Citicoline

Last updated
Citicoline
Citicoline.svg
Citicholine.png
Clinical data
Trade names Neurocoline
Other namesCytidine diphosphate choline
AHFS/Drugs.com International Drug Names
Routes of
administration 		oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 90% oral
Excretion respiration (as CO2) and urine
Identifiers
  • 5'-O-[hydroxy({hydroxy[2-(trimethylammonio)ethoxy]
    phosphoryl}oxy)phosphoryl]cytidine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.012.346 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H27N4O11P2+
Molar mass 489.335 g·mol−1
3D model (JSmol)
  • C[N+](C)(C)CCOP(=O)([O-])OP(=O)(O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@@H](O1)N2C=CC(N)=NC2=O
  • 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 X mark.svgN
  • Key:RZZPDXZPRHQOCG-OJAKKHQRSA-N X mark.svgN
 X mark.svgNYes check.svgY  (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.

Contents

Use as a dietary supplement

Citicoline is available as a supplement in over 70 countries under a variety of brand names: CereBleu, Cebroton, Ceraxon, Cidilin, Citifar, Cognizin, Difosfocin, Hipercol, NeurAxon, Nicholin, Sinkron, Somazina, Synapsine, Startonyl, Trausan, Xerenoos, etc. [1] When taken as a supplement, citicoline is hydrolyzed into choline and cytidine in the intestine. [2] Once these cross the blood–brain barrier it is reformed into citicoline by the rate-limiting enzyme in phosphatidylcholine synthesis, CTP-phosphocholine cytidylyltransferase. [3] [4]

Research

Memory and cognition

Studies suggest, but have not confirmed, potential benefits of citicoline for cognitive impairments. [5]

Ischemic stroke

Some preliminary research suggested that citicoline may reduce the rates of death and disability following an ischemic stroke. [6] [7] However, the largest citicoline clinical trial to date (a randomised, placebo-controlled, sequential trial of 2,298 patients with moderate-to-severe acute ischaemic stroke in Europe), found no benefit of administering citicoline on survival or recovery from stroke. [8] A meta-analysis of seven trials reported no statistically significant benefit for long-term survival or recovery. [9]

Vision

The effect of citicoline on visual function has been studied in patients with glaucoma, with possible positive effect for protecting vision. [10]

Mechanism of action

The CDP-choline pathway; enzymes named in green. Enzymes of the CDP-choline pathway.jpg
The CDP-choline pathway; enzymes named in green.
Enzymes involved in reactions are identified by numbers. See file description. Synthesis of choline from citicoline.png
Enzymes involved in reactions are identified by numbers. See file description.

Neuroprotective effects

Citicoline may have neuroprotective effects 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. [11] Citicoline increases phosphatidylcholine synthesis. [12] [13] [14] The mechanism for this may be:

Neuronal membrane

The brain preferentially uses 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. [11] Supplementation with citicoline can increase the amount of choline available for acetylcholine synthesis and aid in rebuilding membrane phospholipid stores after depletion. [16] Citicoline decreases phospholipase stimulation. This can lower levels of hydroxyl radicals produced after an ischemia and prevent cardiolipin from being catabolized by phospholipase A2. [17] [18] It can also work to restore cardiolipin levels in the inner mitochondrial membrane. [17]

Cell signalling

Citicoline may enhance cellular communication by increasing levels of neurotransmitters. [19] The choline component of citicoline is used to create acetylcholine, which is a neurotransmitter in the human brain. Clinical trials have found that citicoline supplementation might improve focus and attention. [20]

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. [21]

Pharmacokinetics

Citicoline is water-soluble, with more than 90% oral bioavailability. [16] Plasma levels of citicholine peak one hour after oral ingestion, and a majority of the citicoline is excreted as CO2 in respiration with the remaining citicoline being excreted through urine. [22] The pharmacokinetic profile of citicholine cannot be described by a single smooth exponential decrease over time. [22] However, the elimination half-life for citicholine has been reported as approximately 50 hours for citicholine removed via respiration and approximately 70 hours for citicholine removed via urine. [22] Plasma levels of choline peak about four hours after ingestion. [23]

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. [13] [ unreliable medical source? ] There have been suggestions that chronic citicoline use may have adverse psychiatric effects. However, a meta-analysis of the relevant literature does not support this hypothesis. [24] [25] At most, citicoline may exacerbate psychotic episodes or interact with antipsychotic medication.

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

See also

Related Research Articles

<span class="mw-page-title-main">Acetylcholine</span> Organic chemical and neurotransmitter

Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic. Substances that increase or decrease the overall activity of the cholinergic system are called cholinergics and anticholinergics, respectively.

<span class="mw-page-title-main">Cytidine</span> Chemical compound

Cytidine (symbol C or Cyd) is a nucleoside molecule that is formed when cytosine is attached to a ribose ring (also known as a ribofuranose) via a β-N1-glycosidic bond. Cytidine is a component of RNA. It is a white water-soluble solid. which is only slightly soluble in ethanol.

<span class="mw-page-title-main">Choline</span> Chemical compound and essential nutrient

Choline is a cation with the chemical formula [(CH3)3NCH2CH2OH]+. Choline forms various salts, for example choline chloride and choline bitartrate.

<span class="mw-page-title-main">Phosphatidylcholine</span> Class of phospholipids

Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soybeans, from which they are mechanically or chemically extracted using hexane. They are also a member of the lecithin group of yellow-brownish fatty substances occurring in animal and plant tissues. Dipalmitoylphosphatidylcholine (lecithin) is a major component of the pulmonary surfactant, and is often used in the lecithin–sphingomyelin ratio to calculate fetal lung maturity. While phosphatidylcholines are found in all plant and animal cells, they are absent in the membranes of most bacteria, including Escherichia coli. Purified phosphatidylcholine is produced commercially.

<span class="mw-page-title-main">Excitotoxicity</span> Process that kills nerve cells

In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate receptors such as the NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA. In evolved, complex adaptive systems such as biological life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA in subtoxic amounts induces neuronal survival of otherwise toxic levels of glutamate.

Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty acids. They constitute about 0.25% of phospholipids in the bilayer.

<span class="mw-page-title-main">Phospholipase A2</span> Peripheral membrane protein

The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glycerol molecule:

<span class="mw-page-title-main">Glycerophospholipid</span> Class of lipids

Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes. Two major classes are known: those for bacteria and eukaryotes and a separate family for archaea.

<span class="mw-page-title-main">Dipalmitoylphosphatidylcholine</span> Chemical compound

Dipalmitoylphosphatidylcholine (DPPC) is a phospholipid (and a lecithin) consisting of two C16 palmitic acid groups attached to a phosphatidylcholine head-group.

<span class="mw-page-title-main">Phosphatidylserine</span> Chemical compound

Phosphatidylserine is a phospholipid and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via apoptotic mimicry. Its exposure on the outer surface of a membrane marks the cell for destruction via apoptosis.

Phospholipase D (EC 3.1.4.4, lipophosphodiesterase II, lecithinase D, choline phosphatase, PLD; systematic name phosphatidylcholine phosphatidohydrolase) is an enzyme of the phospholipase superfamily that catalyses the following reaction

<span class="mw-page-title-main">Phosphatidylethanolamine</span> Group of chemical compounds

Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine can subsequently methylate the amine of phosphatidylethanolamines to yield phosphatidylcholines.

<span class="mw-page-title-main">Phosphatidylethanolamine N-methyltransferase</span> Protein-coding gene in the species Homo sapiens

Phosphatidylethanolamine N-methyltransferase is a transferase enzyme which converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver. In humans it is encoded by the PEMT gene within the Smith–Magenis syndrome region on chromosome 17.

<span class="mw-page-title-main">Diacylglycerol cholinephosphotransferase</span>

In enzymology, a diacylglycerol cholinephosphotransferase is an enzyme that catalyzes the chemical reaction

In enzymology, a sphingosine cholinephosphotransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Phospholipase C</span> Class of enzymes

Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role in eukaryotic cell physiology, in particular signal transduction pathways. Phospholipase C's role in signal transduction is its cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), which serve as second messengers. Activators of each PLC vary, but typically include heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca2+, and phospholipids.

<span class="mw-page-title-main">PLA2G6</span> Protein-coding gene in the species Homo sapiens

85 kDa calcium-independent phospholipase A2, also known as 85/88 kDa calcium-independent phospholipase A2, Group VI phospholipase A2, Intracellular membrane-associated calcium-independent phospholipase A2 beta, or Patatin-like phospholipase domain-containing protein 9 is an enzyme that in humans is encoded by the PLA2G6 gene.

<span class="mw-page-title-main">Glycerophosphorylcholine</span> Chemical compound

L-α-Glycerophosphorylcholine is a natural choline compound found in the brain. It is also a parasympathomimetic acetylcholine precursor which has been investigated for its potential for the treatment of Alzheimer's disease and other dementias.

Richard Wurtman was an American neuroscientist who spent his career doing basic and translational neuroscience research at Massachusetts Institute of Technology.

<span class="mw-page-title-main">CDP-choline pathway</span>

The CDP-choline pathway, first identified by Eugene P. Kennedy in 1956, is the predominant mechanism by which mammalian cells synthesize phosphatidylcholine (PC) for incorporation into membranes or lipid-derived signalling molecules. The CDP-choline pathway represents one half of what is known as the Kennedy pathway. The other half is the CDP-ethanolamine pathway which is responsible for the biosynthesis of the phospholipid phosphatidylethanolamine (PE).

References

  1. ↑ Single-ingredient Preparations (: Citicoline). In: Martindale: The Complete Drug Reference [ed.by Sweetman S], 35th Ed. 2007, The Pharmaceutical Press: London (UK); e-version. .
  2. ↑ 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. doi:10.1016/S0006-2952(00)00436-6. PMID   10974208. S2CID   18687483.
  3. ↑ 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. doi:10.1358/mf.1999.21.8.794835. PMID   10599052.
  4. ↑ 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. doi:10.1016/s0006-3223(01)01344-0. PMID   12022961. S2CID   21170398.
  5. ↑ 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. doi: 10.2147/CIA.S87886 . PMC   4562749 . PMID   26366063.
  6. ↑ 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. doi:10.1002/1531-8249(200011)48:5<713::aid-ana4>3.0.co;2-#. PMID   11079534. S2CID   196343635.
  7. ↑ 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.
  8. ↑ 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. doi:10.1016/S0140-6736(12)60813-7. hdl: 10400.10/663 . PMID   22691567. S2CID   134947.
  9. ↑ 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. doi:10.1007/s11596-016-1579-6. PMID   27072975. S2CID   25352343.
  10. ↑ 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. doi: 10.3390/ijms161226099 . PMC   4691046 . PMID   26633368.
  11. 1 2 Adibhatla RM, Hatcher JF, Dempsey RJ (Jan 2002). "Citicoline: neuroprotective mechanisms in cerebral ischemia". Journal of Neurochemistry. 80 (1): 12–23. doi: 10.1046/j.0022-3042.2001.00697.x . PMID   11796739.
  12. ↑ 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. doi:10.1046/j.1471-4159.1995.65020889.x. PMID   7616250. S2CID   10184322.
  13. 1 2 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.
  14. ↑ 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. doi:10.1007/s00213-002-1045-y. PMID   12021827. S2CID   28454793.
  15. ↑ 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. doi:10.1002/(sici)1097-4547(19991201)58:5<697::aid-jnr11>3.0.co;2-b. PMID   10561698. S2CID   1159795.
  16. 1 2 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. doi:10.1080/01616412.1995.11740327. PMID   7477743.
  17. 1 2 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. doi:10.1016/S0006-8993(00)03280-7. PMID   11223016. S2CID   37271883.
  18. ↑ 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. doi:10.1002/jnr.10672. PMID   12868064. S2CID   17806057.
  19. ↑ 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.
  20. ↑ Tardner P (2020-08-30). "The use of citicoline for the treatment of cognitive decline and cognitive impairment: A meta-analysis of pharmacological literature • International Journal of Environmental Science & Technology". International Journal of Environmental Science & Technology. Retrieved 2020-08-31.
  21. ↑ 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. doi:10.1016/j.nbd.2004.10.006. PMID   15686962. S2CID   2818533.
  22. 1 2 3 Dinsdale JR, Griffiths GK, Rowlands C, Castelló J, Ortiz JA, Maddock J, Aylward M (1983). "Pharmacokinetics of 14C CDP-choline". Arzneimittel-Forschung. 33 (7A): 1066–1070. PMID   6412727.
  23. ↑ Lopez G-Coviella I, Agut J, Von Borstel R, Wurtman RJ (January 1987). "Metabolism of cytidine (5?)-diphosphocholine (cdp-choline) following oral and intravenous administration to the human and the rat". Neurochemistry International. 11 (3): 293–297. doi:10.1016/0197-0186(87)90049-0. PMID   20501174. S2CID   25557979.
  24. ↑ Tardner P (2020-08-28). "Can Citicoline Cause Depression?: A review of the clinical literature • International Journal of Environmental Science & Technology". International Journal of Environmental Science & Technology. Retrieved 2020-08-31.
  25. ↑ Talih F, Ajaltouni J (2015). "Probable Nootropicinduced Psychiatric Adverse Effects: A Series of Four Cases". Innovations in Clinical Neuroscience. 12 (11–12): 21–25. PMC   4756795 . PMID   27222762.
  26. ↑ 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. doi: 10.1074/jbc.M507700200 . PMID   16172116.
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