Citicoline
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| Clinical data |
| Trade names |
Neurocoline |
| AHFS/Drugs.com |
International Drug Names |
| ATC code |
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| Identifiers |
IUPAC name
- 5'-O-[hydroxy({hydroxy[2-(trimethylammonio)ethoxy]
phosphoryl}oxy)phosphoryl]cytidine
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| Synonyms |
Cytidine diphosphate choline |
| CAS Number |
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| PubChem CID |
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| ChemSpider |
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| UNII |
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| KEGG |
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| ChEBI |
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| ChEMBL |
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| ECHA InfoCard |
100.012.346 |
| Chemical and physical data |
| Formula |
C14H27N4O11P2+ |
| Molar mass |
489.332 g/mol |
| 3D model (JSmol) |
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SMILES
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C[N+](C)(C)CCOP(=O)([O-])OP(=O)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=CC(=NC2=O)N)O)O
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InChI
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InChI=1S/C14H26N4O11P2/c1-18(2,3)6-7-26-30(22,23)29-31(24,25)27-8-9-11(19)12(20)13(28-9)17-5-4-10(15)16-14(17)21/h4-5,9,11-13,19-20H,6-8H2,1-3H3,(H3-,15,16,21,22,23,24,25)/t9-,11-,12-,13-/m1/s1 N
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Key:RZZPDXZPRHQOCG-OJAKKHQRSA-N N
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| NY (what is this?) (verify) |
Citicoline (INN), also known as cytidine diphosphate-choline (CDP-Choline) or cytidine 5'-diphosphocholine is an intermediate in the generation of phosphatidylcholine from choline, a common biochemical process in cell membranes. Citicoline is naturally occurring in the cells of human and animal tissue, in particular the organs.
Studies suggest that CDP-choline supplements increase dopamine receptor densities,[1] and suggest that CDP-choline supplementation helps prevent memory impairment resulting from poor environmental conditions.[2] Preliminary research has found that citicoline supplements help improve focus and mental energy.[3][4]
Citicoline has also been shown to elevate ACTH independently from CRH levels and to amplify the release of other HPA axis hormones such as LH, FSH, GH and TSH in response to hypothalamic releasing factors.[5] These effects on HPA hormone levels may be beneficial for some individuals but may have undesirable effects in those with medical conditions featuring ACTH or cortisol hypersecretion including PCOS, type II diabetes and major depressive disorder.[6][7]
Contents
- 1 Medical uses
- 1.1 Memory disorders
- 1.2 Ischemic stroke
- 1.3 Vision
- 2 Mechanism of action
- 2.1 Neuroprotective effects
- 2.2 Neuronal membrane
- 2.3 Cell signalling
- 2.4 Glutamate transport
- 3 Pharmacokinetics
- 4 Synthesis
- 5 See also
- 6 References
Medical uses
Citicoline is available as a supplement online and in stores. It is sold in over 70 countries under a variety of brand names: Cebroton, Ceraxon, Cidilin, Citifar, Cognizin, Difosfocin, Hipercol, NeurAxon, Nicholin, Sinkron, Somazina, Synapsine, Startonyl, Trausan, etc.[8] When taken as a supplement citicoline is hydrolyzed into choline and cytidine in the intestine.[9] Once these cross the blood–brain barrier it is reformed into citicoline by the rate-limiting enzyme in phosphatidylcholine synthesis, CTP-phosphocholine cytidylyltransferase.[10][11]
Memory disorders
In a review of 14 clinical trials, the authors concluded there was evidence of benefit of citicoline on memory function and behaviour in patients suffering from cognitive deficits ranging from mild cognitive impairment to dementia. Dosing in most of the trials was 1000 mg/day.[12] A more recent review reached the same conclusions, but went on to state that more clinical trials are needed to confirm its benefits.[13]
Ischemic stroke
Citicoline is approved for treatment in cases of head trauma, stroke, and neurodegenerative disease in Japan and Europe.[citation needed] Citicoline improves the clinical outcome following an ischemic stroke, as evidenced by the reduction in size of lesions caused by ischemic strokes after supplementation.[14] It has been claimed that citicoline reduces rates of death and disability following an ischemic stroke.[15] However, the largest trial to date, a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke in Europe, enrolling 2298 patients, found no benefit of administering citicoline on survival or recovery from stroke.[16] A meta-analysis of seven trials reported no statistically significant benefit for long-term survival or recovery.[17]
Vision
Citicoline has been suggested to improve visual function in patients with glaucoma.[18]
Mechanism of action
Enzymes involved in reactions are identified by numbers. See file description.
Neuroprotective effects
The neuroprotective effects exhibited by citicoline may be due to its preservation of cardiolipin and sphingomyelin, preservation of arachidonic acid content of phosphatidylcholine and phosphatidylethanolamine, partial restoration of phosphatidylcholine levels, and stimulation of glutathione synthesis and glutathione reductase activity. Citicoline’s effects may also be explained by the reduction of phospholipase A2 activity.[19] Citicoline increases phosphatidylcholine synthesis.[20][21][22] The mechanism for this may be:
- By converting 1, 2-diacylglycerol into phosphatidylcholine
- Stimulating the synthesis of SAMe, which aids in membrane stabilization and reduces levels of arachidonic acid. This is especially important after an ischemia, when arachidonic acid levels are elevated.[23]
Neuronal membrane
The brain prefers to use choline to synthesize acetylcholine. This limits the amount of choline available to synthesize phosphatidylcholine. When the availability of choline is low or the need for acetylcholine increases, phospholipids containing choline can be catabolized from neuronal membranes. These phospholipids include sphingomyelin and phosphatidylcholine.[19] Supplementation with citicoline can increase the amount of choline available for acetylcholine synthesis and aid in rebuilding membrane phospholipid stores after depletion.[24] Citicoline decreases phospholipase stimulation. This can lower levels of hydroxyl radicals produced after an ischemia and prevent cardiolipin from being catabolized by phospholipase A2.[25][26] It can also work to restore cardiolipin levels in the inner mitochondrial membrane.[25]
Cell signalling
Citicoline enhances cellular communication by increasing the availability of neurotransmitters, including acetylcholine, norepinephrine, and dopamine.[27]
Glutamate transport
Citicoline lowers increased glutamate concentrations and raises decreased ATP concentrations induced by ischemia. Citicoline also increases glutamate uptake by increasing expression of EAAT2, a glutamate transporter, in vitro in rat astrocytes. It is suggested that the neuroprotective effects of citicoline after a stroke are due in part to citicoline’s ability to decrease levels of glutamate in the brain.[28]
Pharmacokinetics
Citicoline is water-soluble, with more than 90% oral bioavailability.[24] Plasma levels peak one hour after oral ingestion, and a majority of the citicoline is excreted as CO2 in respiration, and again 24 hours after ingestion, where the remaining citicoline is excreted through urine.[29]
Side effects
Citicoline has a very low toxicity profile in animals and humans. Clinically, doses of 2000 mg per day have been observed and approved. Minor transient adverse effects are rare and most commonly include stomach pain and diarrhea.[21]
Synthesis
In vivo
Phosphatidylcholine is a major phospholipid in eukaryotic cell membranes. Close regulation of its biosynthesis, degradation, and distribution is essential to proper cell function. Phosphatidylcholine is synthesized in vivo by two pathways
- The Kennedy pathway, which includes the transformation of choline to citicoline, by way of phosphorylcholine, to produce phosphatidylcholine when condensed with diacylglycerol.
- Phosphatidylcholine can also be produced by the methylation pathway, where phosphatidylethanolamine is sequentially methylated.[30]
See also
- 1-alkenyl-2-acylglycerol choline phosphotransferase
- Ceramide cholinephosphotransferase
- Choline-phosphate cytidylyltransferase
- Diacylglycerol cholinephosphotransferase
- Sphingosine cholinephosphotransferase
References
- ^ Giménez R, Raïch J, Aguilar J (Nov 1991). "Changes in brain striatum dopamine and acetylcholine receptors induced by chronic CDP-choline treatment of aging mice". British Journal of Pharmacology. 104 (3): 575–8. PMC 1908237 . PMID 1839138. doi:10.1111/j.1476-5381.1991.tb12471.x.
- ^ Teather LA, Wurtman RJ (2005). "Dietary CDP-choline supplementation prevents memory impairment caused by impoverished environmental conditions in rats". Learning & Memory. 12 (1): 39–43. PMC 548494 . PMID 15647594. doi:10.1101/lm.83905.
- ^ "Supplement naturally boosts ageing brain power". Sydney Morning Herald. 2008-02-25. Retrieved 2009-07-28.
- ^ Silveri MM, Dikan J, Ross AJ, Jensen JE, Kamiya T, Kawada Y, Renshaw PF, Yurgelun-Todd DA (Nov 2008). "Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy". NMR in Biomedicine. 21 (10): 1066–75. PMID 18816480. doi:10.1002/nbm.1281.
- ^ Cavun S, Savci V (Oct 2004). "CDP-choline increases plasma ACTH and potentiates the stimulated release of GH, TSH and LH: the cholinergic involvement". Fundamental & Clinical Pharmacology. 18 (5): 513–23. PMID 15482372. doi:10.1111/j.1472-8206.2004.00272.x.
- ^ Benson S, Arck PC, Tan S, Hahn S, Mann K, Rifaie N, Janssen OE, Schedlowski M, Elsenbruch S (Jun 2009). "Disturbed stress responses in women with polycystic ovary syndrome". Psychoneuroendocrinology. 34 (5): 727–35. PMID 19150179. doi:10.1016/j.psyneuen.2008.12.001.
- ^ Florio P, Zatelli MC, Reis FM, degli Uberti EC, Petraglia F (2007). "Corticotropin releasing hormone: a diagnostic marker for behavioral and reproductive disorders?". Frontiers in Bioscience. 12: 551–60. PMID 17127316. doi:10.2741/2081.
- ^ Single-ingredient Preparations (: Citicoline). In: Martindale: The Complete Drug Reference [ed.by Sweetman S], 35th Ed. 2007, The Pharmaceutical Press: London (UK); e-version. .
- ^ Wurtman RJ, Regan M, Ulus I, Yu L (Oct 2000). "Effect of oral CDP-choline on plasma choline and uridine levels in humans". Biochemical Pharmacology. 60 (7): 989–92. PMID 10974208. doi:10.1016/S0006-2952(00)00436-6.
- ^ Alvarez XA, Sampedro C, Lozano R, Cacabelos R (Oct 1999). "Citicoline protects hippocampal neurons against apoptosis induced by brain beta-amyloid deposits plus cerebral hypoperfusion in rats". Methods and Findings in Experimental and Clinical Pharmacology. 21 (8): 535–40. PMID 10599052. doi:10.1358/mf.1999.21.8.794835.
- ^ Carlezon WA, Pliakas AM, Parow AM, Detke MJ, Cohen BM, Renshaw PF (Jun 2002). "Antidepressant-like effects of cytidine in the forced swim test in rats". Biological Psychiatry. 51 (11): 882–9. PMID 12022961. doi:10.1016/s0006-3223(01)01344-0.
- ^ Fioravanti M, Yanagi M (2005). "Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly". Cochrane Database Syst Rev (2): CD000269. PMID 15846601. doi:10.1002/14651858.CD000269.pub3.
- ^ Gareri P, Castagna A, Cotroneo AM, Putignano S, De Sarro G, Bruni AC (2015). "The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives". Clin Interv Aging. 10: 1421–9. PMC 4562749 . PMID 26366063. doi:10.2147/CIA.S87886.
- ^ Warach S, Pettigrew LC, Dashe JF, Pullicino P, Lefkowitz DM, Sabounjian L, Harnett K, Schwiderski U, Gammans R (Nov 2000). "Effect of citicoline on ischemic lesions as measured by diffusion-weighted magnetic resonance imaging. Citicoline 010 Investigators". Annals of Neurology. 48 (5): 713–22. PMID 11079534. doi:10.1002/1531-8249(200011)48:5<713::aid-ana4>3.0.co;2-#.
- ^ Saver JL (Fall 2008). "Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair". Reviews in Neurological Diseases. 5 (4): 167–77. PMID 19122569.
- ^ Dávalos A, Alvarez-Sabín J, Castillo J, Díez-Tejedor E, Ferro J, Martínez-Vila E, Serena J, Segura T, Cruz VT, Masjuan J, Cobo E, Secades JJ (Jul 2012). "Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial)". Lancet. 380 (9839): 349–57. PMID 22691567. doi:10.1016/S0140-6736(12)60813-7.
- ^ Shi PY, Zhou XC, Yin XX, Xu LL, Zhang XM, Bai HY (2016). "Early application of citicoline in the treatment of acute stroke: A meta-analysis of randomized controlled trials". J. Huazhong Univ. Sci. Technol. Med. Sci. 36 (2): 270–7. PMID 27072975. doi:10.1007/s11596-016-1579-6.
- ^ Roberti G, Tanga L, Michelessi M, Quaranta L, Parisi V, Manni G, Oddone F (2015). "Cytidine 5'-Diphosphocholine (Citicoline) in Glaucoma: Rationale of Its Use, Current Evidence and Future Perspectives". Int J Mol Sci. 16 (12): 28401–17. PMC 4691046 . PMID 26633368. doi:10.3390/ijms161226099.
- ^ a b Adibhatla RM, Hatcher JF, Dempsey RJ (Jan 2002). "Citicoline: neuroprotective mechanisms in cerebral ischemia". Journal of Neurochemistry. 80 (1): 12–23. PMID 11796739. doi:10.1046/j.0022-3042.2001.00697.x.
- ^ López-Coviella I, Agut J, Savci V, Ortiz JA, Wurtman RJ (Aug 1995). "Evidence that 5'-cytidinediphosphocholine can affect brain phospholipid composition by increasing choline and cytidine plasma levels". Journal of Neurochemistry. 65 (2): 889–94. PMID 7616250. doi:10.1046/j.1471-4159.1995.65020889.x.
- ^ a b Conant R, Schauss AG (Mar 2004). "Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature". Alternative Medicine Review. 9 (1): 17–31. PMID 15005642.
- ^ Babb SM, Wald LL, Cohen BM, Villafuerte RA, Gruber SA, Yurgelun-Todd DA, Renshaw PF (May 2002). "Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study". Psychopharmacology. 161 (3): 248–54. PMID 12021827. doi:10.1007/s00213-002-1045-y.
- ^ Rao AM, Hatcher JF, Dempsey RJ (Dec 1999). "CDP-choline: neuroprotection in transient forebrain ischemia of gerbils". Journal of Neuroscience Research. 58 (5): 697–705. PMID 10561698. doi:10.1002/(sici)1097-4547(19991201)58:5<697::aid-jnr11>3.0.co;2-b.
- ^ a b D'Orlando KJ, Sandage BW (Aug 1995). "Citicoline (CDP-choline): mechanisms of action and effects in ischemic brain injury". Neurological Research. 17 (4): 281–4. PMID 7477743.
- ^ a b Rao AM, Hatcher JF, Dempsey RJ (Mar 2001). "Does CDP-choline modulate phospholipase activities after transient forebrain ischemia?". Brain Research. 893 (1-2): 268–72. PMID 11223016. doi:10.1016/S0006-8993(00)03280-7.
- ^ Adibhatla RM, Hatcher JF (Aug 2003). "Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia". Journal of Neuroscience Research. 73 (3): 308–15. PMID 12868064. doi:10.1002/jnr.10672.
- ^ Secades JJ, Lorenzo JL (Sep 2006). "Citicoline: pharmacological and clinical review, 2006 update". Methods and Findings in Experimental and Clinical Pharmacology. 28 Suppl B: 1–56. PMID 17171187.
- ^ Hurtado O, Moro MA, Cárdenas A, Sánchez V, Fernández-Tomé P, Leza JC, Lorenzo P, Secades JJ, Lozano R, Dávalos A, Castillo J, Lizasoain I (Mar 2005). "Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport". Neurobiology of Disease. 18 (2): 336–345. PMID 15686962. doi:10.1016/j.nbd.2004.10.006.
- ^ Dinsdale JR, Griffiths GK, Rowlands C, Castelló J, Ortiz JA, Maddock J, Aylward M (1983). "Pharmacokinetics of 14C CDP-choline". Arzneimittel-Forschung. 33 (7A): 1066–70. PMID 6412727.
- ^ Fernández-Murray JP, McMaster CR (Nov 2005). "Glycerophosphocholine catabolism as a new route for choline formation for phosphatidylcholine synthesis by the Kennedy pathway". The Journal of Biological Chemistry. 280 (46): 38290–6. PMID 16172116. doi:10.1074/jbc.M507700200.
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Acetylcholine receptor modulators
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Receptor modulators
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| mACh |
- Agonists: 77-LH-28-1
- AC-42
- AC-260,584
- Aceclidine
- Acetylcholine
- AF30
- AF150(S)
- AF267B
- AFDX-384
- Alvameline
- AQRA-741
- Arecoline
- Bethanechol
- Butyrylcholine
- Carbachol
- CDD-0034
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- Cevimeline
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- cis-Dioxolane
- Ethoxysebacylcholine
- Itameline
- LY-593,039
- L-689,660
- LY-2,033,298
- McNA343
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- NGX-267
- Ocvimeline
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- PD-151,832
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- RS86
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- SDZ 210-086
- Sebacylcholine
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- Thiopilocarpine
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- VU-0029767
- VU-0090157
- VU-0152099
- VU-0152100
- VU-0238429
- WAY-132,983
- Xanomeline
- YM-796
- Antagonists: 3-Quinuclidinyl benzilate
- 4-DAMP
- Aclidinium bromide
- Anisodamine
- Anisodine
- Antihistamines (first-generation) (e.g., brompheniramine, chlorphenamine, cyproheptadine, dimenhydrinate, diphenhydramine, doxylamine, mepyramine (pyrilamine), phenindamine, pheniramine, promethazine, tripelennamine, triprolidine)
- Atropine
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- Atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, zotepine)
- Benactyzine
- Benzatropine (benztropine)
- Benzilylcholine mustard
- Benzydamine
- BIBN 99
- Biperiden
- Bornaprine
- CAR-226,086
- CAR-301,060
- CAR-302,196
- CAR-302,282
- CAR-302,368
- CAR-302,537
- CAR-302,668
- Caramiphen
- Cloperastine
- CS-27349
- Cyclobenzaprine
- Cyclopentolate
- Darifenacin
- DAU-5884
- Dimethindene
- Dexetimide
- DIBD
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- EA-3167
- EA-3443
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- Flavoxate
- Himbacine
- HL-031,120
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- J-104,129
- Hyoscyamine
- Mamba toxin 3
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- Mazaticol
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- Orphenadrine
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- PBID
- PD-102,807
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- Phenglutarimide
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- Profenamine
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- RU-47,213
- SCH-57,790
- SCH-72,788
- SCH-217,443
- Scopolamine (hyoscine)
- Sofpironium bromide
- Solifenacin
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- WIN-2299
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| nACh |
- Agonists: 5-HIAA
- A-84,543
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- A-582,941
- A-867,744
- ABT-202
- ABT-418
- ABT-560
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- GTS-21
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- Lobeline
- MEM-63,908 (RG-3487)
- Morantel
- Nicotine (tobacco)
- NS-1738
- PHA-543,613
- PHA-709,829
- PNU-120,596
- PNU-282,987
- Pozanicline
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- RJR-2429
- Sazetidine A
- SB-206553
- Sebacylcholine
- SIB-1508Y
- SIB-1553A
- SSR-180,711
- Suberyldicholine
- Suxamethonium (succinylcholine)
- TC-1698
- TC-1734
- TC-1827
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- TC-5214
- TC-5619
- TC-6683
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- UB-165
- Varenicline
- WAY-317,538
- XY-4083
- Antagonists: 18-MAC
- 18-MC
- α-Neurotoxins (e.g., α-bungarotoxin, α-cobratoxin, α-conotoxin, many others)
- ABT-126
- Alcuronium
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- Amantadine
- Anatruxonium
- AQW051
- Atracurium
- Barbiturates (e.g., pentobarbital, sodium thiopental)
- Bungarotoxins (e.g., α-bungarotoxin, κ-bungarotoxin)
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- Tropeinium
- Tubocurarine
- Vanoxerine
- Vecuronium bromide
- Xenon
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Transporter modulators
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| CHT |
- Inhibitors: Hemicholinium-3 (hemicholine)
- Triethylcholine
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| VAChT |
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Enzyme modulators
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| ChAT |
- Inhibitors: 1-(-Benzoylethyl)pyridinium
- 2-(α-Naphthoyl)ethyltrimethylammonium
- 3-Chloro-4-stillbazole
- 4-(1-Naphthylvinyl)pyridine
- Acetylseco hemicholinium-3
- Acryloylcholine
- AF64A
- B115
- BETA
- CM-54,903
- N,N-Dimethylaminoethylacrylate
- N,N-Dimethylaminoethylchloroacetate
|
| AChE |
|
| BChE |
- Inhibitors: Cymserine
- Many of the AChE inhibitors listed above
|
|
|
|
Release modulators
|
| Inhibitors |
- SNAP-25 inactivators: Botulinum toxin (A, C, E)
- VAMP inactivators: Botulinum toxin (B, D, F, G)
- Others: Bungarotoxins (β-bungarotoxin, γ-bungarotoxin)
|
| Enhancers |
- LPHN agonists: α-Latrotoxin
- Others: Atracotoxin (e.g., robustoxin, versutoxin)
- Crotoxin
|
|
|
|
Others
|
Precursors /
prodrugs |
- Adafenoxate
- Choline (lecithin)
- Citicoline
- Cyprodenate
- Dimethylethanolamine
- Glycerophosphocholine
- Meclofenoxate (centrophenoxine)
- Phosphatidylcholine
- Phosphatidylethanolamine
- Phosphorylcholine
- Pirisudanol
|
| Cofactors |
- Acetic acid
- Acetylcarnitine
- Acetyl-coA
- Vitamin B5
|
|
|
|
See also: Receptor/signaling modulators
|
|
Lipids: phospholipids
|
Glycerol backbone
(Glycerophospholipids/
Phosphoglycerides) |
| Phosphatidyl-: |
- -ethanolamine/cephalin (PE)
- -choline/lecithin (PC)
- -serine (PS)
- -glycerol (PG)
- -inositol (PI)
|
| Phosphoinositides: |
- PIP
- PIP2
- PI(3,4)P2
- PI(3,5)P2
- PI(4,5)P2
- PIP3
|
| Ether lipids: |
- Plasmalogen
- Platelet-activating factor
|
|
|
|
| Sphingosine backbone |
|
| Metabolites |
- Inositol phosphate
- Inositol
|
|
|
- Choline
- Phosphocholine
- Citicoline
|
|
