What is the action of citicoline

While it seems reasonable to assume that, at least in rodents, citicoline given systemically is quickly hydrolysed and further dephosphorylated, the particulars of this decomposition process are uncertain. Does it take place in blood plasma or in other location s? Of note is that, following injection or ingestion of citicoline in the rat, the increase in plasma cytidine was, on a molar basis, several times larger than the concomitant increase in plasma choline [ 20 ]. Was it taken up by the liver?

How is citicoline catabolized? In humans, an oral challenge with citicoline was accompanied by an increase in plasma uridine instead of cytidine [ 53 ]. In this last study, the participants took oral citicoline doses of up to 4 g still much less per kilogram of bodyweight than the doses used in most rodent experiments , and significant dose-related increases in blood plasma uridine were observed.

The data resembled the rat data reported previously by the same laboratory [ 20 ] in that the magnitude of the choline increases was several times smaller than the magnitude of the pyrimidine increase.

Choline increments obtained after 2 or 4 g doses were comparable, on a molar basis, to those seen after similar doses of choline chloride, although the peaks were delayed by one or more hours. The authors failed, however, to detect any significant quantities of cytidine in human blood, either before or after citicoline intake. They interpreted this finding as evidence that the human gastrointestinal tract and liver quantitatively transform cytidine liberated from citicoline to circulating uridine.

Would this indicate that hydrolysis of citicoline to CMP and PCho and consecutive dephosphorylations of these products to cytidine and choline occur almost immediately, followed by conversion of cytidine to uridine?

But why is the final effect—namely, an increase in circulating choline—delayed by one or more hours? Resynthesis of CDP-choline in the brain following citicoline intake and the pharmacodynamics of citicoline. It is usually assumed that following citicoline intake, cytidine and choline enter brain cells separately and are used for intracellular synthesis of CDP-choline [ 36 ]. For example, in a recent paper, Ramos-Cabrer et al. These statements seem to imply that resynthesis of citicoline from cytidine and choline in the brain is the only event—or at least the most important event—of systemic citicoline application.

At this point, the difference between citicoline synthesized exogenously and CDP-choline synthesized endogenously acquires its key importance, for at least three reasons. First, it must be appreciated that only a minor fraction of the choline dose administered as citicoline enters the brain.

Tolvanen et al. They found that the highest uptake of the tracer was by the kidney, lung and adrenal glands, whereas the brain cortex and cerebellum were the organs taking up less than 0. Second, stimulation following citicoline intake of at least two other major synthetic pathways of choline in the brain, one leading to betaine an important donor of methyl groups and the other leading to acetylcholine an important CNS neurotransmitter , should also be taken into account [ 56 ].

Third, the ischaemic heart is the source of increased choline in the blood of patients with an acute coronary syndrome related to coronary plaque instability [ 57 ]. Moreover, the authors mention small unpublished pilot studies in which elevated levels of whole blood choline were also found in patients with stroke or cerebral ischaemia in combination with advanced plaques in the carotid artery.

It is reasonable to assume that degradation of membrane phospholipids and elevation of blood choline levels occur in all cases of brain ischaemia, i. Is there any difference between the metabolic effects of choline increases in plasma consequential to citicoline intake and those resulting from a heart attack or stroke?

Why were preclinical results with citicoline for stroke not reproduced in the clinical setting? The systematic review and meta-analysis of data obtained with preclinical models of embolic stoke [ 58 ] provided evidence that citicoline does indeed deliver some neuroprotection; however, the effect is stronger for infarct volume reduction and more limited for neurological outcome.

However, the most important cause of the irreproducibility of preclinical results in a clinical setting may be the use of excessively large doses of citicoline in most animal experiments. For example, in a series of papers authored by Savci and collaborators see the paper by Eyigor et al. Among them were an increase in blood pressure and large rises in plasma levels of catecholamines and several pituitary hormones, including vasopressin and oxytocin.

Evidence of histaminergic system involvement in the responses to citicoline has also been presented [ 60 ]. Can these effects be of potential benefit, e. On the other hand, it would be of importance to find an explanation for the observation that in rats—both normotensive and haemorrhagic—these massive doses of citicoline increased blood pressure, whereas no such effect occurred following equivalent doses of either cytidine or choline. The problem with this paper was that whereas the rt-PA dose used per kg of bodyweight was 5 to 8 times the dose used in the treatment of human embolic stroke 0.

The rationale for investigating the effects of injecting citicoline in doses corresponding to 30— g per person assuming an average human bodyweight of 70 kg is doubtful.

Why is citicoline so much less toxic than choline? The acute toxicity of citicoline and choline after oral and intravenous application was compared by Agut et al. These authors concluded that CDP-choline given either orally or intravenously did not cause any cholinergic intoxication in the treated groups, whereas such toxic effects were observed after administration of an equimolar dose of choline. Apparently, CDP-choline given by the oral or intravenous route yields toxicological consequences that are different from those yielded by choline.

A mechanistic interpretation of the substantially lower toxicity of citicoline compared with that of choline is lacking to date. Can intact citicoline be delivered orally? Yashima et al. Apparently, they could not rule out the possibility that following oral intake, some fraction of intact citicoline is absorbed. Is citicoline a prodrug or an active compound? The consequences of the assumed fast hydrolysis and subsequent dephosphorylation of citicoline after injection or oral intake are usually interpreted in terms of a prodrug, which is administered in an inactive or less than fully active form and is subsequently metabolically converted bioactivated to the active pharmacological agents, cytidine and choline.

However, one may assume that the reverse is true, i. One reason for not discarding the idea of intact citicoline being significantly neuroprotective is the magnitude of the protective effect of citicoline in vitro versus in vivo.

Neuroprotective effects in vitro occurred upon exposure of retinal cells or brain neurons to citicoline concentrations as low as submicromolar to micromolar [ 66 , 67 ], whereas in the in vivo animal experiments, the minimal doses necessary to produce appreciable neuroprotection were within the range of 0. Thus, citicoline seems to be a neuroprotectant that acts weakly in vivo but is much more potent in vitro.

The other reason concerns the activity of liposomal citicoline. A few studies have indicated that in experimental ischaemic stroke, liposomal formulations of citicoline are significantly more neuroprotective i. The most recent study of this kind [ 54 ] indicated that liposomal citicoline is more neuroprotective than the equivalent intravenous dose of the free drug which, in turn, is more neuroprotective than the equivalent intraperitoneal dose.

Although other explanations may be speculated upon, the aforementioned result is compatible with the idea that intact citicoline is pharmacologically more active than its metabolites. Does intact citicoline modulate some kinases?

Perhaps the neuroprotective actions of citicoline are exerted not by its hydrolysis products but by the unhydrolysed molecules acting extracellularly as signalling molecules. In this context, one should consider the possibility of binding of citicoline to plasma proteins such as albumin. Albumin binding has been reported for cytidine [ 74 ] and also for sphingosylphosphorylcholine [ 75 ], a compound remotely similar to citicoline. If intact citicoline binds to albumin, its hydrolysis could be retarded and its action as a signalling molecule could be prolonged.

In spite of the negative results of recent pivotal studies in acute ischaemic stroke and traumatic brain injury, there is continuing interest in the neuroprotective properties of citicoline. The drug is non-toxic, and numerous preclinical data support the view that it displays neuroprotective properties.

However, no adequate mechanistic explanation for these observations has ever been provided. The most frequently presented explanation for the neuroprotective effects of citicoline on the brain is based on the assumption that it is a prodrug which, following injection or ingestion, is sequentially hydrolysed and dephosphorylated, finally, to cytidine or uridine in humans and choline.

Then these two metabolites separately enter the brain tissues and are used to resynthesize CDP-choline, which exerts neuroprotection intracellularly by supporting biosynthesis of cellular phospholipids.

An alternative explanation—i. The enzymatic formation of lecithin from cytidine diphosphate choline and d -1,2-diglyceride. J Biol Chem. Gibellini F, Smith TK.

The Kennedy pathway—de novo synthesis of phosphatidylethanolamine and phosphatidylcholine. Highly saturated endonuclear phosphatidylcholine is synthesized in situ and colocated with CDP-choline pathway enzymes. Kent C, Carman GM. Interactions among pathways for phosphatidylcholine metabolism, CTP synthesis and secretion through the Golgi apparatus.

Trends Biochem Sci. Berger L, Gimenez WT. Crystallization of cytidine diphosphate choline from yeast. The cytidine diphosphate choline content of rat brain. Biochem J. Mechanism of action CDP-choline in parkinsonism. Prog Lipid Res. Therapeutic agents for preventing phospholipid degradation and free fatty acid proliferation.

United States Patent. Citicoline, use in cognitive decline: vascular and degenerative. J Neurol Sci. PubMed Article Google Scholar. Citicoline in vascular cognitive impairment and vascular dementia after stroke. CDP-choline as a biological supplement during neurorecovery: a focused review. Article Google Scholar. Neuroprotection and recovery: recent data at the bench on citicoline. Secades JJ. Probably role of citicoline in stroke rehabilitation: review of the literature.

Rev Neurol. PubMed Google Scholar. Int J Toxicol. Efficacy and safety of oral citicoline in acute ischemic stroke: drug surveillance study in 4, cases. Methods Find Exp Clin Pharmacol. Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials. Biochemical rationale for the use of CDPcholine in traumatic brain injury: pharmacokinetics of the orally administered drug.

A recent systematic review and meta-analysis comparing intra-arterial thrombolysis vs. However, lesion-size increase was significantly smaller in those treated with i.

Therefore, recanalization treatment only controls partially the biochemical and molecular events triggered by cerebral ischemia, indicating that other factors must be controlled [ 11 , 12 ]; such factors include, but are not limited to, collateral blood flow, body temperature, hyperglycemia [ 13 , 14 , 15 , 16 ], and blood pressure fluctuations. Ideally, sufficient protection must be provided to the ischemic brain neuroprotection along with enhanced recovery of the damaged brain neurorepair.

Finally, incorporating stroke unit care and thrombolysis into medical services is difficult and even impossible in many low- and middle-income countries—which have the greatest burden of stroke—because the required high levels of infrastructure, expertise, and resources are unavailable.

Therefore, safe and effective neuroprotective drugs that could be given at medical services with limited resources would improve the outcome of millions of acute stroke patients. Ischemic neuroprotection brain protection may be defined as any strategy, or combination of strategies, that antagonizes, interrupts, or slows down the sequence of injurious biochemical and molecular events that, if left unchecked, eventually result in irreversible ischemic injury [ 12 ].

Neuroprotection attempts to limit the brain damage produced by ischemia. Experimental studies have demonstrated the complexity of the pathophysiology of stroke [ 17 , 18 , 19 , 20 ]. Among others, it involves excitotoxicity mechanisms [ 18 ], oxidative stress damage [ 19 , 20 , 21 ], inflammatory pathways [ 22 , 23 ], ionic imbalances, apoptosis, and angiogenesis [ 24 , 25 ] that are potential targets being evaluated in clinical trials [ 17 , 18 ].

Although successful in experimental models, translation to bedside treatments has been disappointing and complicated by some of the following reasons:. There is a need to protect the entire neurovascular unit that comprises neurons, glia, pericytes and blood vessels [ 26 , 27 ]. For many years the goal was to salvage neurons in the ischemic penumbra but recently it became clear that this goal is insufficient and that all the elements of the neurovascular unit must be rescued from ischemia [ 28 ].

Many of the potential targets have a biphasic cycle whereby the same mediator or molecule plays a different role under pathologic or physiological conditions. For instance, in the earliest phase of ischemic stroke the excitatory glutamate NMDA receptors become hyperactive and mediate cell death, but these same receptors are critical for neurogenesis and neuronal plasticity during the recovery phase of stroke. A similar mechanism occurs with metalloproteases [ 29 , 30 , 31 , 32 , 33 , 34 ] that contribute to the breakdown of the blood brain barrier BBB enlarging the ischemic lesion but are critical also for angiogenesis during the rec.

Therefore, better animal models are required to explore the complexity of acute ischemic stroke. The use of preclinical STAIR criteria [ 35 ] provides adequate guidelines but even the strict adherence to these criteria does not predict clinical success. Because of the above reasons, and despite the large number of neuroprotective agents that have been proposed to interrupt the ischemic cascade based on successful animal studies, most therapeutic clinical trials of these agents have yet to show consistent benefit.

According to Sahota and Savitz [ 18 ] the most promising interventions that provide acute neuroprotection tested in larger clinical trials include hypothermia, magnesium sulfate, citicoline, and albumin.

The most promising therapies enhancing neurorecovery in the subacute phase of stroke include granulocyte colony stimulating factor, G-CSF [ 36 ], citicoline, and cell-based therapies. Of all the above agents and methods, only citicoline appears to provide both neuroprotection and enhanced neurorepair with remarkable absence of side effects [ 37 ].

Citicoline is composed of two essential molecules, cytidine and choline Figure 1 , the structural phospholipids of cell membranes. Phospholipids are essential constituents of cells and have a high turnover rate, which requires the continuous synthesis of these compounds to ensure the adequate function of cell membranes.

Damaged cell membranes and impaired metabolism of phospholipids have been implicated in the pathophysiology of cerebral ischemia. It appears that an important component of citicoline neuroprotective capacity is its ability to improve phosphatidylcholine synthesis in the injured brain [ 39 , 40 ]. Chemical structure of citicoline, showing cytidine on the left and diphospho-choline trimethyl-ethanol-ammonium on the right. Cytidine is a nucleoside formed by cytosine attached to a ribose ring.

A large number of research studies have explored the protective effects of citicoline in experimental stroke models [ 37 , 41 ]. At the experimental level, citicoline has been reported to decrease infarct volume and to reduce brain edema, with improvement of neurologic deficits either as a single therapy or in combination with other agents, including rtPA and nimodipine [ 42 ].

A large meta-analysis of experimental stroke studies with citicoline in ischemic stroke concluded that citicoline reduces infarct volume by However, as mentioned later, its effects vary with the dose whereby higher doses of citicoline produced greater reduction of brain damage compared with lower doses. Using a recent experimental model of stereotactic drug delivery to bypass the BBB delivering citicoline in direct contact with ischemic neurons in a MCA occlusion model in rats, Xu et al.

Citicoline has therapeutic effects at several stages of the ischemic cascade in acute ischemic stroke. First, it stabilizes cell membranes by increasing phosphatidylcholine and sphingomyelin synthesis [ 37 , 44 ] and by inhibiting the release of free fatty acids [ 45 ]. By protecting membranes, citicoline inhibits glutamate release during ischemia. In an experimental model of ischemia in the rat, citicoline treatment decreased glutamate levels and stroke size [ 46 ].

Caspase is activated in human stroke [ 47 ] and citicoline has been shown to decrease the release of damaging caspase activation products [ 48 ] inhibiting apoptosis in animal models of brain ischemia [ 23 ]. Citicoline favors the synthesis of nucleic acids, proteins, acetylcholine and other neurotransmitters, and decreases free radical formation [ 49 , 50 ]. Therefore, citicoline simultaneously inhibits different steps of the ischemic cascade protecting the injured tissue against early and delayed mechanisms responsible for ischemic brain injury.

Finally, citicoline may facilitate recovery by enhancing synaptic outgrowth and increased neuroplasticity [ 50 ] with decrease of neurologic deficits and improvement of behavioral performance, as well as learning and memory tasks [ 40 ]. For the past two decades, multiple randomized clinical stroke trials on citicoline reported the effectiveness of this pharmacological intervention when used early after onset of ischemia, as demonstrated by improvements in level of consciousness and modified Rankin score [ 51 ].

Given that various populations of stroke patients were included in these studies using different sample sizes, multiple doses, and several outcome endpoints, it became difficult to reach valid conclusions. Most studies, however, demonstrated a positive effect with the use of citicoline during the acute and subacute phases of ischemic stroke [ 52 ]. For instance, the ECCO trial [ 53 ] included 90 patients that underwent diffusion-MRI prior to the onset of the treatment and a second one with T2 sequences 12 weeks later.

Patients treated with 2 g daily of citicoline orally had an initial lesion volume of 62 mL and this was reduced six weeks later to 17 mL; in comparison with controls, the MRI reduction in infarct size was statistically significant [ 53 ]. This study reviewed all randomized double-blind, parallel, placebo-controlled studies performed in patients with ischemic stroke treated with either citicoline or placebo within the first 24 h of the onset of symptoms and during a period of six weeks.

The daily oral doses used ranged from mg, mg, to mg. Following a comprehensive review, a total of patients were included in the data pooling analysis, treated with citicoline and with placebo, from four controlled clinical trials performed in the USA [ 55 , 56 , 57 , 58 ]. After 12 weeks of treatment Upon individual analysis of each one of the three variables that conform to the main global variable, it was determined that improvement occurred both with neurological deficits measured by the NIH-SS, as well as with functional scales BI and mRS.

In comparison with placebo-treated subjects, citicoline-treated patients reached a higher percentage of complete neurological and functional recovery. This was particularly clear with mRS scores OR 1. There were no differences in side effects or number of cases withdrawing from the trial between the two groups. A meta-analysis by Sever [ 59 ] of 10 controlled clinical trials using citicoline studied patients, including both ischemic and hemorrhagic stroke distributed as follows, ischemic stroke: on citicoline vs.

This meta-analysis demonstrated similar results to those of the data pooling analysis. In comparison with placebo, patients treated with citicoline showed significant reduction in the frequency of death or disability at follow-up Safety analysis showed no adverse effects in comparison with placebo ICTUS was an international, multicenter, prospective, double-blind, randomized, placebo-controlled trial with participation of neurology services from 37 centers in Spain, 11 in Portugal, and 11 in Germany.

Patients were randomized in a ratio to citicoline or placebo. The main objective of the study was to confirm the results of the data pooling analysis; i. The main global variable was studied using GEE analysis.

The results were as follows [ 60 ]: from a total of patients enrolled into the study were assigned to citicoline and to placebo. The trial was stopped for futility at the 3rd interim analysis on the basis of complete data from patients. Global recovery at 90 days was similar in both groups. The median unbiased estimate of the adjusted odds ratio of the primary efficacy endpoint was 1. The odds ratios were also neutral in the sub-groups defined by minimization factors.

Adverse events occurred with similar frequency in both groups. Citicoline had no significant effect on the risk of hemorrhage from rtPA and had a comparable safety and tolerability profile compared to placebo. Global recovery at 90 days was similar in patients who received citicoline and in those who received placebo. Results were also neutral in the secondary endpoints and in the predetermined protocol analyses. Under the circumstances of the ICTUS trial, citicoline is safe but does not provide efficacy evidence for the treatment of moderate-to-severe acute ischemic stroke.

It is conceivable that larger doses for a longer period could have had a positive effect. Larger reduction of stroke volume was also documented in another study [ 61 ]; moreover, citicoline at high doses is as effective as i.

Patients enrolled in the ICTUS trial were not required to have neuroimaging studies of ischemic penumbra. Therefore, it was impossible to determine if at the onset of therapy salvageable brain tissue was present; moreover, this lack of images prevented accurate evaluation of stroke evolution. Finally, a substantial number of patients received i.

Thus, a ceiling effect resulting from an already maximal improvement due to rtPA effect cannot be ruled out. Additionally, the trials were done 10 years apart, a period of time during which the standard of stroke care has improved substantially.

This was a pilot, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of citicoline in patients with acute intracerebral hemorrhage AICH.

The study enrolled patients aged 40—85 years old with a primary hemispheric supratentorial hemorrhage within less than 6 h of evolution. Safety analysis showed no differences with placebo in terms of adverse effects, mortality or study withdrawals. The results showed that 6. In conclusion, citicoline is a safe and effective pharmacological product in patients with AICH and can be used in acute stroke patients even before images are obtained to separate ischemic from hemorrhagic stroke.

Spontaneous recovery of function occurs naturally after stroke in both humans and in animal models. This functional recovery is generally incomplete and results from reversal of diaschisis, activation of cellular genesis, repair mechanisms, change in the properties of the existing neuronal pathways and stimulation of neuronal plasticity leading to new neuronal connections [ 64 , 65 ].

In patients with ischemic stroke neurological recovery occurs over a period of three months, and this is the usual evaluation time for final outcome in neuroprotection trials. However, recovery is only possible when neurorepair occurs, including not only repair of the damaged neurons, but also enhancement of angiogenesis [ 66 ] and brain plasticity neuronal and synaptic.

The adult human brain has the capacity to undergo physiological and anatomical modifications leading to motor and cognitive recovery [ 67 ]. Cerebral ischemia launches concurrently neurogenesis and angiogenesis, two closely interconnected processes that enhance neural repair. There is definitive evidence that neurogenesis occurs in the adult brain following a stroke.

Endogenous progenitor neural stem cells are normally present in the normal brain and maintain the capacity to produce new neurons and glial cells during adult life. Progenitor neural stem cells capable of producing neuroblasts in the adult human brain are situated in the subventricular zone of the lateral ventricle and in the dentate gyrus of the hippocampus.

Under physiological conditions the neuroblasts of the subventricular zone migrate towards the olfactory bulb where they are transformed into neurons. In response to brain ischemia, the adult progenitor neural cells proliferate in the ipsilateral subventricular zone and migrate towards the zone surrounding the infarction where they mature into adult neurons that may become part of functional neuronal circuits [ 68 ].

Neuropathological studies have shown the increase in cellular proliferation and in neuroblasts in the subventricular zone in patients who died shortly after an acute ischemic stroke [ 68 ]. However, many of the newly formed immature neurons and neural cells die and are never integrated into functional neuronal circuits. For this reason, it is important to develop novel cellular and pharmacological strategies to increase neurogenesis leading to functional neuronal circuits.

Repair of focal cortical strokes [ 69 ] is not done by neuroblasts migrating from the subventricular zone but from clonal neural spheres originating from the peri-infarct area that differentiate into neurons, astrocytes, oligodendrocytes, and smooth muscle cells.

Angiogenesis [ 66 ] is one of the main components of the processes of post-ictal neurovascular remodeling. It induces capillary neoformation in response to proliferation and migration of primordial stem cells originating from the existing blood vessels.

The pericytes appear to have a major role in neurogeneration responses. The pericyte is a pluripotent stem cell in the brain with the potential of differentiating into cells of neural lineage such as astrocytes, oligodendrocytes and neurons [ 70 ]. Angiogenesis can be observed several days following an ischemic stroke and it has been shown that a higher capillary density correlates with longer survival.

Proangiogeneic factors such as vascular endothelial growth factor or VEGF [ 71 ], and metalloproteinases increase following cerebral ischemia. The effect of angiogenesis is to increase collateral circulation to meet the metabolic demands in terms of oxygen, glucose and nutrients required by the damaged and repaired tissues.

Also, the newly generated blood vessels provide the neurotrophic support required by neurogenesis and synaptogenesis that eventually lead to functional recovery.

In summary, angiogenesis provides the stimulation required to launch and enhance endogenous mechanisms repair and recovery including neurogenesis and synaptogenesis, as well as neuronal and synaptic plasticity. These events are all involved in the long-term repair and restoration process that take place in the brain after acute or chronic ischemic events [ 72 ]; therefore, angiogenesis is one of the most promising areas of research in the field of stroke treatment [ 66 , 67 ].

Repair therapies aim to restore the brain, a goal that differs from that of neuroprotection therapies, in which the aim is to limit acute stroke injury.

Neuromuscular electrical stimulation has been found to improve neuromuscular function and to stimulate cerebral plasticity [ 74 ]. Transcranial magnetic stimulation [ 75 ], in addition to physical and occupational therapy, significantly improves motor function. Improvement is due to stronger stimulation of intact motor cortical regions homolateral to the hemiplegic side [ 75 ].

Finally, there is an enormous potential with the use of robotic therapy after stroke [ 75 ]. A number of medications have been used to enhance recovery and tissue repair following ischemic stroke. Among the anti-depressants, serotonine uptake inhibitors SSRIs and noradrenergic inhibitors have been demonstrated to improve motor recovery in patients with ischemic stroke [ 76 , 77 ].

The mechanism of action of SSRIs is unknown. The role of the CDP-choline pathway. The major sites of cellular phospholipid synthesis and molecular determinants of Fatty Acid and lipid head group specificity. Mol Biol Cell. Citicoline: pharmacological and clinical review.

Clin Pharmacol. Citicoline CDP-choline : What role in the treatment of complications of infectious diseases. Int J Biochem Cell Biol. Weiss GB. Citicoline CDP-choline : mechanisms of action and effects in ischemic brain injury. Neurol Res. Differential effect of CDP-choline on brain cytosolic choline levels in younger and older subjects as measured by proton magnetic resonance spectroscopy.

Psychopharmacology Berl. Effect of oral CDP-choline on plasma choline and uridine levels in humans. Biochem Pharmacol. Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy. NMR Biomed. Secades JJ, Frontera G. CDP-choline: pharmacological and clinical review. Methods Find Exp Clin Pharmacol. Effects of cytidine-diphosphocholine on acetylcholine-mediated behaviors in the rat.

Brain Res Bull. Citicoline: neuroprotective mechanisms in cerebral ischemia. J Neurochem. Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia.

J Neurosci Res. Cytidinediphosphocholine supplement in early life induces stable increase in dendritic complexity of neurons in the somatosensory cortex of adult rats.

Potential benefits of Methylcobalamin; A Review. Austin Journal of Pharmacology and Therapeutics. Effect of CDP-choline on learning and memory processes in rodents. Effects of cytidine diphosphate choline on rats with memory deficits. Dietary cytidine 5' -diphosphocholine supplementation protects against development of memory deficits in aging rats.

Prog Neuropsychopharmacol Biol Psychiatry. Dietary CDP-choline supplementation prevents memory impairment caused by impoverished environmental conditions in rats. Learn Mem. Citicoline improves verbal memory in aging. Arch Neurol. Citicoline improves memory performance in elderly subjects.

Effects of CDP-choline on cognition and cerebral hemodynamics in patients with Alzheimer's disease. CDP-choline-induced blood histamine changes in Alzheimer's disease. Effect of CDP-choline on cognition and immune function in Alzheimer's disease and multi-infarct dementia. Ann N Y Acad Sci. Therapeutic effects of CDP-choline in Alzheimer's disease. Cognition, brain mapping, cerebrovascular hemodynamics, and immune factors.

Systematic evaluation of rating scales for impairment and disability in Parkinson's disease. Mov Disord. Citicoline in the treatment of Parkinson's disease. Clin Ther. Overgaard K, Meden P.

Citicoline--the first effective neuroprotectant to be combined with thrombolysis in acute ischemic stroke? J Neurol Sci. The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives. Clin Interv Aging. The role of citicoline in neuroprotection and neurorepair in ischemic stroke.