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Cytidine 5'-diphosphocholin.

Cytidine 5′-Diphosphocholine (CDP-Choline) in Stroke and Other CNS D. Note: Performing your original search, Cdp-Choline side effects stroke, in PubMed Central will retrieve 5 citations.
Journal List > NIHPA Author Manuscripts
Neurochem Res. Author manuscript; available in PMC 2007 July 28.
Neurochem Res. 2005 January; 30(1): 15–23.
Related material:
Cytidine 5′-Diphosphocholine (CDP-Choline) in Stroke and Other
CNS Disorders

PubMed articles by:
Rao Muralikrishna Adibhatla1,2,3,4 and J. F. Hatcher1 1 Department of Neurological Surgery, University of Wisconsin, Madison, WI 2 Cardiovascular Research Center University of Wisconsin, Madison, WI 3 Veterans Administration Hospital, Madison, WI 4Address reprint requests to: R. M. Adibhatla Department of Neurological Surgery, H4-330, Clinical Science Center, 600Highland Avenue, University of Wisconsin-Madison, Madison, WI 53792-3232. Tel: +608-263-1791; Fax: +608-263-1409;E-mail: The publisher's final edited version of this article is available at Neurochem Res.
See other articles in PMC that cite the published article.
Brain phosphatidylcholine (PC) levels are regulated by a balance between synthesis and hydrolysis.
Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1α/β) activate phospholipase A2 (PLA2) and PC-phospholipase C (PC-PLC) to hydrolyze PC. PC 2 releases free fatty acids including arachidonic acid, and lyso-PC, an inhibitor of CTP-phosphocholine cytidylyltransferase (CCT). Arachidonic acid metabolism by cyclooxygenases/lipoxygenases is a significant source of reactive oxygen species. CDP-choline might increase the PC levels by attenuating PLA2 stimulation and loss of CCT activity. TNF-α also stimulates proteolysis of CCT. TNF-α and IL-1β are induced in brain ischemia and may disrupt PC homeostasis by increasing its hydrolysis (increase PLA2 and PC-PLC activities) and inhibiting itssynthesis (decrease CCT activity). The beneficial effects of CDP-choline may result by counteractingTNF-α and/or IL-1 mediated events, integrating cytokine biology and lipid metabolism.
Re-evaluation of CDP-choline phase III stroke clinical trial data is encouraging and future trails arewarranted. CDP-choline is non-xenobiotic, safe, well tolerated, and can be considered as one of theagents in multi-drug treatment of stroke.
Keywords: Cerebral ischemia, citicoline, clinical trials, interleukin-1β, phospholipases, phospholipids, reactive
oxygen species, tumor necrosis factor, lipidomics
Stroke or “brain attack” is the first leading cause of long-lasting disability, third leading cause of Cytidine 5′-Diphosphocholine (CDP-Choline) in Stroke and Other CNS D. death and continues to be a problem of vast clinical significance. Approximately 3.9 million Americans are stroke survivors, and the after-effects of stroke require more than $51 billion in healthcare costs annually. Presently, tissue plasminogen activator (tPA) is the only FDA approved drug for the treatment of acute ischemic stroke but needs to be administered within 3 h (1). However, there are some concerns that tPA has neurotoxic side effects in addition to its beneficial (thrombolytic) actions (2). Many neuroprotective agents have undergone phase III clinical trials for stroke; most of the trials were abandoned due to ineffectiveness or toxicity of the drug.
Cytidine-5′-diphosphocholine (CDP-choline or Citicoline) is composed of cytidine and choline linkedby a diphosphate bridge and is an essential intermediate in the synthesis of phosphatidylcholine (PC),a major brain phospholipid, via Kennedy pathway. Exogenous CDP-choline is hydrolyzed andabsorbed as cytidine and choline (3), and CDP-choline is re-synthesized from cytidine triphosphate(CTP) and phosphocholine by CTP-phosphocholine cytidylyltransferase (CCT), the rate-limitingenzyme in PC synthesis (see [4] and references therein). CDP-choline also serves as a choline donorin the biosynthesis of the neurotransmitter acetylcholine (5). As the intermediate in PC biosynthesis,it was believed that CDP-choline would rectify membrane damage and provide benefit in CNSdisorders and injury (including stroke).
CDP-choline has been studied in >11,000 volunteers and patients and showed beneficial effects incerebral ischemia, traumatic brain injury, hypoxia, Alzheimer’s and Parkinson’s diseases, learningand memory disorders, alcoholism, drug addiction, amblyopia and glaucoma (Table I.) Citicoline, aninternational non-proprietary name of CDP-choline, is marketed as a prescription drug (in Japan,Spain, France and Italy) or as an over-the-counter dietary supplement in USA. CDP-choline wasoriginally developed for stroke treatment by Ferrer Internacional, S. A. (Barcelona, Spain) and isbeing tested for treatment of Alzheimer’s and Parkinson’s disorders (7). CDP-choline is the onlyagent that is non-xenobiotic and has virtually no side effects. In 1983, 22 articles were published thatdescribed the physi-co-chemical properties, pharmacokinetics, toxicity and bioavailability of thisagent (54). CDP-choline (600 or 1000 mg/day) or placebo to healthy volunteers did not show anyabnormal side effects in terms of hematological or clinical analysis (3). No clinically significant ECGand EEG abnormalities were noticed. Neurological tests, tendon reflexes, blood pressure and heartrate were not affected by any dose of the drug or placebo. The tolerance of CDP-choline is excellentand side effects were rare, never severe and consisted mainly of digestive intolerance, gastrointestinaldiscomfort and restlessness. In no case was it necessary to interrupt the treatment for side effectsattributed to CDP-choline use (55). Recent re-evaluation of USA phase III stroke clinical trial data isencouraging (49) and this agent still holds promise for treatment of acute ischemic stroke. IndevusInc. licensed exclusive North American rights from Ferrer Internacional, S. A. for the manufacture,use and sale of CDP-choline for the treatment of stroke.
Table I
CDP-Choline Studies in in vivo (Normal and Pathological) and in vitro Conditions
There have been 13 stroke clinical trials of CDP-choline since 1980 (nine in Europe and Japan and four in the USA) (5). The European clinical trials showed that CDP-choline improved global and neurological function and promoted earlier motor and cognitive recovery. A large multi-center study Cytidine 5′-Diphosphocholine (CDP-Choline) in Stroke and Other CNS D. in Japan found that CDP-choline showed improvement in a global outcome rating scale. Four major clinical trials in the USA have provided ambiguous results, and thus the beneficial effects of CDP-choline have not been established (49 and references therein). In the first study, CDP-choline improved functional outcome and reduced neurologic deficit. However, two subsequent studies failedto demonstrate improvement in the outcome. On post-hoc analysis, CDP-choline was shown toprovide beneficial effects in a subgroup of moderate-to-severe stroke cases. Subsequent pooling ofindividual patient data from four US trials showed that CDP-choline treatment for 6 weeks improvedoverall recovery at 12 weeks in acute ischemic stroke patients (49 and references therein). Pooleddiffusion-weighted magnetic resonance imaging (DW-MRI) data from two clinical trials showed asignificant dose-dependent reduction on percent change in lesion volume (56). We have summarizedrecent experimental data on the effects of CDP-choline in cerebral ischemia and evaluated severalfactors which might have hindered efficacy of CDP-choline in stroke clinical trials in the USA. Oneof the factors is the brain uptake of CDP-choline. The European and Japanese trials used i.v.
administration in contrast to oral route used in the USA trails. In animal studies, brain uptake ofCDP-choline or its metabolites was 0.5% of the oral dose, whereas i.v. administration elevated brainuptake to 2%. Liposome encapsulation of the drug can further increase brain uptake up to 23%(8,21) and also circumvent CCT, the key rate-limiting enzyme in PC synthesis. Liposomeencapsulation suggests a possible strategy to increase the CDP-choline levels in the CNS and enhanceits clinical effectiveness (8). In the light of recent clinical evaluations, experimental data in cerebralischemia, and realization that oral administration was not appropriate, new phase III stroke clinicaltrials are warranted. Benefit from CDP-choline in humans is far from proven, however future trialsare essential before making any conclusions that CDP-choline is ineffective for stroke treatment.
Alzheimer’s Disease and Other Memory Disorders
Clinical studies have demonstrated that CDP-choline improves cognitive performance in elderlysubjects (36). Blocking synthesis of PC is sufficient in itself to cause cell death (57,58), and a 10%loss of cellular membrane is a threatening situation for neuronal viability (59). Alzheimer’s brainshave shown loss of PC and phosphatidylethanolamine (60) and CDP-choline may rectify themembrane damage in these brains (36). Additionally, the cholinergic system is dysfunctional inAlzheimer’s brain (50), and CDP-choline may provide benefit by enhancing acetylcholine synthesis(Fig. 1A).
Fig. 1
CDP-choline: (A) possible neuroprotective pathways based on the published reports,
(B) effects mediated by attenuating PLA2 stimulation (based on authors’ work). ↑
indicates increase; ↓ indicates decrease.
Parkinson’s Disease
CDP-choline stimulates tyrosine hydroxylase activity and dopamine release (3), which may be due toincreases in brain acetylcholine since choline administration produced the same effects (61).
Parkinson’s disease is characterized by a selective degeneration of the dopaminergic neurons of thesubstantia nigra (62), however the phospholipid abnormalities present in Alzheimer’s brains were notobserved (60). Levodopa is the main therapeutic option for treatment of Parkinson’s disease; its maindisadvantage is progressive loss of efficacy (63). CDP-choline has been tested in treatment ofParkinson’s disease because of its ability to increase the availability of dopamine (3). Combinationtreatment of Parkinson’s patients with CDP-choline and levodopa allowed significant reduction ofthe levodopa dose, thus minimizing side effects of levodopa therapy (3).


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