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CNS Drugs (2014) 28:185–193

DOI 10.1007/s40263-014-0144-8


Neuroprotective Properties of Citicoline: Facts, Doubts
and Unresolved Issues
Pawel Grieb

Published online: 7 February 2014 
The Author(s) 2014. This article is published with open access at

Abstract Citicoline is the generic name of the pharma-
ceutical substance that chemically is cytidine-50 -diph- Key Points for Decision Makers
osphocholine (CDP-choline), which is identical to the
natural intracellular precursor of phospholipid phosphati- Citicoline is chemically identical to CDP-choline,
dylcholine. Following injection or ingestion, citicoline is the natural precursor of the major cell membrane
believed to undergo quick hydrolysis and dephosphoryla- phospholipid phosphatidylcholine.
tion to yield cytidine and choline, which then enter the Given orally or by injection, citicoline is non-toxic
brain separately and are used to resynthesize CDP-choline and very well tolerated.
inside brain cells. Neuroprotective activity of citicoline has
Preclinical experiments with various models of
been repeatedly shown in preclinical models of brain
central neurodegenerative diseases have shown that
ischaemia and trauma, but two recent, large, pivotal clini-
citicoline displays significant neuroprotective
cal trials have revealed no benefits in ischaemic stroke and
traumatic brain injury. However, the substance seems to be
beneficial in some slowly advancing neurodegenerative However, recent large and well-controlled data have
disorders such as glaucoma and mild vascular cognitive shown no benefit from citicoline in acute ischaemic
impairment. This paper critically discusses issues related to stroke and traumatic brain injury.
the clinical pharmacology of citicoline, including its
The pharmacological actions of citicoline in the
pharmacokinetics/biotransformation and pharmacodynam-
central nervous system seem to be pleiotropic and
ics/mode of action. It is concluded that at present, there is
involve, amongst other things, modulation of some
no adequate description of the mechanism(s) of the phar-
kinases and sirtuin-1. However, our understanding of
macological actions of this substance. The possibility
the mechanisms involved is, at most, fragmentary.
should be considered and tested that, in spite of apparently
fast catabolism, the intact citicoline molecule or the
phosphorylated intermediate products of its hydrolysis,
cytidine monophosphate and phosphocholine, are phar- 1 Introduction
macologically active.
Citicoline is the generic name, or the International Non-
proprietary Name (INN) of cytidine-50 -diphosphocholine
(CDP-choline, CDPCho), a pharmaceutical substance that
is chemically identical to the naturally occurring metabo-
lite, which plays crucial role in the synthesis of phospho-
P. Grieb (&) lipids. The work of Kennedy and collaborators in the 1950s
Department of Experimental Pharmacology, Mossakowski
showed that this phosphorylated choline nucleotide is a
Medical Research Centre, Polish Academy of Sciences, 5
Pawinskiego str., 02-106 Warsaw, Poland precursor of glycerophospholipid phosphatidylcholine (PC)
e-mail: [1]. PC and its twin compound phosphatidylethanolamine

which occurred in the 1970s. those that are likely misinterpreted. the LD50 of an acute single intravenous dose exist until the substance became used as the drug. Several relevant reviews have also appeared in high-ranking journals. using the term ‘CDP-choline’.g. i. doubts. Needless to say. novo synthesis of PC.e. For compari- stance of endogenous origin). some papers cur- rently indexed under the term ‘citicoline’ are dated earlier. In the Anglophone medical literature. including at Fig. but others (e. in mice.) and ‘citicoline’. Grieb enzymes in the brain. approximately 8 g/kg in both mice and rats. The LD50 for ingested citicoline is even higher at the natural metabolite synthesized inside the cells (a sub. These enzymes are located intracellularly. Notwithstanding. respectively. which its variants (‘CDPcholine’. The compound is plasmic reticulum and cell nucleus [3].2-dicacylglycerol. 2). as clinical—was performed in the PubMed. accounting for more than half of the total classification is subjective: facts. describing crystallization of CDP-choline from yeast) could be qualified as concerning citicoline (the compound synthesized exogenously). an acute single intravenous application of citicoline. stemmed from the observation. for the treatment of Parkinson’s disease. 2 Presumed catabolism of citicoline (Cyt-P-P-Cho) in the rodent as a drug was advocated as early as 1974.150 mg/kg in mice and rats. confirmed in rodents and dogs (see the most recent report The search for relevant literature—non-clinical as well by Schauss et al. In the first step. 1 The cytidine-50 -diphosphocholine (CDP-choline) pathway of least five during the last 4 years [10–14]. clarified. reporting on the concentration of endogenous CDP-choline in the rat brain) undoubtedly concern CDP-choline (the compound synthesized endoge- nously). The present review is an attempt to classify the CPT CDP-choline:1. ADP adenosine diphos- phate. supposedly. major issues concerning the neuroprotective properties of CTP cytidine triphosphate. the paper by Berger and Gimenez [5]. The pathway of de issues are.600 and 4. Scopus and An impressive example is the median lethal dose (LD50) of Web of Science databases. intermingled. those that remain unexplained. the term ‘citicoline’ did not son. ATP adenosine triphosphate.186 P. The first patent for the use of CDP- ethanolamine. The lack of choline into the cell or from phospholipase D-mediated acute and chronic toxicity of citicoline has been repeatedly turnover of PC [4]. Whereas ‘CDP-choline’ designates tively. hundreds of studies concerning various aspects of the preclinical and clinical pharmacology of citicoline have been published.e. i. [15] and the references quoted therein). cytidine monophosphate (Cyt-P) and phosphocholine (Cho-P) are dephospho- few years later. the enzymatic synthesis of phosphatidylcholine. ‘cytidine-diphosphocholine’. to reverse neurodegenerative diseases was issued in 1981 [9]. the use citicoline Fig. includes the enzymes cytidine kinase (CK). In the second step. as will be discussed later. of the reversibility of phosphotransferase may explain the unexpectedly low cholinergic toxicity of citicoline) . CK cytidine kinase. subsequently available for diverse biosynthetic pathways choline pathway is derived from transport of exogenous and ultimately excreted as carbon dioxide. and the products arising are for synthesis of phosphatidylcholine through the CDP. by Manaka et al. those that are dylcholine. respec- etc. the CDP-choline pathway (Fig. some of them (e. such otic cells. PPi pyrophosphate solved with an acceptable degree of certainty. 1). Citicoline displays negligible toxicity. Since that time. choline phos- phate cytidilyltransferase (CCT) and CDP-choline:1. i. intravascular compartment.g. DAG 1. The difference between CDP-choline (synthesized endogenously) and citicoline (synthesized exogenously) is not trivial. doubts and unresolved phospholipid content in membranes. made by Horrocks and a large part of the liberated choline is taken up by the liver (which collaborators [8]. PC phosphati. citicoline into three categories: facts. 2 Facts diacylglycerol choline phosphotransferase (CPT) [2]. Choline that is used quickly catabolized (Fig. CMP cytidine monophosphate. the idea of using it as a neuroprotectant rylated to cytidine (Cyt) and choline (Cho). CCT choline phosphate cytidi.2-diacylglycerol choline phosphotransferase. (PEt) are the two most abundant phospholipids in eukary. However. in many cases. and unresolved issues. the paper by Ansell and Bayliss [6].e. subject of citicoline’s mode of action is far from being lyltransferase.2. A pyrophosphate bridge takes place. equals 4. alone or in combination with CDP-choline. in the endo. hydrolysis of the [7] from Japan.

enter the brain separately and. converted to its cholinergic and pyrimidinergic catabolites.191 between choline intake and cancer—if any—are weak. Johansson et al. A recently published paper [21] the citicoline breakdown products cytidine and choline reported on the use of a liquid chromatography electro. on the basis of the afore. and sister chromatid exchange) [25]. citicoline is in vivo models of acute and chronic brain ischaemic and relatively quickly (i. phospholipids. [29] found that mentioned toxicology data. citicoline is relatively quickly clinical) experimental paradigms. although it should humans. Lee et al. but a similar (even ing 1. In agreement with this assumption. Biphasic concentration–time necessary for membrane repair [36]. in turn. patients. One The usual daily therapeutic dosage of citicoline in may therefore pose a question as to whether increasing humans is 500–2. choline chloride has have corroborated preclinical toxicological findings. significant rise in brain choline following therapeutic doses slightly smaller but much broader peak with a maximum at of citicoline in humans does not seem probable—indeed. mostly related to digestive dis. [27] found that elevated plasma controlled trials has shown that the overall frequency of concentrations of choline may be associated with a slightly adverse effects was comparable between groups compris. .36 lg/mL [22] in a healthy human 518 mg/kg. However. brain and spinal cord trauma perfusate within 10 min [18. whereas Xu et al. Moreover. The compound has catabolized and is the source of choline that appears in the offered marked neuroprotection in several in vitro and blood. Is citicoline carcinogenic? In a wide variety of cancers. a large peak of 2 lg/mL at approximately 2 h and a second. an enhanced threat of dietary choline intake was inversely associated with breast hyperphosphataemia may be predicted in patients with cancer risk. In adult and elderly stroke data have been obtained for citicoline [26]. For Korean stroke patients).e. is MS) method to evaluate the pharmacokinetics of choline in believed to result in slowing down of phospholipid blood from human volunteers following ingestion of breakdown and acceleration of phospholipid resynthesis 1. and this was confirmed recently [23].652 actively treated and 686 placebo-treated subjects slightly stronger) association has been found for vitamin [17]. change in those of younger subjects have been observed which makes the whole picture a bit unclear. However. One older following oral citicoline.000 mg citicoline tablets. displayed no mutagenic potential when tested in vitro revealing a favourable safety profile. increases in serum creati. and similar negative turbances following oral intake. Increases in brain phospholipids following citicoline given orally to rats produced pronounced oral administration of citicoline have also been observed in increases in plasma cytidine and choline.Citicoline for Neuroprotection 187 of sodium chloride is 645 mg/kg. nine and in renal tubular mineralization. 7–28 mg/kg in a person choline exposure doesn’t induce carcinogenesis and/or of average bodyweight (70 kg). amyloid toxicity [34]. with only a few (using Ames testing. with a icoline is devoid of cholinergic toxicity (see below). Unfortunately. lation of the synthesis and increase in the content of brain tases in blood plasma. kidney failure. However. 100–1. There are no data concerning the effects of liver or B2. for example. and that of vitamin C is oscillating around 1. likely caused by choline phospholipid metabolism is altered in such a way phosphate liberation from citicoline. (CMP) and phosphocholine (PCho) yielded from hydroly. On the other hand. including brain hypoxia. 33] and in vivo substrates are considered unable to penetrate cell mem. Data from clinical trials accelerate cancer growth.000 mg/kg daily doses. it is usually assumed that cytidine monophosphate neuroprotection are far from being understood. a approximately 24 h following ingestion. they act as spray ionization tandem mass spectrometry (LC–ESI–MS/ substrates for resynthesis of CDP-choline. inside brain cells. example. the study by Cho and Kim [16] in 4. In a 90-day rat oral toxicity study of subject. One major effect of citicoline is believed to be stimu- sis of citicoline are further dephosphorylated by phospha. of colorectal cancer. with use of phosphorous magnetic resonance be noted that the rise of cytidine was several-fold larger spectroscopy [35]. concomitant degenerative or inflammatory reactions. Citicoline is neuroprotective in various animal (pre- Upon administration. no decrease in choline in the brains of older subjects and no data on the initial plasma level of choline were shown. and a meta-analysis of placebo. were found. since cit- curves of choline in plasma have been recorded. This. with use of proton magnetic source reported an arithmetic mean plasma choline level resonance spectroscopy (MRS) [37]. 19]. Administered parenterally or orally. association between choline (or betaine) intake and the risk kinetics of citicoline although. ischaemia and intracerebral haemorrhage (reviewed by In the perfused rat liver. without that cancer cells display elevated levels of phosphocholine. citicoline disappeared from the Adibhatla and Hatcher [30]). yeast gene conversion.000 mg—that is. [28] did not find any kidney insufficiency on the safety profile and pharmaco. in vitro glutamate excitotoxicity [32. within minutes rather than hours) neurodegenerative diseases. clastogenicity reports of adverse events. Since phosphorylated [31]. increased risk of prostate cancer. the drug has lacked significant adverse events epidemiological data have shown that the associations (see. The relevant hypothesis assumes that than that of choline [20]. the mechanisms of this branes. as well as total choline-containing compounds [24].

of citicoline in the rat. mood. or is resyn. stabilized or even improved glaucomatous visual administration [40. multicentre. may be significantly effective in certain slowly which is degraded in response to cellular insults and dis. in particular. does not in noradrenaline and dopamine levels. citicoline treatment death) has also been noted [39]. improves functional independence and reduces the burden citicoline was ineffective in SIRT1 knock-out homozygotic of care [52]. does the drug act extracellularly. oline administration leads to attenuation of MAPK activity and increases sirtuin-1 protein content in brain tissues. This effect seems to be of critical importance Mental State Examination score and positively influenced for neuroprotection in experimental stroke because sirtinol. citicoline given sys- studies with animal models of neurodegenerative diseases temically is quickly hydrolysed and further dephosphoryl- have prompted clinical trials with citicoline as a treatment ated. Whereas several previous small uncertain. 3 Doubts thesis of CDP-choline inside brain cells a prerequisite? Citicoline is not beneficial in patients with stroke and Where is citicoline catabolized? While it seems reasonable traumatic brain injury. in circulating blood mononuclear cells and taken for up to 9 months significantly improved the Mini- in the brain. which would be influence infarct volume. at least in rodents. However.000 mg for 5 or 10 days used in doses that were individually ineffective. injection. Citicoline displayed by Rejdak et al. treatment with citicoline has been impairment. the increase in plasma cytidine was.298 patients with moderate-to. although not exclusively. oral citicoline tured neurons.188 P. and the interna. One is glaucoma. What was not commented on was the lack of a neuroprotective effects of citicoline in stroke models mechanistic explanation for the putative neuroprotective include prevention of activation of phospholipase A2 properties of citicoline. Decadimento Vascolare Lieve) study [50]. oline Brain Injury Treatment) trial performed in 1. The uniqueness of citicoline may lie not only mice subjected to focal brain ischaemia. an oral prising and prompted a few comments. Last. on methodological in plasma uridine instead of cytidine [53]. placebo-controlled ‘surplus’ choline? Was it taken up by the liver? Does the sequential ICTUS (International Citicoline Trial on Acute several-fold ‘domination’ of the cytidine increase over the Stroke) trial performed in 2. preventing loss neurodegenerative diseases. given orally or by phospholipid essential for mitochondrial electron transport. In glaucoma bioactive phospholipid implicated in neuronal excitotoxic patients with moderate visual defects. and mitogen-activated protein kinases (MAPKs) and caspase continuation of treatment for 2–8 years significantly slo- activation have been observed following citicoline wed. Positive results of preclinical to assume that. several times larger than the concomitant patients with traumatic brain injury [43]. The related effects comprise attenuation of Citicoline treatment seems beneficial in some chronic the increase in hydroxyl radical generation. Some recent data are sugges- of cardiolipin (an exclusive inner mitochondrial membrane tive that prolonged intake of citicoline. increase in plasma choline [20]. attenuation of improved retinal function and neural conduction. an currently considered a neurodegenerative disease. it has recently been shown that in sub-acute to be a SIRT1 activator). Does it take place in blood plasma or in other clinical studies had achieved promising results. Moreover. [51] and the references cited therein). In rats. there is no explanation as to how citic. by itself. (PLA2) [38]. randomized. rupts the mitochondrial respiratory chain). In aged rats. In the open IDEALE (Studio di Intervento nel found to increase sirtuin-1 (SIRT1) protein levels in cul. has been shown to abolish the expected on the basis of animal experiments (see the paper neuroprotection offered by citicoline. developing neurodegenerative diseases. a potent synergistic effect with resveratrol (which is known Also. How is citicoline catabolized? In humans.213 on a molar basis. which increase in the brain level of platelet-activating factor (a involves the entire central visual pathway. equimolar choline (see below)? The negative outcomes of these studies were deemed sur. the latter effect could have been related to increases a specific inhibitor of SIRT1 which. 49]. which focused challenge with citicoline was accompanied by an increase mostly. For example. detailed in its negligible toxicity and virtual lack of side effects but mechanistic explanations for all of these effects are lack. In this last study. leading to a 60 % reduction in the ischaemic cerebrovascular disease. jective improvement and mood-enhancing effect. 41]. also in the fact that it appears to deliver a significant sub- ing. but not least. choline increase provide an explanation for the lack of severe acute ischaemic stroke [44]—led to the conclusion cholinergic toxicity of citicoline versus the toxic effects of that citicoline is not efficacious in these clinical settings. Grieb The other mechanisms suggested to be involved in the [45–47]. What happened to the tional. administration of cit- experimental infarct volume in rats when both drugs were icoline in an intravenous dose of 2. two recent location(s)? Of note is that. according to the dysfunction [48. The other is mild vascular cognitive most recent report [42]. following injection or ingestion large randomized multicenter trials—the COBRIT (Citic. the particulars of this decomposition process are for human brain diseases. aspects of the evaluation of the clinical effects of the drug the participants took oral citicoline doses of up to 4 g (still .

Similar doubts may be raised against the recent report whereas the brain cortex and cerebellum were the organs by Gutiérrez-Fernández et al. Is there any difference between the metabolic peaks were delayed by one or more hours. cytidine results in a clinical setting may be the use of excessively and choline enter brain cells separately and are used for large doses of citicoline in most animal experiments. i. Evi- At this point. Would this indicate that hydrolysis of citicoline to models of embolic stoke [58] provided evidence that cit- CMP and PCho and consecutive dephosphorylations of icoline does indeed deliver some neuroprotection. ischaemic seen after similar doses of choline chloride. Second.Citicoline for Neuroprotection 189 much less per kilogram of bodyweight than the doses used syndrome related to coronary plaque instability [57].g. intravenously. the difference between citicoline (syn. or are they instead minor fraction of the choline dose administered as citico.) the tracer was by the kidney. who compared the taking up less than 0. lung and adrenal glands. various cardiovascular and as sodium salt. However. to detect any significant quantities of citicoline intake and those resulting from a heart attack or cytidine in human blood. For example. followed by conversion of cytidine to uri. Can endogenously) acquires its key importance. on a molar basis. the ischaemic heart is the source of increased cho. see Wardlaw et al. the effect is stronger for infarct volume reduction and immediately. effects of citicoline (1. it must be appreciated that only a shock (as suggested by Savci et al. [59] and the believed that when citicoline is exogenously administered references quoted therein). in a series of papers authored by Savci and col- in a recent paper. Ramos-Cabrer et al. itary hormones. First. The data studies in which elevated levels of whole blood choline resembled the rat data reported previously by the same were also found in patients with stroke or cerebral laboratory [20] in that the magnitude of the choline ischaemia in combination with advanced plaques in the increases was several times smaller than the magnitude of carotid artery. in most rodent experiments). The authors con- dine? But why is the final effect—namely. [62]. e. either before or after citicoline stroke? intake. however. it would be of line enters the brain. not reproduced in the clinical setting? The systematic form cytidine liberated from citicoline to circulating uri. more limited for neurological outcome. dence of histaminergic system involvement in the thesized exogenously) and CDP-choline (synthesized responses to citicoline has also been presented [60]. infarct size and/or neurological deficit. The leading to betaine (an important donor of methyl groups) problem with this paper was that whereas the rt-PA dose and the other leading to acetylcholine (an important CNS used per kg of bodyweight was 5 to 8 times the dose used neurotransmitter). It is reasonable to assume that degradation the pyrimidine increase. to those levels occur in all cases of brain ischaemia. Tolvanen et al. it is hydrolysed into choline and cytidine to endocrine effects of large. [54] stated ‘‘It is laborators (see the paper by Eyigor et al. although the stroke. [55] investigated the importance to find an explanation for the observation that biodistribution and biokinetics of [11C]choline (a radio. the authors mention small unpublished pilot increases in blood plasma uridine were observed. the citicoline dose line in the blood of patients with an acute coronary was 15 to 30 times the dose used in clinical trials of . [61]). although subtoxic. the most icoline intake and the pharmacodynamics of citicoline.5–2 g/kg) given intravenously were described. in hypovolaemic three reasons. including vasopressin and oxytocin. It is important cause of the irreproducibility of preclinical usually assumed that following citicoline intake.6–1. For intracellular synthesis of CDP-choline [36]. These statements citicoline (0. should also be taken into account [56].e. The authors effects of choline increases in plasma consequential to failed. for at least these effects be of potential benefit. one intravenously) in a rat model of embolic stroke. doses of be re-synthesized later in the brain…’’. seem to imply that resynthesis of citicoline from cytidine Among them were an increase in blood pressure and large and choline in the brain is the only event—or at least the rises in plasma levels of catecholamines and several pitu- most important event—of systemic citicoline application. an early sign of toxicity? (On the other hand. in the treatment of human embolic stroke (0. in rats—both normotensive and haemorrhagic—these pharmaceutical used for oncological positron emission massive doses of citicoline increased blood pressure. They found that the highest uptake of of either cytidine or choline. Choline increments obtained after of membrane phospholipids and elevation of blood choline 2 or 4 g doses were comparable. [63]). They interpreted this finding as evidence that the Why were preclinical results with citicoline for stroke human gastrointestinal tract and liver quantitatively trans.000 mg/kg intraperitoneally) and stimulation following citicoline intake of at least two other recombinant tissue plasminogen activator [rt-PA] (5 mg/kg major synthetic pathways of choline in the brain. tomography [PET] studies) in rats and humans following whereas no such effect occurred following equivalent doses intravenous injection. review and meta-analysis of data obtained with preclinical dine.1 % of the tracer dose. and significant dose-related Moreover.1 mg/kg Third. an increase in cluded that factors shown to be important for translation circulating choline—delayed by one or more hours? into human studies are multiple-dose administration. large Resynthesis of CDP-choline in the brain following cit. how- these products to cytidine and choline occur almost ever. example.

Although other expla- interpretation of the substantially lower toxicity of citico. postischaemic brain [40] and extracellular signal-regulated phosphatases. 70] and Adibhatla et al. liposomal formulations of citicoline are intravenous application was compared by Agut et al. one should consider the possi- oral intake are usually interpreted in terms of a prodrug. compound remotely similar to citicoline. a (bioactivated) to the active pharmacological agents.190 P. resulting in release of choline and cytidine. [64]. they could not rule out the possibility that following occurs through transduction of extracellular signals [72. However.3–1 g/kg [68].e. oral intake. whereas in roprotective effects of citicoline on the brain is based on . the authors concluded that ‘‘these kinase 1/2 (ERK1/2) in the rat retina after kainic acid (KA) split compounds as well as the original CDP-choline may treatment [71]. nations may be speculated upon. and. In this context. However. 73]. citicoline. no adequate mechanistic explanation Neuroprotective effects in vitro occurred upon exposure of for these observations has ever been provided. The other reason concerns the activity of liposomal cit- Why is citicoline so much less toxic than choline? The icoline. the aforementioned result line compared with that of choline is lacking to date. some fraction of intact citicoline is absorbed. involved in neuronal death—namely. members of the ERK/MAPK family. whereas such toxic [69. Grieb citicoline in stroke. ently. ing observations have been reported on the modulation by and obtained evidence of CDP-choline being broken down citicoline of the activity/expression of some protein kinases in the intestine. properties. A few studies have indicated that in experimental acute toxicity of citicoline and choline after oral and ischaemic stroke. in turn. Thus. retinal cells or brain neurons to citicoline concentrations as The most frequently presented explanation for the neu- low as submicromolar to micromolar [66. i. CDP-choline given by the oral more neuroprotective than the equivalent intravenous dose or intravenous route yields toxicological consequences that of the free drug which. In spite of the negative results of recent pivotal studies in display their own activities. 5 Conclusions several observations may indicate that intact citicoline molecules. [69. the most active form is unhydrolysed action as a signalling molecule could be prolonged. citicoline seems to be a neu- roprotectant that acts weakly in vivo but is much more 4 Unresolved Issues potent in vitro. continuing interest in the neuroprotective properties of One reason for not discarding the idea of intact citico. The drug is non-toxic. drolysed molecules acting extracellularly as signalling sequent dephosphorylation of citicoline after injection or molecules. Perhaps the neuroprotective actions of citicoline are Is citicoline a prodrug or an active compound? The exerted not by its hydrolysis products but by the unhy- consequences of the assumed fast hydrolysis and sub.6–2 mmol/kg. The rationale for investigating the the in vivo (animal) experiments. macologically more active than its metabolites. MAPKs—in the likely due to the actions of intestinal esterases and pyro. whereas cytidine and choline are its pharmacologically less active metabolites. Modulation of activity of cellular kinases be absorbed from the intestinal mucosa as such’’. 67]. which are different from and/or acute ischaemic stroke and traumatic brain injury.e. Apparently. or perhaps CMP and/or PCho intermediates. by means of These authors concluded that CDP-choline given either decreasing the ischaemic infarct volume) than equivalent orally or intravenously did not cause any cholinergic doses of free citicoline (see. If intact citicoline dine and choline. assuming even distribution throughout the body. equivalent to 0. its hydrolysis could be retarded and its reverse is true. Appar. significantly more neuroprotective (i. However. there is more potent than the actions of cytidine and choline. bility of binding of citicoline to plasma proteins such as which is administered in an inactive or less than fully albumin. one may assume that the binds to albumin. the minimal doses nec- effects of injecting citicoline in doses corresponding to essary to produce appreciable neuroprotection were within 30–150 g per person (assuming an average human body. in particular. an amount that could be weight of 70 kg) is doubtful. the range of 0. 70]). Although the prodrug concept clearly prevails in the scientific literature. A mechanistic the equivalent intraperitoneal dose. (intact) citicoline. for example Fresta and Puglisi intoxication in the treated groups. The most recent effects were observed after administration of an equimolar study of this kind [54] indicated that liposomal citicoline is dose of choline. and numerous preclinical line being significantly neuroprotective is the magnitude of data support the view that it displays neuroprotective the protective effect of citicoline in vitro versus in vivo. [65] used citicoline doubly-labelled with carbon-14 at the Does intact citicoline modulate some kinases? Interest- methyl groups of choline and tritium at C5 of pyrimidine. cyti. is compatible with the idea that intact citicoline is phar- Can intact citicoline be delivered orally? Yashima et al. is more neuroprotective than are different from those yielded by choline. Albumin binding has been reported for cytidine active form and is subsequently metabolically converted [74] and also for sphingosylphosphorylcholine [75].

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