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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

the use citicoline Fig. 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]. Since that time. intermingled.g. but others (e. made by Horrocks and a large part of the liberated choline is taken up by the liver (which collaborators [8]. stemmed from the observation. These enzymes are located intracellularly. describing crystallization of CDP-choline from yeast) could be qualified as concerning citicoline (the compound synthesized exogenously). clarified. ADP adenosine diphos- phate. and unresolved issues. includes the enzymes cytidine kinase (CK). intravascular compartment. by Manaka et al. subject of citicoline’s mode of action is far from being lyltransferase. [15] and the references quoted therein). Notwithstanding. For compari- stance of endogenous origin). citicoline into three categories: facts. ‘cytidine-diphosphocholine’. i. 1). the paper by Ansell and Bayliss [6]. i. such otic cells. Citicoline displays negligible toxicity. ATP adenosine triphosphate.g. The pathway of de issues are. as clinical—was performed in the PubMed. respectively.) and ‘citicoline’. cytidine monophosphate (Cyt-P) and phosphocholine (Cho-P) are dephospho- few years later. hundreds of studies concerning various aspects of the preclinical and clinical pharmacology of citicoline have been published. in the endo.2-dicacylglycerol.e. The LD50 for ingested citicoline is even higher at the natural metabolite synthesized inside the cells (a sub. In the first step. CK cytidine kinase. Needless to say. In the second step. The present review is an attempt to classify the CPT CDP-choline:1. CMP cytidine monophosphate. those that are dylcholine. those that remain unexplained. respec- etc. Whereas ‘CDP-choline’ designates tively. 2 Facts diacylglycerol choline phosphotransferase (CPT) [2]. doubts and unresolved phospholipid content in membranes. PC phosphati. and the products arising are for synthesis of phosphatidylcholine through the CDP.2. PPi pyrophosphate solved with an acceptable degree of certainty. of the reversibility of phosphotransferase may explain the unexpectedly low cholinergic toxicity of citicoline) .186 P. A pyrophosphate bridge takes place. in many cases. the term ‘citicoline’ did not son. confirmed in rodents and dogs (see the most recent report The search for relevant literature—non-clinical as well by Schauss et al. 2). the CDP-choline pathway (Fig. the LD50 of an acute single intravenous dose exist until the substance became used as the drug. Choline that is used quickly catabolized (Fig. DAG 1. major issues concerning the neuroprotective properties of CTP cytidine triphosphate. the idea of using it as a neuroprotectant rylated to cytidine (Cyt) and choline (Cho). doubts. equals 4. for the treatment of Parkinson’s disease. an acute single intravenous application of citicoline. some papers cur- rently indexed under the term ‘citicoline’ are dated earlier. The first patent for the use of CDP- ethanolamine.e.150 mg/kg in mice and rats. choline phos- phate cytidilyltransferase (CCT) and CDP-choline:1. accounting for more than half of the total classification is subjective: facts. (PEt) are the two most abundant phospholipids in eukary. to reverse neurodegenerative diseases was issued in 1981 [9]. which its variants (‘CDPcholine’. subsequently available for diverse biosynthetic pathways choline pathway is derived from transport of exogenous and ultimately excreted as carbon dioxide. 1 The cytidine-50 -diphosphocholine (CDP-choline) pathway of least five during the last 4 years [10–14]. 2 Presumed catabolism of citicoline (Cyt-P-P-Cho) in the rodent as a drug was advocated as early as 1974. In the Anglophone medical literature. approximately 8 g/kg in both mice and rats. those that are likely misinterpreted. CCT choline phosphate cytidi. in mice. alone or in combination with CDP-choline.e. as will be discussed later. some of them (e. the paper by Berger and Gimenez [5]. which occurred in the 1970s. i. hydrolysis of the [7] from Japan. The difference between CDP-choline (synthesized endogenously) and citicoline (synthesized exogenously) is not trivial. novo synthesis of PC. the enzymatic synthesis of phosphatidylcholine. Scopus and An impressive example is the median lethal dose (LD50) of Web of Science databases. Grieb enzymes in the brain. However. using the term ‘CDP-choline’. supposedly. Several relevant reviews have also appeared in high-ranking journals.600 and 4. including at Fig.2-diacylglycerol choline phosphotransferase. The compound is plasmic reticulum and cell nucleus [3]. reporting on the concentration of endogenous CDP-choline in the rat brain) undoubtedly concern CDP-choline (the compound synthesized endoge- nously).

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

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

The authors con- dine? But why is the final effect—namely. 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 . [55] investigated the importance to find an explanation for the observation that biodistribution and biokinetics of [11C]choline (a radio. followed by conversion of cytidine to uri. more limited for neurological outcome. and significant dose-related Moreover. The authors effects of choline increases in plasma consequential to failed. one intravenously) in a rat model of embolic stroke. ischaemic seen after similar doses of choline chloride. in hypovolaemic three reasons. it is hydrolysed into choline and cytidine to endocrine effects of large. for at least these effects be of potential benefit. doses of be re-synthesized later in the brain…’’. First. see Wardlaw et al. either before or after citicoline stroke? intake. although the stroke. For intracellular synthesis of CDP-choline [36]. should also be taken into account [56]. in most rodent experiments). dence of histaminergic system involvement in the thesized exogenously) and CDP-choline (synthesized responses to citicoline has also been presented [60]. e. it would be of line enters the brain. They interpreted this finding as evidence that the Why were preclinical results with citicoline for stroke human gastrointestinal tract and liver quantitatively trans. However. [59] and the believed that when citicoline is exogenously administered references quoted therein). For example. Evi- At this point. 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. Ramos-Cabrer et al. These statements citicoline (0. Tolvanen et al. 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. the most icoline intake and the pharmacodynamics of citicoline. Is there any difference between the metabolic peaks were delayed by one or more hours. Second. lung and adrenal glands. it must be appreciated that only a shock (as suggested by Savci et al. They found that the highest uptake of of either cytidine or choline.g. 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.e. on a molar basis. large Resynthesis of CDP-choline in the brain following cit. to those levels occur in all cases of brain ischaemia. Can endogenously) acquires its key importance. various cardiovascular and as sodium salt. an early sign of toxicity? (On the other hand. Choline increments obtained after of membrane phospholipids and elevation of blood choline 2 or 4 g doses were comparable.1 mg/kg Third. Similar doubts may be raised against the recent report whereas the brain cortex and cerebellum were the organs by Gutiérrez-Fernández et al. [62]. 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. [54] stated ‘‘It is laborators (see the paper by Eyigor et al. tomography [PET] studies) in rats and humans following whereas no such effect occurred following equivalent doses intravenous injection. who compared the taking up less than 0.) the tracer was by the kidney.1 % of the tracer dose. effects of citicoline (1. review and meta-analysis of data obtained with preclinical dine. example. the ischaemic heart is the source of increased cho. It is important cause of the irreproducibility of preclinical usually assumed that following citicoline intake. in a series of papers authored by Savci and col- in a recent paper.Citicoline for Neuroprotection 189 much less per kilogram of bodyweight than the doses used syndrome related to coronary plaque instability [57]. 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. in the treatment of human embolic stroke (0. It is reasonable to assume that degradation the pyrimidine increase. to detect any significant quantities of citicoline intake and those resulting from a heart attack or cytidine in human blood. intravenously. itary hormones. [61]). i. however. infarct size and/or neurological deficit. not reproduced in the clinical setting? The systematic form cytidine liberated from citicoline to circulating uri. [63]).5–2 g/kg) given intravenously were described. 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). including vasopressin and oxytocin. the authors mention small unpublished pilot increases in blood plasma uridine were observed. the difference between citicoline (syn. although subtoxic.6–1.000 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. in rats—both normotensive and haemorrhagic—these pharmaceutical used for oncological positron emission massive doses of citicoline increased blood pressure. the effect is stronger for infarct volume reduction and immediately. or are they instead minor fraction of the choline dose administered as citico. how- these products to cytidine and choline occur almost ever.

whereas in roprotective effects of citicoline on the brain is based on . 70]). The other reason concerns the activity of liposomal cit- Why is citicoline so much less toxic than choline? The icoline. Grieb citicoline in stroke. 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. [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. there is more potent than the actions of cytidine and choline. 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. The rationale for investigating the the in vivo (animal) experiments. cyti. i. whereas such toxic [69. the aforementioned result line compared with that of choline is lacking to date. Thus. in turn. no adequate mechanistic explanation Neuroprotective effects in vitro occurred upon exposure of for these observations has ever been provided. nations may be speculated upon. the most active form is unhydrolysed action as a signalling molecule could be prolonged. (intact) citicoline. is more neuroprotective than are different from those yielded by choline. for example Fresta and Puglisi intoxication in the treated groups. 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. continuing interest in the neuroprotective properties of One reason for not discarding the idea of intact citico. compound remotely similar to citicoline. one should consider the possi- oral intake are usually interpreted in terms of a prodrug. or perhaps CMP and/or PCho intermediates. assuming even distribution throughout the body. However.e.6–2 mmol/kg. Although other expla- interpretation of the substantially lower toxicity of citico. 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. 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]. its hydrolysis could be retarded and its reverse is true. ently. citicoline seems to be a neu- roprotectant that acts weakly in vivo but is much more 4 Unresolved Issues potent in vitro. an amount that could be weight of 70 kg) is doubtful. Appar. In this context. postischaemic brain [40] and extracellular signal-regulated phosphatases. The drug is non-toxic. they could not rule out the possibility that following occurs through transduction of extracellular signals [72.e. Apparently. in particular. properties. [69. a (bioactivated) to the active pharmacological agents. bility of binding of citicoline to plasma proteins such as which is administered in an inactive or less than fully albumin. Albumin binding has been reported for cytidine active form and is subsequently metabolically converted [74] and also for sphingosylphosphorylcholine [75]. [64]. one may assume that the binds to albumin. whereas cytidine and choline are its pharmacologically less active metabolites. which are different from and/or acute ischaemic stroke and traumatic brain injury.190 P. 5 Conclusions several observations may indicate that intact citicoline molecules. 70] and Adibhatla et al. involved in neuronal death—namely. macologically more active than its metabolites. and. 73]. Although the prodrug concept clearly prevails in the scientific literature. If intact citicoline dine and choline. the range of 0. liposomal formulations of citicoline are intravenous application was compared by Agut et al. Modulation of activity of cellular kinases be absorbed from the intestinal mucosa as such’’. equivalent to 0. In spite of the negative results of recent pivotal studies in display their own activities. members of the ERK/MAPK family. citicoline. resulting in release of choline and cytidine. A mechanistic the equivalent intraperitoneal dose. The most recent effects were observed after administration of an equimolar study of this kind [54] indicated that liposomal citicoline is dose of choline. MAPKs—in the likely due to the actions of intestinal esterases and pyro. oral intake. drolysed molecules acting extracellularly as signalling sequent dephosphorylation of citicoline after injection or molecules. significantly more neuroprotective (i. However. 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. However. 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. is compatible with the idea that intact citicoline is phar- Can intact citicoline be delivered orally? Yashima et al. 67]. some fraction of intact citicoline is absorbed. A few studies have indicated that in experimental acute toxicity of citicoline and choline after oral and ischaemic stroke. retinal cells or brain neurons to citicoline concentrations as The most frequently presented explanation for the neu- low as submicromolar to micromolar [66.3–1 g/kg [68].

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