Citicoline (INN), also known ascytidine diphosphate-choline (CDP-choline) orcytidine 5'-diphosphocholine is an intermediate in the generation ofphosphatidylcholine fromcholine, a common biochemical process incell membranes. Citicoline is naturally occurring in thecells of human and animal tissue, in particular the organs.
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 intocholine andcytidine in theintestine.[2] Once these cross theblood–brain barrier, they are reformed into citicoline by the rate-limiting enzyme inphosphatidylcholine synthesis,CTP-phosphocholine cytidylyltransferase.[3][4]
Some preliminary research suggested that citicoline may reduce the rates of death and disability following anischemic stroke.[5][6]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.[7] A meta-analysis of seven trials reported no statistically significant benefit for long-term survival or recovery.[8]
By converting 1, 2-diacylglycerol into phosphatidylcholine
Stimulating the synthesis ofSAMe, which aids in membrane stabilization and reduces levels ofarachidonic acid. This is especially important after anischemia when arachidonic acid levels are elevated.[14]
The brain preferentially usescholine to synthesizeacetylcholine. 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 andphosphatidylcholine.[10] Supplementation with citicoline can increase the amount of choline available for acetylcholine synthesis and aid in rebuilding membranephospholipid stores after depletion.[15] Citicoline decreasesphospholipase stimulation. This can lower levels ofhydroxyl radicals produced after anischemia and preventcardiolipin from being catabolized byphospholipase A2.[16][17] It can also work to restore cardiolipin levels in theinner mitochondrial membrane.[16]
Citicoline may enhance cellular communication by increasing levels of neurotransmitters.[18] 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.[19]
Citicoline lowers increasedglutamate concentrations and raises decreasedATP concentrations induced byischemia. Citicoline also increasesglutamate uptake by increasing expression ofEAAT2, aglutamate transporter, in vitro in rat astrocytes. It is suggested that the neuroprotective effects of citicoline after astroke are due in part to citicoline's ability to decrease levels ofglutamate in the brain. This is in part due to an indirect decrease in theextrasynapticNMDA-TRMP4 death signaling pathway. It's important to also note it is only the extrasynaptic NMDA receptors responsible forexcitotoxicity.[20]
Citicoline is water-soluble, with more than 90% oralbioavailability.[15] Plasma levels of citicholine peak one hour after oral ingestion, and a majority of the citicoline is excreted asCO2 in respiration with the remaining citicoline being excreted throughurine.[21] The pharmacokinetic profile of citicholine cannot be described by a single smooth exponential decrease over time.[21] 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.[21] Plasma levels of choline peak about four hours after ingestion.[22]
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.[12][23] A 2020 study reported that concerns had emerged that chronic citicoline use may have adverse psychiatric effects, however, the study's meta-analysis of the relevant literature did not support this hypothesis.[24][23] Citicoline may exacerbate psychotic episodes or interact with antipsychotic medication.
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 synthesizedin vivo by two pathways
^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.PMID10599052.
^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.PMID12022961.S2CID21170398.
^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-#.PMID11079534.S2CID196343635.
^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.PMID19122569.
^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.PMID22691567.S2CID134947.
^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.PMID27072975.S2CID25352343.
^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.PMID7616250.S2CID10184322.
^abConant 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.PMID15005642.
^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.PMID12021827.S2CID28454793.
^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.PMID12868064.S2CID17806057.
^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.PMID17171187.
^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.PMID15686962.S2CID2818533.
^abcDinsdale 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.PMID6412727.
^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.PMID20501174.S2CID25557979.
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