Citicoline: Difference between revisions

Browse history interactively

← Previous edit

Content deleted Content added

VisualWikitext

@@ Line 1: / Line 1: @@
+{{Short description|Chemical compound}}
 {{Drugbox
+| Verifiedfields = changed
-| verifiedrevid = 444399797
+| Watchedfields = changed
+| verifiedrevid = 449576702
 | IUPAC_name = 5'-''O''-[hydroxy({hydroxy[2-(trimethylammonio)ethoxy]<br />phosphoryl}oxy)phosphoryl]cytidine
 | image = Citicoline.svg
+| image2 = Citicholine.png
 <!--Clinical data-->
-| tradename =
+| tradename =  Neurocoline
 | Drugs.com = {{drugs.com|international|citicoline}}
 | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
@@ Line 13: / Line 16: @@
 | legal_CA = <!--             / Schedule I, II, III, IV, V, VI, VII, VIII -->
 | legal_UK = <!-- GSL         / P       / POM / CD / Class A, B, C -->
+| legal_US = OTC
-| legal_US = <!-- OTC                   / Rx-only  / Schedule I, II, III, IV, V -->
 | legal_status =
-| routes_of_administration =
+| routes_of_administration = oral
 <!--Pharmacokinetic data-->
-| bioavailability =
+| bioavailability = 90% oral
 | protein_bound =
 | metabolism =
 | elimination_half-life =
-| excretion =
+| excretion =respiration (as [[CO2]]) and urine
 <!--Identifiers-->
-| CASNo_Ref = {{cascite|correct|CAS}}
+| CAS_number_Ref = {{cascite|correct|??}}
 | CAS_number = 987-78-0
-| CAS_supplemental = {{CAS|33818-15-4}}
 | ATC_prefix = N06
 | ATC_suffix = BX06
-| PubChem = 13805
 | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
 | DrugBank =
+| ChEBI_Ref = {{ebicite|changed|EBI}}
-| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
+| ChEBI = 16436
-| ChemSpiderID = 16736209
+| ChEMBL_Ref = {{ebicite|changed|EBI}}
+| ChEMBL = 1618340
 | UNII_Ref = {{fdacite|correct|FDA}}
 | UNII = 536BQ2JVC7
 | KEGG_Ref = {{keggcite|correct|kegg}}
 | KEGG = D00057
+| PubChem = 11583971
+| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
+| ChemSpiderID = 13207
 <!--Chemical data-->
-| C=14 | H=27 | N=4 | O=11 | P=2 | charge = +
+| C=14 | H=27 | N=4 | O=11 | P=2| charge = +
+| smiles = 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
-| molecular_weight = 489.332 g/mol
+| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
-| smiles = C[N+](C)(C)OP([O-])(=O)OP(O)(=O)OC[C@H]2O[C@@H](N1/C=C\C(\N)=N/C1=O)[C@H](O)[C@@H]2O
-| InChI = 1/C12H22N4O11P2/c1-16(2,3)26-29(22,23)27-28(20,21)24-6-7-9(17)10(18)11(25-7)15-5-4-8(13)14-12(15)19/h4-5,7,9-11,17-18H,6H2,1-3H3,(H3-,13,14,19,20,21,22,23)/t7-,9-,10-,11-/m1/s1
+| StdInChI = 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
+| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
-| InChIKey = OPDHNBAEGPICKZ-QCNRFFRDBT
+| StdInChIKey = RZZPDXZPRHQOCG-OJAKKHQRSA-N
-| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
-| StdInChI = 1S/C12H22N4O11P2/c1-16(2,3)26-29(22,23)27-28(20,21)24-6-7-9(17)10(18)11(25-7)15-5-4-8(13)14-12(15)19/h4-5,7,9-11,17-18H,6H2,1-3H3,(H3-,13,14,19,20,21,22,23)/t7-,9-,10-,11-/m1/s1
-| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
-| StdInChIKey = OPDHNBAEGPICKZ-QCNRFFRDSA-N
 | synonyms = Cytidine diphosphate choline
+|drug_name=|alt=|caption=|type=|MedlinePlus=|licence_EU=|licence_US=}}
-}}
-'''Citicoline''' ([[International Nonproprietary Name|INN]]), also known as '''[[cytidine diphosphate]]-choline''' ('''CDP-Choline''') & '''cytidine 5'-diphosphocholine''' is a [[psychostimulant]]/[[nootropic]]. It is an intermediate in the generation of [[phosphatidylcholine]] from [[choline]]. Sold in over 70 countries under a variety of brand names: Ceraxon, Cognizin, NeurAxon, Somazina etc.
+'''Citicoline''' ([[International Nonproprietary Name|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 membrane]]s. Citicoline is naturally occurring in the [[cell (biology)|cells]] of human and animal tissue, in particular the organs.
+==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.<ref>Single-ingredient Preparations (: Citicoline). In: Martindale: The Complete Drug Reference [ed.by Sweetman S], 35th Ed. 2007, The Pharmaceutical Press: London (UK); e-version. .</ref> When taken as a supplement, citicoline is hydrolyzed into [[choline]] and [[cytidine]] in the [[intestine]].<ref>{{cite journal | vauthors = Wurtman RJ, Regan M, Ulus I, Yu L | title = Effect of oral CDP-choline on plasma choline and uridine levels in humans | journal = Biochemical Pharmacology | volume = 60 | issue = 7 | pages = 989–92 | date = Oct 2000 | pmid = 10974208 | doi = 10.1016/S0006-2952(00)00436-6 | s2cid = 18687483 }}</ref> Once these cross the [[blood–brain barrier]] it is reformed into citicoline by the rate-limiting enzyme in [[phosphatidylcholine]] synthesis, [[Choline-phosphate cytidylyltransferase|CTP-phosphocholine cytidylyltransferase]].<ref name="Alvarez 1999">{{cite journal | vauthors = Alvarez XA, Sampedro C, Lozano R, Cacabelos R | title = Citicoline protects hippocampal neurons against apoptosis induced by brain beta-amyloid deposits plus cerebral hypoperfusion in rats | journal = Methods and Findings in Experimental and Clinical Pharmacology | volume = 21 | issue = 8 | pages = 535–40 | date = Oct 1999 | pmid = 10599052 | doi = 10.1358/mf.1999.21.8.794835 }}</ref><ref>{{cite journal | vauthors = Carlezon WA, Pliakas AM, Parow AM, Detke MJ, Cohen BM, Renshaw PF | title = Antidepressant-like effects of cytidine in the forced swim test in rats | journal = Biological Psychiatry | volume = 51 | issue = 11 | pages = 882–9 | date = Jun 2002 | pmid = 12022961 | doi = 10.1016/s0006-3223(01)01344-0 | s2cid = 21170398 }}</ref>
+==Research==
+===Memory and cognition===
+Studies suggest, but have not confirmed, potential benefits of citicoline for cognitive impairments.<ref>{{cite journal |vauthors=Gareri P, Castagna A, Cotroneo AM, Putignano S, De Sarro G, Bruni AC |title=The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives |journal=Clin Interv Aging |volume=10 |pages=1421–9 |year=2015 |pmid=26366063 |pmc=4562749 |doi=10.2147/CIA.S87886 |doi-access=free }}</ref>
+===Ischemic stroke===
+Some preliminary research suggested that citicoline may reduce the rates of death and disability following an [[ischemic stroke]].<ref>{{cite journal | vauthors = Warach S, Pettigrew LC, Dashe JF, Pullicino P, Lefkowitz DM, Sabounjian L, Harnett K, Schwiderski U, Gammans R | title = Effect of citicoline on ischemic lesions as measured by diffusion-weighted magnetic resonance imaging. Citicoline 010 Investigators | journal = Annals of Neurology | volume = 48 | issue = 5 | pages = 713–22 | date = Nov 2000 | pmid = 11079534 | doi = 10.1002/1531-8249(200011)48:5<713::aid-ana4>3.0.co;2-# | s2cid = 196343635 }}</ref><ref>{{cite journal | vauthors = Saver JL | title = Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair | journal = Reviews in Neurological Diseases | volume = 5 | issue = 4 | pages = 167–77 | date = Fall 2008 | pmid = 19122569 }}</ref>
+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.<ref>{{cite journal | vauthors = 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 | title = Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial) | journal = Lancet | volume = 380 | issue = 9839 | date = Jul 2012 | pmid = 22691567 | doi = 10.1016/S0140-6736(12)60813-7 | pages=349–57| hdl = 10400.10/663 | s2cid = 134947 | hdl-access = free }}</ref> A meta-analysis of seven trials reported no statistically significant benefit for long-term survival or recovery.<ref>{{cite journal |vauthors=Shi PY, Zhou XC, Yin XX, Xu LL, Zhang XM, Bai HY |title=Early application of citicoline in the treatment of acute stroke: A meta-analysis of randomized controlled trials |journal=J. Huazhong Univ. Sci. Technol. Med. Sci. |volume=36 |issue=2 |pages=270–7 |year=2016 |pmid=27072975 |doi=10.1007/s11596-016-1579-6 |s2cid=25352343 }}</ref>
+=== Vision ===
+The effect of citicoline on visual function has been studied in patients with [[glaucoma]], with possible positive effect for protecting vision.<ref>{{cite journal |vauthors=Roberti G, Tanga L, Michelessi M, Quaranta L, Parisi V, Manni G, Oddone F |title=Cytidine 5'-Diphosphocholine (Citicoline) in Glaucoma: Rationale of Its Use, Current Evidence and Future Perspectives |journal=Int J Mol Sci |volume=16 |issue=12 |pages=28401–17 |year=2015 |pmid=26633368 |pmc=4691046 |doi=10.3390/ijms161226099 |doi-access=free }}</ref>
+== Mechanism of action ==
+[[File:Enzymes of the CDP-choline pathway.jpg|thumb|The CDP-choline pathway; enzymes named in green.]]
+[[File:Synthesis of choline from citicoline.png|thumb|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.<ref name="Adibhatla 2002">{{cite journal | vauthors = Adibhatla RM, Hatcher JF, Dempsey RJ | title = Citicoline: neuroprotective mechanisms in cerebral ischemia | journal = Journal of Neurochemistry | volume = 80 | issue = 1 | pages = 12–23 | date = Jan 2002 | pmid = 11796739 | doi = 10.1046/j.0022-3042.2001.00697.x | doi-access = free }}</ref>
+Citicoline increases phosphatidylcholine synthesis.<ref>{{cite journal | vauthors = López-Coviella I, Agut J, Savci V, Ortiz JA, Wurtman RJ | title = Evidence that 5'-cytidinediphosphocholine can affect brain phospholipid composition by increasing choline and cytidine plasma levels | journal = Journal of Neurochemistry | volume = 65 | issue = 2 | pages = 889–94 | date = Aug 1995 | pmid = 7616250 | doi = 10.1046/j.1471-4159.1995.65020889.x | s2cid = 10184322 }}</ref><ref name="Conant 2004">{{cite journal | vauthors = Conant R, Schauss AG | title = Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature | journal = Alternative Medicine Review | volume = 9 | issue = 1 | pages = 17–31 | date = Mar 2004 | pmid = 15005642 }}</ref><ref>{{cite journal | vauthors = Babb SM, Wald LL, Cohen BM, Villafuerte RA, Gruber SA, Yurgelun-Todd DA, Renshaw PF | title = Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study | journal = Psychopharmacology | volume = 161 | issue = 3 | pages = 248–54 | date = May 2002 | pmid = 12021827 | doi = 10.1007/s00213-002-1045-y | s2cid = 28454793 }}</ref> 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.<ref>{{cite journal | vauthors = Rao AM, Hatcher JF, Dempsey RJ | title = CDP-choline: neuroprotection in transient forebrain ischemia of gerbils | journal = Journal of Neuroscience Research | volume = 58 | issue = 5 | pages = 697–705 | date = Dec 1999 | pmid = 10561698 | doi = 10.1002/(sici)1097-4547(19991201)58:5<697::aid-jnr11>3.0.co;2-b | s2cid = 1159795 }}</ref>
+=== 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]].<ref name="Adibhatla 2002" /> Supplementation with citicoline can increase the amount of choline available for acetylcholine synthesis and aid in rebuilding membrane [[phospholipid]] stores after depletion.<ref name="D’Orlando 1995">{{cite journal | vauthors = D'Orlando KJ, Sandage BW | title = Citicoline (CDP-choline): mechanisms of action and effects in ischemic brain injury | journal = Neurological Research | volume = 17 | issue = 4 | pages = 281–4 | date = Aug 1995 | pmid = 7477743 | doi = 10.1080/01616412.1995.11740327 }}</ref>
+Citicoline decreases [[phospholipase]] stimulation. This can lower levels of [[hydroxyl radicals]] produced after an [[ischemia]] and prevent [[cardiolipin]] from being catabolized by [[phospholipase A2]].<ref name="Rao 2001">{{cite journal | vauthors = Rao AM, Hatcher JF, Dempsey RJ | title = Does CDP-choline modulate phospholipase activities after transient forebrain ischemia? | journal = Brain Research | volume = 893 | issue = 1–2 | pages = 268–72 | date = Mar 2001 | pmid = 11223016 | doi = 10.1016/S0006-8993(00)03280-7 | s2cid = 37271883 }}</ref><ref>{{cite journal | vauthors = Adibhatla RM, Hatcher JF | title = Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia | journal = Journal of Neuroscience Research | volume = 73 | issue = 3 | pages = 308–15 | date = Aug 2003 | pmid = 12868064 | doi = 10.1002/jnr.10672 | s2cid = 17806057 }}</ref> It can also work to restore cardiolipin levels in the [[inner mitochondrial membrane]].<ref name="Rao 2001" />
+=== Cell signalling ===
+Citicoline may enhance cellular communication by increasing levels of neurotransmitters.<ref>{{cite journal | vauthors = Secades JJ, Lorenzo JL | title = Citicoline: pharmacological and clinical review, 2006 update | journal = Methods and Findings in Experimental and Clinical Pharmacology | volume = 28 | issue = Suppl B | pages = 1–56 | date = Sep 2006 | pmid = 17171187 }}</ref> 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.<ref>{{Cite web| vauthors = Tardner P |date=2020-08-30|title=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|url=https://www.ijest.org/citicoline-cognitive-decline-ptardner-0820/|access-date=2020-08-31|website=International Journal of Environmental Science & Technology|language=en-US}}</ref>
+=== Glutamate transport ===
+Citicoline lowers increased [[glutamate]] concentrations and raises decreased [[Adenosine triphosphate|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.<ref>{{cite journal | vauthors = 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 | title = Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport | journal = Neurobiology of Disease | volume = 18 | issue = 2 | pages = 336–345 | date = Mar 2005 | pmid = 15686962 | doi = 10.1016/j.nbd.2004.10.006 | s2cid = 2818533 }}</ref>
+== Pharmacokinetics ==
+Citicoline is water-soluble, with more than 90% oral [[bioavailability]].<ref name="D’Orlando 1995" /> Plasma levels of citicholine peak one hour after oral ingestion, and a majority of the citicoline is excreted as {{CO2|link=yes}} in respiration with the remaining citicoline being excreted through [[urine]].<ref name="pharacokinetics">{{cite journal | vauthors = Dinsdale JR, Griffiths GK, Rowlands C, Castelló J, Ortiz JA, Maddock J, Aylward M | title = Pharmacokinetics of 14C CDP-choline | journal = Arzneimittel-Forschung | volume = 33 | issue = 7A | pages = 1066–1070 | year = 1983 | pmid = 6412727 }}</ref> The pharmacokinetic profile of citicholine cannot be described by a single smooth exponential decrease over time.<ref name="pharacokinetics"/> 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.<ref name="pharacokinetics"/> Plasma levels of choline peak about four hours after ingestion.<ref>{{cite journal | vauthors = Lopez G-Coviella I, Agut J, Von Borstel R, Wurtman RJ | title = Metabolism of cytidine (5?)-diphosphocholine (cdp-choline) following oral and intravenous administration to the human and the rat | journal = Neurochemistry International | volume = 11 | issue = 3 | pages = 293–297 | date = January 1987 | pmid = 20501174 | doi = 10.1016/0197-0186(87)90049-0 | s2cid = 25557979 }}</ref>
+=== Side effects ===
+Citicoline has a very low toxicity profile in animals and humans. Clinically, doses of 2000&nbsp;mg per day have been observed and approved. Minor transient adverse effects are rare and most commonly include stomach pain and diarrhea.<ref name="Conant 2004" />{{ums|date=December 2017}} 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.<ref>{{Cite web| vauthors = Tardner P |date=2020-08-28|title=Can Citicoline Cause Depression?: A review of the clinical literature • International Journal of Environmental Science & Technology|url=https://www.ijest.org/citicoline-depression-ptardner-0820/|access-date=2020-08-31|website=International Journal of Environmental Science & Technology|language=en-US}}</ref><ref>{{cite journal | vauthors = Talih F, Ajaltouni J | title = Probable Nootropicinduced Psychiatric Adverse Effects: A Series of Four Cases | journal = Innovations in Clinical Neuroscience | volume = 12 | issue = 11–12 | pages = 21–25 | date = 2015 | pmid = 27222762 | pmc = 4756795 }}</ref> At most, citicoline may exacerbate psychotic episodes or interact with antipsychotic medication.
+== Synthesis ==
-Studies suggest that CDP-choline supplements increase dopamine receptor densities,<ref>{{cite journal |author=Giménez R, Raïch J, Aguilar J |title=Changes in brain striatum dopamine and acetylcholine receptors induced by chronic CDP-choline treatment of aging mice |journal=British Journal of Pharmacology |volume=104 |issue=3 |pages=575–8 |year=1991 |month=November |pmid=1839138 |pmc=1908237}}</ref> and suggest that CDP-choline supplementation can ameliorate memory impairment caused by environmental conditions.<ref>{{cite journal |author=Teather LA, Wurtman RJ |title=Dietary CDP-choline supplementation prevents memory impairment caused by impoverished environmental conditions in rats |journal=Learning & Memory |volume=12 |issue=1 |pages=39–43 |year=2005 |pmid=15647594 |pmc=548494 |doi=10.1101/lm.83905}}</ref> Preliminary research has found that citicoline supplements help improve focus and mental energy and may possibly be useful in the treatment of attention deficit disorder.<ref>{{cite news |url=http://www.smh.com.au/articles/2008/02/24/1203788130776.html |title=Supplement naturally boosts ageing brain power |date=2008-02-25 |work=[[Sydney Morning Herald]] |accessdate=2009-07-28}}</ref><ref>{{cite journal |author=Silveri MM, Dikan J, Ross AJ, ''et al.'' |title=Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy |journal=NMR in Biomedicine |volume=21 |issue=10 |pages=1066–75 |year=2008 |month=November |pmid=18816480 |doi=10.1002/nbm.1281}}</ref>  Citicoline has also been shown to elevate [[ACTH]] independent of [[CRH]] levels and to amplify the release of other [[HPA axis]] hormones such as [[luteinizing hormone|LH]], [[FSH]], [[growth hormone|GH]] and [[TSH]] in response to hypothalamic releasing factors.<ref>{{cite journal |author=Cavun S, Savci V |title=CDP-choline increases plasma ACTH and potentiates the stimulated release of GH, TSH and LH: the cholinergic involvement |journal=Fundamental & Clinical Pharmacology |volume=18 |issue=5 |pages=513–23 |year=2004 |month=October |pmid=15482372 |doi=10.1111/j.1472-8206.2004.00272.x}}</ref>
+=== In vivo ===
-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, but not limited to, [[PCOS]], [[type II diabetes]] and [[major depressive disorder]].<ref>{{cite journal |author=Benson S, Arck PC, Tan S, ''et al.'' |title=Disturbed stress responses in women with polycystic ovary syndrome |journal=Psychoneuroendocrinology |volume=34 |issue=5 |pages=727–35 |year=2009 |month=June |pmid=19150179 |doi=10.1016/j.psyneuen.2008.12.001}}</ref><ref>{{cite journal |author=Florio P, Zatelli MC, Reis FM, degli Uberti EC, Petraglia F |title=Corticotropin releasing hormone: a diagnostic marker for behavioral and reproductive disorders? |journal=Frontiers in Bioscience |volume=12 |issue= |pages=551–60 |year=2007 |pmid=17127316 |doi=10.2741/2081}}</ref>
+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]], produces phosphatidylcholine when condensed with [[diacylglycerol]].
+* Phosphatidylcholine can also be produced by the methylation pathway, where [[phosphatidylethanolamine]] is sequentially [[methylated]].<ref>{{cite journal | vauthors = Fernández-Murray JP, McMaster CR | title = Glycerophosphocholine catabolism as a new route for choline formation for phosphatidylcholine synthesis by the Kennedy pathway | journal = The Journal of Biological Chemistry | volume = 280 | issue = 46 | pages = 38290–6 | date = Nov 2005 | pmid = 16172116 | doi = 10.1074/jbc.M507700200 | doi-access = free }}</ref>
-==See also==
+== See also ==
+<!-- keep alphabetical -->
+{{div col|colwidth=20em}}
 * [[1-alkenyl-2-acylglycerol choline phosphotransferase]]
 * [[Ceramide cholinephosphotransferase]]
@@ Line 63: / Line 108: @@
 * [[Diacylglycerol cholinephosphotransferase]]
 * [[Sphingosine cholinephosphotransferase]]
+{{Div col end}}
+<!-- keep alphabetical -->
 == References ==
-{{Reflist|2}}
+{{Reflist|33em}}
+{{Dietary supplements}}
-{{Dietary_supplements}}
-{{Nootropics}}
-{{Cholinergics}}
 {{Phospholipids}}
+{{Acetylcholine receptor modulators}}
+[[Category:Cholinergics]]
 [[Category:Nootropics]]
 [[Category:Nucleotides]]
 [[Category:Quaternary ammonium compounds]]
 [[Category:Choline esters]]
+[[Category:Organophosphates]]
-{{nervous-system-drug-stub}}
-[[de:CDP-Cholin]]
-[[es:Citicolina]]
-[[fa:سیتیکولین]]
-[[it:Citicolina]]
-[[pt:Citicolina]]