differences were noted in: the definition of NAFLD, the opportunity of NAFLD screening in high-risk patients, the non-invasive test proposed for the diagnosis of NAFLD and the identification of NAFLD patients with advanced fibrosis, in the follow-up protocols and, finally, in the treatment strategy (especially in the proposed pharmacological management). These difference have been discussed in the light of the possible evolution of the scenario of NAFLD in the next years.
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Choline is an essential nutrient for humans. It is a precursor of membrane phospholipids (e.g., phosphatidylcholine (PC)), the neurotransmitter acetylcholine, and via betaine, the methyl group donor S-adenosylmethionine. High choline intake during gestation and early postnatal development in rat and mouse models improves cognitive function in adulthood, prevents age-related memory decline, and protects the brain from the neuropathological changes associated with Alzheimer’s disease (AD), and neurological damage associated with epilepsy, fetal alcohol syndrome, and inherited conditions such as Down and Rett syndromes. These effects of choline are correlated with modifications in histone and DNA methylation in brain, and with alterations in the expression of genes that encode proteins important for learning and memory processing, suggesting a possible epigenomic mechanism of action. Dietary choline intake in the adult may also influence cognitive function via an effect on PC containing eicosapentaenoic and docosahexaenoic acids; polyunsaturated species of PC whose levels are reduced in brains from AD patients, and is associated with higher memory performance, and resistance to cognitive decline.
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Trimethylamine N‐oxide (TMAO) is an independent risk factor of cardiovascular disease. Our objective was to explore the relation between TMAO and ischemic stroke (IS) in patients with atrial fibrillation (AF). A total of 68 patients with AF with IS and 111 ones without IS were enrolled. The plasma levels of TMAO remarkably increased in IS‐AF patients (8.25 ± 1.58 µM) compared with patients with AF (2.22 ± 0.09 µM, P < 0.01). The receiver operating characteristic analysis revealed that the best cutoff value of TMAO to predict IS in patients with AF was 3.53 µM with 75.0% sensitivity and 92.8% specificity (area under the curve: 0.917, 95% confidence intervals: 0.877‐0.957). Univariate and multivariate logistic regression analysis showed that TMAO was an independent predictor in IS. The level of TMAO was correlated with the CHA2DS2‐VASc score. In conclusion, TMAO was an independent predictor of IS, which could potentially refine stroke stratification in patients with AF.
Article
Background: A high homocysteine concentration is a potential risk factor for cardiovascular disease that can be reduced through betaine supplementation. Choline is the precursor for betaine, but the effects of choline supplementation on plasma total homocysteine (tHcy) concentrations in healthy humans are unknown. Objective: The objective was to investigate whether supplementation with phosphatidylcholine, the form in which choline occurs in foods, reduces fasting and postmethionine-loading concentrations of plasma tHcy in healthy men with mildly elevated plasma tHcy concentrations. Design: In a crossover study, 26 men ingested ≈2.6 g choline/d (as phosphatidylcholine) or a placebo oil mixture for 2 wk in random order. Fatty acid composition and fat content were similar for both treatments. A methionine-loading test was performed on the first and last days of each supplementation period. Results: Phosphatidylcholine supplementation for 2 wk decreased mean fasting plasma tHcy by 18% (−3.0 μmol/L; 95% CI: −3.9, −2.1 μmol/L). On the first day of supplementation, a single dose of phosphatidylcholine containing 1.5 g choline reduced the postmethionine-loading increase in tHcy by 15% (−4.8 μmol/L; 95% CI: −6.8, −2.8 μmol/L). Phosphatidylcholine supplementation for 2 wk reduced the postmethionine-loading increase in tHcy by 29% (−9.2 μmol/L; 95% CI: −11.3, −7.2 μmol/L). All changes were relative to placebo. Conclusions: A high daily dose of choline, supplemented as phosphatidylcholine, lowers fasting as well as postmethionine-loading plasma tHcy concentrations in healthy men with mildly elevated tHcy concentrations. If high homocysteine concentrations indeed cause cardiovascular disease, choline intake may reduce cardiovascular disease risk in humans.