| 词条 | Citicoline |
| 释义 |
| Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 449576702 | IUPAC_name = 5'-O-[hydroxy({hydroxy[2-(trimethylammonio)ethoxy] phosphoryl}oxy)phosphoryl]cytidine | image = Citicoline.svg | image2 = Citicholine.png | tradename = Neurocoline | Drugs.com = {{drugs.com|international|citicoline}} | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = | routes_of_administration = | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 987-78-0 | ATC_prefix = N06 | ATC_suffix = BX06 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = | ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI = 16436 | 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 | C=14 | H=27 | N=4 | O=11 | P=2| charge = + | molecular_weight = 489.332 g/mol | 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 | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | 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}} | StdInChIKey = RZZPDXZPRHQOCG-OJAKKHQRSA-N | synonyms = Cytidine diphosphate choline }} 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] Intracerebroventricular administration of 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.[2] 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.[3][4] Use as a dietary supplementCiticoline 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, Xerenoos, etc.[5] When taken as a supplement citicoline is hydrolyzed into choline and cytidine in the intestine.[6] Once these cross the blood–brain barrier it is reformed into citicoline by the rate-limiting enzyme in phosphatidylcholine synthesis, CTP-phosphocholine cytidylyltransferase.[7][8] ResearchMemory and cognitionA 2015 review of published clinical trials of citicoline noted that while some studies have demonstrated positive effects of the compound on cognition, other studies have failed to confirm these results and additional clinical trials would be needed to confirm any potential benefits of citicoline.[9] Ischemic strokeDespite some suggestions that citicoline may reduce the rates of death and disability following an ischemic stroke,[10] [11] the largest citicoline clinical 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.[12] A meta-analysis of seven trials reported no statistically significant benefit for long-term survival or recovery.[13] VisionThe effect of citicoline on visual function has been studied in patients with glaucoma.[14] Mechanism of actionNeuroprotective effectsThe 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.[15] Citicoline increases phosphatidylcholine synthesis.[16][17][18] The mechanism for this may be:
Neuronal membraneThe 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.[15] Supplementation with citicoline can increase the amount of choline available for acetylcholine synthesis and aid in rebuilding membrane phospholipid stores after depletion.[20] Citicoline decreases phospholipase stimulation. This can lower levels of hydroxyl radicals produced after an ischemia and prevent cardiolipin from being catabolized by phospholipase A2.[21][22] It can also work to restore cardiolipin levels in the inner mitochondrial membrane.[21] Cell signallingCiticoline enhances cellular communication by increasing the availability of neurotransmitters, including acetylcholine, norepinephrine, and dopamine.[23] Glutamate transportCiticoline 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.[24] PharmacokineticsCiticoline is water-soluble, with more than 90% oral bioavailability.[20] 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.[25] Side effectsCiticoline 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.[17]{{ums|date=December 2017}} SynthesisIn vivoPhosphatidylcholine 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
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References1. ^{{cite journal | vauthors = 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 | date = Nov 1991 | pmid = 1839138 | pmc = 1908237 | doi = 10.1111/j.1476-5381.1991.tb12471.x }} {{Dietary supplements}}{{Nootropics}}{{Phospholipids}}{{Acetylcholine receptor modulators}}2. ^{{cite journal | vauthors = 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 | date = Oct 2004 | pmid = 15482372 | doi = 10.1111/j.1472-8206.2004.00272.x }} 3. ^{{cite journal | vauthors = Benson S, Arck PC, Tan S, Hahn S, Mann K, Rifaie N, Janssen OE, Schedlowski M, Elsenbruch S | title = Disturbed stress responses in women with polycystic ovary syndrome | journal = Psychoneuroendocrinology | volume = 34 | issue = 5 | pages = 727–35 | date = Jun 2009 | pmid = 19150179 | doi = 10.1016/j.psyneuen.2008.12.001 }} 4. ^{{cite journal | vauthors = 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 }} 5. ^Single-ingredient Preparations (: Citicoline). In: Martindale: The Complete Drug Reference [ed.by Sweetman S], 35th Ed. 2007, The Pharmaceutical Press: London (UK); e-version. . 6. ^{{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 }} 7. ^{{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 }} 8. ^{{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 }} 9. ^{{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 |issue= |pages=1421–9 |year=2015 |pmid=26366063 |pmc=4562749 |doi=10.2147/CIA.S87886 |url=}} 10. ^{{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-# }} 11. ^{{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 }} 12. ^{{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}} 13. ^{{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 |url=}} 14. ^{{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 |url=}} 15. ^1 {{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 }} 16. ^{{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 }} 17. ^1 {{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 }} 18. ^{{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 }} 19. ^{{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 }} 20. ^1 {{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 }} 21. ^1 {{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 }} 22. ^{{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 }} 23. ^{{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 Suppl B | pages = 1–56 | date = Sep 2006 | pmid = 17171187 }} 24. ^{{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 }} 25. ^{{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 = 1066–70 | year = 1983 | pmid = 6412727 }} 26. ^{{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 }} 5 : Cholinergics|Nootropics|Nucleotides|Quaternary ammonium compounds|Choline esters |
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