Uridine

Last Updated: September 28, 2022

Uridine is a nucleotide base found in high levels in beer which is used for increasing synthesis of cellular membranes and for other neurological properties. It appears to have potentially cognitive enhancing properties, and is synergistic with fish oil.

Uridine is most often used for.



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1.

Sources and Structure

1.1

Sources

Uridine per se has been noted in the following foods:

  • Beer, usually said to be 0.05mg/mL (210.6+/-27.2umol/L)[1] although greater concentrations (91-161mg/L) have been noted when using more samples from different breweries[2]
  • Breast milk[3][4] and many infant formulations[5]

Beer seems to be a great source of uridine, relatively speaking

Whereas a significant DNA and RNA content (possibly indicative of some Uridine content) has been noted in (all values dry weight unless specified):[6]

  • Liver (Pig and Beef) at 2.12-2.3% for beef and 3.1-3.5% for pig (RNA) and 1.7-2% for beef and 1.4-1.8% for pig (DNA); all dry weight
  • Pancreas, the largest source of RNA at 6.4-7.8% (pig) and 7.4-10.2% (beef)
  • Lymph Nodes, the largest source of DNA at 6.7-7.0% (pig) and 6.7-11.5% (beef)
  • Fish at 0.17-0.47% (RNA) and 0.03-0.1% (DNA), with Herring having the highest RNA at 1.53%
  • Baker's Yeast (6.62% RNA, 0.6% DNA)
  • Mushrooms; Boletus at 1.9-2.4% RNA, Champignon at 2.05% RNA, and Chestnut at 2.1% RNA all with minute (0.06-0.1%) DNA
  • Broccoli at 2.06% RNA and 0.51% DNA
  • Oats at 0.3% RNA with no detectable DNA
  • Chinese Cabbage, Spinach, and Cauliflower with similar levels at 1.5% RNA and 0.2-0.3% DNA
  • Parsley at 0.81% RNA and 0.27% DNA

Organ meats and, surprisingly, Cruciferous vegetables appear to generally have a high RNA and DNA content which insinuates they have a Uridine content

Ingestion of beer at 10mL/kg can increase serum Uridine levels 1.8-fold, which is similar levels at supplemental intake of the same uridine dosage (0.05mg/kg); alcohol content does not influence absorption and urinary levels of Uridine increased by similar degrees.[1] Uridine in beer does not appear to be causative of the increases seen in Uric Acid after beer consumption,[1] and inhibiting Uric Acid synthesis with Allopurinol does not appear to influence the serum levels of Uridine achieved via beer.[7][8]

1.2

Structure and Properties

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It has been noted that uridine, in aqueous solution and subject to UV radiation, readily degrades and forms into photohydrates.[9]

May not be stable in solution subject to UV radiation

1.3

Dietary Interactions

During periods of undernutrition (from 1600kcal to 400kcal of only sugar; similar to a juice fast), plasma uridine can decrease up to 36% by three days after fasting and is reduced by 13% (nonsignificant) after one day.[10] These results mimick previous results obtained in rabbits during starvation.[11]

1.4

NucleoMaxX (Mitocnol)

Mitocnol is a patented blend of Uridine derived from Cane Sugar with a high (17%) Nucleoside content, with 6g out of 36g satchels consisting of nucleosides. These satchels contain 0.58g Uridine (1.61%) and 5.4g (15%) 2′,3′,5′-tri-O-acetyluridine (TAU), a structure similar to Uridine; when considering the weight of both molecules, each satchel contains about 1.7x10-2mol Uridine.[12]

Simply a source of Uridine and TAU, the latter of which is a better absorbed form of Uridine (a pro-drug)

2.

Pharmacology

2.1

Bioavailability and Absorption

Uridine is absorbed from the intestinal tract via either facilitated diffusion or specific Uridine transporters.[13]

Due to limits on absorption, the maximum tolerated dose (with doses higher than this inducing diarrhea) is either 12-15g/m2 (20-25g for an average sized male) acutely which elevates serum levels up to 60-80uM or 5g/m2 (8.5g for an average sized male) thrice a day every 6 hours, which maintains serum concentrations of 50uM; this confers a bioavailability of 5.8-9.9%.[14]

Practical limits on absorption exist for Uridine since high doses may induce diarrhea, but these limits appear to be much higher than standard supplemental dosages

Mitocnol is a cane sugar extract with a high (17%) content of nucleosides, and a pharmacokinetic study on one 'satchet' of the brand NucleoMaxX (36g) with 200mL orange juice noted that serum uridine levels were elevated from 5.4-5.8uM at baseline to 152+/-29.2uM (Cmax) after 80 minutes (Tmax), with high interindividual variability of Cmax values from 116-212uM.[15] This study also noted a half-life of 2 hours initially and a terminal half-life of 11.4 hours, with serum concentrations after 8 and 24 hours declining to 19.3+/-4.7uM and 7.5+/-1.6uM, respectively.[15] This study was later replicated in a proper pharmacokinetic study,[12] and replicated similarly high values for Cmax (150.9uM) at 80 minutes (Tmax) but noted a half-life of 3.4h and an AUC of 620.8+/-140.5uM; both studies noted higher concentrations of uridine in women that was due to differences in body mass, which disappeared upon factoring that into the equation.[12] When Mitocnol was compared against isolated Uridine when the two were controlled for Uridine content, it noted 4-fold enhanced absorption[12] and the concentrations reached with Mitocnol exceed those with isolated Uridine.

The increased bioavailability of Mitocnol may simply be due to the high Triacetyluridine (TAU) content, as TAU has 7-fold greater bioavailability than an equimolar amount of Uridine[16] secondary to its lipophilicity and passive diffusion, as claimed by the patents on it.[17] It is degraded into Uridine by intestinal and plasma esterases,[17] but is resistant to Uridine phosphorylase.[18]

Mitocnol appears to be useful for situations when one wants a high serum Uridine concentrations without gastrointestinal side-effects, due to enhanced bioavailability

2.2

Endogenous Regulation

Serum levels of Uridine under resting conditions fluctuate in the 3-8uM range.[19][12]

Erythrocytes contain the enzyme UDP-Glucose, which is involved in the P450 system; if needed, this enzyme can be lysed to provide free Uridine and Glucose to the body when Uridine levels are depleted.[19]

3.

Neurology (Mechanisms)

3.1

Kinetics

Uridine is known to be bypass the blood brain barrier[20][21] and is taken up by one of two transporters, one class being known as equilibrative[22] (SLC29 family; specifically the transporters ENT1, ENT2, and ENT3) which are low affinity (100–800μM range[23]) and sodium independent and concentrative[24] (SLC28 family consisting of ENT4 as well as CNT1, 2, and 3) which are sodium dependent active transporters with higher affinity (1-50μM[23]).[25][26]

3.2

Phospholipids

Uridine is a substrate in phosphatidylcholine (PC) synthesis via the Kennedy cycle (also known as the CDP-choline pathway, phosphatidylethanolamine also made via this pathway).[27][28][29]

In this pathway, choline kinase (CK) catalyzes choline into phosphocholine consuming an ATP molecule in the process[30][31] and has a micrmolar affinity in doing so (thus, much cellular choline is readily converted into phosphocholine[29]), and although this is not the only possible way to create phosphocholine (sphingomyelin degradation also confers phosphocholine[32]) it is the most prominent one and the first committed step of PC synthesis via the Kennedy cycle[29] and concentrations of phosphocholine are readily influenced by increasing choline intake.[33]

Elsewhere, Phosphocholine cytidylyltransferase (CCT) converts cytidine triphosphate (CTP) into CDP-choline plus pyrophosphate (using the previously created phosphocholine as the source of choline). This stage is the slowest in the Kennedy cycle and rate-limiting, thus its activity determines overall PC synthesis.[34][35][36] Usually in cellular cultures, there is an abundance of phosphocholine and a lack of CDP-choline[29] and the rate-limit at this step is thought to be determined by availability of CTP.[37] This enzyme is also negatively regulated by brain phospholipids,[38][39] which seems to be one of the main mechanisms behind phospholipid homeostasis and prevent excessive phospholipid synthesis.[40]

Finally, Choline phosphotransferase (CPT, not to be confused with carnitine palmitoyltransferase which shares the CPT acronym) transfers the phosphocholine from CDP-choline to diacylglycerol (DAG).[41][42] There is also an enzyme called choline–ethanolamine phosphotransferase (CEPT) which has dual specificity for CDP-choline and CDP-ethanolamine[43][44] (and one specific for CDP-ethanolamine[45]), the donation of phosphocholine towards DAG is what finally creates phospholipids such as phosphatidylcholine (the other enzymes that use CDP-ethanolamine instead create phosphatidylethanolamine). This enzyme is not stimulated by incubation with uridine,[46] but is stimulated by nerve growth factor (NGF).[47]

Uridine and Cytidine are synthesized into phospholipids via the Kennedy cycle, and in the above cycle there is a rate-limit just before the CCT enzyme. The thing that determines the rate is the provision of cytidine for the enzyme to act upon

Uridine is used as a substrate from which CDP-Choline is synthesized from (albeit before the rate-limiting step) vicariously through cytidine.[46] Provision of cytidine (synthesized from uridine) is the rate-limit in the above pathway, and providing extra cytidine to cells or brain slices under adequate choline concentrations accelerates CDP-Choline synthesis.[37][48][49] Uridine is demonstrated to have the same property[46] via converting into cytidine through initial conversion to uridine triphosphate (UTP) and then CTP[46][50] and this has been confirmed in a living model.[51]

While uridine produced UTP at 5µM, it stimulated CDP-Choline synthesis maximally at 50µM in vitro;[46] the production of CDP-Choline from uridine has been confirmed in vivo from orally administered uridine.[52]

Adding uridine or cytidine to cellular cultures will increase cellular levels of cytidine and overcome the rate limit, which results in production of phospholipids

When looking at interventions, one study in otherwise healthy males given 500mg Uridine once daily for a week reported an increase in total brain phosphomonoesters (6.32%) mostly due to an increase in total brain phosphoethanolamine (7.17%), as the increase in phosphatidylcholine in the uridine group failed to be statistically significant.[53] This increase in phosphoethanolamine has been noted elsewhere with CDP-choline, and is not necessarily met with an increase in phosphatidylethanolamine.[54][55]

In regards to phosphatidylcholine, it has been hypothesized[53] that the lack of increase is due to rapid accumulation of PC into phospholipid membranes; this was due to previous studies noting a decrease in PC concentrations with uridine or uridine prodrugs.[56][54]

Oral intake of uridine does appear to increase brain phospholipid precursors in otherwise healthy persons, and seems to favor phosphatidylethanolamine. Although an increase in phosphatidylcholine cannot be ruled out, it has not been reliably detected in humans

3.3

P2 receptors

P2 receptors are a meta-class of receptors that respond to extracellular purines and pyrimidines (such as ATP[57]), and mediate what is known as purinergic neurotransmission.[57] This class of receptors are structurally similar to adenosine receptors (insofar that they are classically referred to as such) and are divided into a P2Y and P2X class (which differ as P2Y receptors are GPCRs while P2X are ligand-gated ion channels).[58][57][59][60] Uridine is known to be an agonist of P2 receptors, particularly the P2Y subclass,[61] of which consist eight known human P2Y receptors (1,2,4,6, and 11-14) with the missing numbers being non-mammalian[62] with phosphorylated uridine having affinity mostly for the P2Y2 receptor[63] and to a lesser extent P2Y4,[64] P2Y6,[65][66] and P2Y14.[67]

The nervous system is also known to express seven P2X receptors, although seemingly uninvovled with uridine.[68][69]

Uridine has its own set of receptors that it can act upon, the P2 receptors, where it seems to most influence activity of P2Y2, P2Y4, P2Y6, and P2Y14. When uridine is not acting as a substrate for phospholipid synthesis, it is likely acting as a novel neurotransmitter via purinergic receptors

The P2Y2 receptor has structural motifs that promote interactions with integrins and growth factor receptors[70][71] and activation of this receptor is known to activate NGF/TrkA signalling[72] and be generally neuroprotective.[73]

3.4

Synapses

Uridine is thought to benefit synaptic functions due to increasing levels of brain phosphatidylcholine, which is a component of dendrite membranes. This is thought to then confer benefit to populations suffering from a loss of synaptic function or regulation such as Alzheimer's Disease,[74][75] where loss of synaptic function is thought to be downstream of the typical amyloid-beta aggregates exerting toxic effects on neruonal synapses and dendritic spines.[76]

Via providing phoshpatidylcholine, Uridine supposedly helps to create membranes and dendrites which may aid synaptic function

Studies assessing synaptic construction in response to Uridine supplementation tend to measure dendritic spines, due to complications in quantifying synaptic function per se but dendritic spines being the most reliable biomarker as 90% of dendrites form synapses.[77][78][79][80]

Feeding animals a combination of Uridine, choline, and omega-3 fatty acids (from fish oil) appears to increase synaptic formation and function[81][82] and has shown improvement in a cohort of persons (n=221) with mild Alzheimer's Disease.[83]

3.5

Neurite Outgrowth

Purines and pyrimidines have been known to induce cellular differentiation in neurons[84] and uridine is thought to induce neuronal differentiation and outgrowth due to activating NGF signalling via its receptor TrkA (well known to increase neuronal growth[85][86]) secondary to acting on its own receptor, P2Y2.[72] Ablating the P2Y2 receptor prevents proper NGF signalling via TrkA,[73] and the two receptors appear to interact with each other to function as they coimmunoprecipitate.[73]

In this sense P2Y2 agonists augment NGF signalling via increasing neuronal sensitivity to NGF[73] and NGF-induced neuronal growth,[87] and this has been noted with the P2Y2 agonist uridine (triphosphate).[73]

Activation of the P2Y2 receptor appears to promote the actions of NGF via its own receptor (TrkA), which ultimately appears that agonists of the P2Y2 receptor augment NGF-induced neuronal growth

6 weeks, but not 1 week, of feeding 330mg/kg (1mmol/kg) Uridine to aged rats increases levels of Neurofilament-70 (+82%) and Neurofilament-M (+121%),[88] two cytoskeletal proteins involved in neurite outgrowth and used as biomarkers[89] that have previously been induced in vitro with NGF differentiated PC12 neuronal cells in response to Uridine, where neurite outgrowth was noted.[61] Interestingly, the in vitro study noted that Uridine may act via a P2Y receptor to induce neurite growth.[61]

3.6

Catecholamines

A elderly rat diet fortified with 2.5% Disodium Uridine (500mg/kg, or 330mg/kg Uridine and a human equivalent of around 50mg/kg) failed to influence resting levels of dopamine in neuronal slices from the rats, but enhanced the K+ invoked dopamine release, with 1 and 6 weeks of supplementation increasing average dopamine levels by 11.6-20.5% with no difference in the transient decrease after action potential, and no influence on DOPAC or HVA concentrations.[88]

Uridine supplementation appears to enhance dopamine output from activated neurons without significantly affecting basal levels of dopamine

3.7

Cognition and Learning

One study using a brand name called Cognitex (50mg Uridine-5'-Monophosphate, but otherwise highly confounded with 600mg Alpha-GPC, 100mg Phosphatidylserin, 50mg Pregnenolone, 20mg Vinpocetine and others) that 3 capsules daily for 12 weeks in an open-label study noted improvements in spatial short term memory, recognition, recall, attention, and executive functions which increased further after 10 more weeks of supplementation.[90]

3.8

Alzheimer's Disease

Uridine is thought to aid Alzheimer's Disease due to helping with synaptic connections, which appear to be reduced in the state of Alzheimer's.[74][75]

Due to proliferating synapses, uridine supplementation is thought to be therapeutic for Alzheimer's disease

One study noting significant improvements in Alzheimer's pathology in rats with accelerated β-amyloid production (and thus are predisposed to Alzheimer's), but was too confounded with other nutrients to assess the effects of Uridine.[91]

The evidence currently for uridine is lacklustre and not suited to assess the efficacy of uridine

3.9

Bipolar Disorder

6 weeks supplementation of Uridine in an open-label trial of bipolar disorder in children noted that 500mg twice daily (1,000mg total) was associated with significantly less depressive symptoms relative to baseline (from an average score of 65.6 on the CDRS-R to 27.2 with efficacy within a week); manic symptoms were not assessed.[92]

Triacetyluridine (TAU) has been used in treatment of bipolar disorder in adults at 18g daily over 6 weeks, where a significant improvement in depressive symptoms was noted.[93]

4.

Cardiovascular Health

4.1

Cardiac Tissue

Uridine is able to exert an acute cardioprotective effect against myocardial ischemia when preloaded which is abolished by blocking potassium channels on the mitochondria (with 5-hydroxydecanoate);[94] it appears that uridine preloading preserves levels of energy metabolites (ATP, creatine phosphate, and uridine) and subsequently reduced lipid peroxidation.[94]

5.

Fat Mass and Obesity

5.1

Lipodystrophy

Lipodystrophy is a localized loss of fat mass, and usually seen alongside HIV therapy using Nucleoside reverse transcriptase inhibitors (NRTIs).[95]

In a multicenter study, Uridine was associated with an increase of limb fat (seen as an endpoint marker of normalizing lipodystrophy) after 24 weeks but was no longer present at 48 weeks; it was well tolerated and did not negatively influence virological response.[96] These lacklustre results were replicated in a double-blind trial, where Uridine supplementation via NucleoMaxX (brand name product) beneficially influenced mitochondrial RNA yet negatively influenced mitochondrial DNA without influencing limb fat; this was met with an increase in systemic inflammation (asssessed by IL-6 and CRP)[97] yet another trial suggests significant improvements with a similar Uridine protocol on fat mass.[98]

Mixed results on interventions assessing Lipodystrophy in persons being given standard HIV therapy

6.

Interactions with Cancer

6.1

Pancreatic

Activation of the P2Y2 receptor by uridine triphosphate appears to induce proliferation of the pancreatic cancer cell line PANC-1, which was replicated by a selective agonist of the receptor and was mediated via PKC-dependent activation of Akt.[99]

7.

Interactions with Aesthetics

7.1

Hair

During the early anagen phase of hair growth, there is a marked increase in uridine accumulation into dermal papillae cells and hair germ cells relative to the dormant phase (telogen) in vitro,[100] which seems to extend to other nucleotides (such as thymidine[101] and cytidine[102]); it is thought that this is indicative of an increased RNA and DNA synthesis rate during spontaneous growth of hair cells.[100]

No studies have currently assessed whether provision of uridine is at all rate-limiting in this context, so the role of supplementing exogenous uridine to act as a substrate for DNA synthesis is not certain.

Uridine is accumulated into hair cells during the growth phase (anagen), but it is not ascertained if uridine acting as a substrate for DNA/RNA synthesis as mentioned above is at all relevant to supplementation of uridine

It has been noted that P2Y1 and P2Y2 receptors (the latter of which is a target of uridine) are expressed in hair cells undergoing anagen, with the P2Y2 receptors expressed in the living cells at the edge of the cortex/medulla and the P2Y1 receptors in the root sheath and bulb;[103] P2X5 receptors were detected in the inner and outer root sheaths and medulla while P2X7 receptors were noted to not be present.[103] The P2Y2 receptors were detected early on, as they were no longer present in the differentiated hair cuticle, and due to the roles of uridine as an agonist of this receptor causing proliferation in keratinocytes[104][105][106] it was hypothesized that uridine may stimulate hair cell differentiation.[103]

It is theoretically possible, but not yet demonstrated, that uridine can act via the P2Y2 receptor to stimulate hair cell differentiation at the beginning of the growth (anagen) phase

8.

Nutrient-Nutrient Interactions

8.1

Choline

Choline and Uridine are both seen as dietary influences on neuronal function, as oral choline can increase brain phosphocholine levels in rats[33] and humans where a 3-6% in choline levels in serum result in an increase of 10-22% phosphocholine in the brain.[107] Uridine administration increases CDP-choline levels in the brain.[52]

8.2

Docosahexaenoic Acid

DHA, one of the two fish oil fatty acids, can increase brain levels of phosphatidylcholine up to 30% higher than control at 300mg/kg feed intake when it is paired with 0.5% Uridine.[82]

References
1.^Yamamoto T, Moriwaki Y, Takahashi S, Tsutsumi Z, Ka T, Fukuchi M, Hada TEffect of beer on the plasma concentrations of uridine and purine basesMetabolism.(2002 Oct)
2.^Almeida C, Duarte IF, Barros A, Rodrigues J, Spraul M, Gil AMComposition of beer by 1H NMR spectroscopy: effects of brewing site and date of productionJ Agric Food Chem.(2006 Feb 8)
3.^Sugawara M, Sato N, Nakano T, Idota T, Nakajima IProfile of nucleotides and nucleosides of human milkJ Nutr Sci Vitaminol (Tokyo).(1995 Aug)
4.^Thorell L, Sjöberg LB, Hernell ONucleotides in human milk: sources and metabolism by the newborn infantPediatr Res.(1996 Dec)
6.^Jonas DA, Elmadfa I, Engel KH, Heller KJ, Kozianowski G, König A, Müller D, Narbonne JF, Wackernagel W, Kleiner JSafety considerations of DNA in foodAnn Nutr Metab.(2001)
7.^Ka T, Moriwaki Y, Inokuchi T, Yamamoto A, Takahashi S, Tsutsumi Z, Yamamoto TEffects of allopurinol on beer-induced increases in plasma concentrations and urinary excretion of purine bases (uric acid, hypoxanthine, and xanthine)Horm Metab Res.(2006 Mar)
8.^Inokuchi T, Ka T, Yamamoto A, Takahashi S, Tsutsumi Z, Moriwaki Y, Yamamoto TEffects of allopurinol on beer-induced increases in plasma concentrations of purine bases and uridineNucleosides Nucleotides Nucleic Acids.(2008 Jun)
12.^Weinberg ME, Roman MC, Jacob P, Wen M, Cheung P, Walker UA, Mulligan K, Schambelan MEnhanced uridine bioavailability following administration of a triacetyluridine-rich nutritional supplementPLoS One.(2011 Feb 17)
13.^Pizzorno G, Cao D, Leffert JJ, Russell RL, Zhang D, Handschumacher REHomeostatic control of uridine and the role of uridine phosphorylase: a biological and clinical updateBiochim Biophys Acta.(2002 Jul 18)
14.^van Groeningen CJ, Peters GJ, Nadal JC, Laurensse E, Pinedo HMClinical and pharmacologic study of orally administered uridineJ Natl Cancer Inst.(1991 Mar 20)
15.^Venhoff N, Zilly M, Lebrecht D, Schirmer D, Klinker H, Thoden J, Langmann P, Walker UAUridine pharmacokinetics of mitocnol, a sugar cane extractAIDS.(2005 Apr 29)
19.^Connolly GP, Duley JAUridine and its nucleotides: biological actions, therapeutic potentialsTrends Pharmacol Sci.(1999 May)
21.^Cornford EM, Oldendorf WHIndependent blood-brain barrier transport systems for nucleic acid precursorsBiochim Biophys Acta.(1975 Jun 25)
22.^Baldwin SA, Beal PR, Yao SY, King AE, Cass CE, Young JDThe equilibrative nucleoside transporter family, SLC29Pflugers Arch.(2004 Feb)
23.^Pastor-Anglada M, Felipe A, Casado FJTransport and mode of action of nucleoside derivatives used in chemical and antiviral therapiesTrends Pharmacol Sci.(1998 Oct)
24.^Gray JH, Owen RP, Giacomini KMThe concentrative nucleoside transporter family, SLC28Pflugers Arch.(2004 Feb)
25.^Kong W, Engel K, Wang JMammalian nucleoside transportersCurr Drug Metab.(2004 Feb)
28.^Vance JE, Vance DEPhospholipid biosynthesis in mammalian cellsBiochem Cell Biol.(2004 Feb)
29.^Fagone P, Jackowski SPhosphatidylcholine and the CDP-choline cycleBiochim Biophys Acta.(2013 Mar)
30.^Aoyama C, Liao H, Ishidate KStructure and function of choline kinase isoforms in mammalian cellsProg Lipid Res.(2004 May)
31.^Wu G, Vance DECholine kinase and its functionBiochem Cell Biol.(2010 Aug)
32.^Jansen SM, Groener JE, Bax W, Suter A, Saftig P, Somerharju P, Poorthuis BJBiosynthesis of phosphatidylcholine from a phosphocholine precursor pool derived from the late endosomal/lysosomal degradation of sphingomyelinJ Biol Chem.(2001 Jun 1)
33.^Millington WR, Wurtman RJCholine administration elevates brain phosphorylcholine concentrationsJ Neurochem.(1982 Jun)
40.^Baburina I, Jackowski SCellular responses to excess phospholipidJ Biol Chem.(1999 Apr 2)
41.^Cornell RBCholinephosphotransferase from mammalian sourcesMethods Enzymol.(1992)
43.^Henneberry AL, Wistow G, McMaster CRCloning, genomic organization, and characterization of a human cholinephosphotransferaseJ Biol Chem.(2000 Sep 22)
46.^Richardson UI, Watkins CJ, Pierre C, Ulus IH, Wurtman RJStimulation of CDP-choline synthesis by uridine or cytidine in PC12 rat pheochromocytoma cellsBrain Res.(2003 May 9)
49.^G-Coviella IL, Wurtman RJEnhancement by cytidine of membrane phospholipid synthesisJ Neurochem.(1992 Jul)
50.^Wurtman RJ, Regan M, Ulus I, Yu LEffect of oral CDP-choline on plasma choline and uridine levels in humansBiochem Pharmacol.(2000 Oct 1)
51.^Ulus IH, Watkins CJ, Cansev M, Wurtman RJCytidine and uridine increase striatal CDP-choline levels without decreasing acetylcholine synthesis or releaseCell Mol Neurobiol.(2006 Jul-Aug)
52.^Cansev M, Watkins CJ, van der Beek EM, Wurtman RJOral uridine-5'-monophosphate (UMP) increases brain CDP-choline levels in gerbilsBrain Res.(2005 Oct 5)
54.^Silveri MM, Dikan J, Ross AJ, Jensen JE, Kamiya T, Kawada Y, Renshaw PF, Yurgelun-Todd DACiticoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopyNMR Biomed.(2008 Nov)
55.^Babb SM, Wald LL, Cohen BM, Villafuerte RA, Gruber SA, Yurgelun-Todd DA, Renshaw PFChronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy studyPsychopharmacology (Berl).(2002 May)
58.^Van Poecke S, Barrett MO, Santhosh Kumar T, Sinnaeve D, Martins JC, Jacobson KA, Kendall Harden T, Van Calenbergh SSynthesis and P2Y₂ receptor agonist activities of uridine 5'-phosphonate analoguesBioorg Med Chem.(2012 Apr 1)
59.^Weisman GA, Yu N, Liao Z, Gonzaléz F, Erb L, Seye CIP2 receptors in health and diseaseBiotechnol Genet Eng Rev.(2006)
60.^Erb L, Liao Z, Seye CI, Weisman GAP2 receptors: intracellular signalingPflugers Arch.(2006 Aug)
61.^Pooler AM, Guez DH, Benedictus R, Wurtman RJUridine enhances neurite outgrowth in nerve growth factor-differentiated PC12 {corrected}Neuroscience.(2005)
62.^Brunschweiger A, Müller CEP2 receptors activated by uracil nucleotides--an updateCurr Med Chem.(2006)
64.^Dobolyi A, Juhász G, Kovács Z, Kardos JUridine function in the central nervous systemCurr Top Med Chem.(2011)
67.^Harden TK, Sesma JI, Fricks IP, Lazarowski ERSignalling and pharmacological properties of the P2Y receptorActa Physiol (Oxf).(2010 Jun)
68.^Illes P, Alexandre Ribeiro JMolecular physiology of P2 receptors in the central nervous systemEur J Pharmacol.(2004 Jan 1)
69.^Köles L, Leichsenring A, Rubini P, Illes PP2 receptor signaling in neurons and glial cells of the central nervous systemAdv Pharmacol.(2011)
70.^Erb L, Liu J, Ockerhausen J, Kong Q, Garrad RC, Griffin K, Neal C, Krugh B, Santiago-Pérez LI, González FA, Gresham HD, Turner JT, Weisman GAAn RGD sequence in the P2Y(2) receptor interacts with alpha(V)beta(3) integrins and is required for G(o)-mediated signal transductionJ Cell Biol.(2001 Apr 30)
71.^Bagchi S, Liao Z, Gonzalez FA, Chorna NE, Seye CI, Weisman GA, Erb LThe P2Y2 nucleotide receptor interacts with alphav integrins to activate Go and induce cell migrationJ Biol Chem.(2005 Nov 25)
72.^Arthur DB, Akassoglou K, Insel PAP2Y2 receptor activates nerve growth factor/TrkA signaling to enhance neuronal differentiationProc Natl Acad Sci U S A.(2005 Dec 27)
73.^Weisman GA, Ajit D, Garrad R, Peterson TS, Woods LT, Thebeau C, Camden JM, Erb LNeuroprotective roles of the P2Y(2) receptorPurinergic Signal.(2012 Sep)
74.^Selkoe DJAlzheimer's disease is a synaptic failureScience.(2002 Oct 25)
75.^Terry RDAlzheimer's disease and the aging brainJ Geriatr Psychiatry Neurol.(2006 Sep)
76.^Spires-Jones TL, Meyer-Luehmann M, Osetek JD, Jones PB, Stern EA, Bacskai BJ, Hyman BTImpaired spine stability underlies plaque-related spine loss in an Alzheimer's disease mouse modelAm J Pathol.(2007 Oct)
78.^Alvarez VA, Sabatini BLAnatomical and physiological plasticity of dendritic spinesAnnu Rev Neurosci.(2007)
79.^Arellano JI, Espinosa A, Fairén A, Yuste R, DeFelipe JNon-synaptic dendritic spines in neocortexNeuroscience.(2007 Mar 16)
80.^Harms KJ, Dunaevsky ADendritic spine plasticity: looking beyond developmentBrain Res.(2007 Dec 12)
81.^Wurtman RJ, Cansev M, Sakamoto T, Ulus IHUse of phosphatide precursors to promote synaptogenesisAnnu Rev Nutr.(2009)
82.^Wurtman RJ, Ulus IH, Cansev M, Watkins CJ, Wang L, Marzloff GSynaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orallyBrain Res.(2006 May 9)
84.^Neary JT, Rathbone MP, Cattabeni F, Abbracchio MP, Burnstock GTrophic actions of extracellular nucleotides and nucleosides on glial and neuronal cellsTrends Neurosci.(1996 Jan)
86.^Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao MV, Julius DBradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibitionNature.(2001 Jun 21)
87.^Rathbone MP, Middlemiss PJ, Gysbers JW, Andrew C, Herman MA, Reed JK, Ciccarelli R, Di Iorio P, Caciagli FTrophic effects of purines in neurons and glial cellsProg Neurobiol.(1999 Dec)
89.^Lee V, Trojanowski JQ, Schlaepfer WWInduction of neurofilament triplet proteins in PC12 cells by nerve growth factorBrain Res.(1982 Apr 22)
91.^Broersen LM, Kuipers AA, Balvers M, van Wijk N, Savelkoul PJ, de Wilde MC, van der Beek EM, Sijben JW, Hageman RJ, Kamphuis PJ, Kiliaan AJA Specific Multi-Nutrient Diet Reduces Alzheimer-Like Pathology in Young Adult AβPPswe/PS1dE9 MiceJ Alzheimers Dis.(2012 Aug 22)
93.^Jensen JE, Daniels M, Haws C, Bolo NR, Lyoo IK, Yoon SJ, Cohen BM, Stoll AL, Rusche JR, Renshaw PFTriacetyluridine (TAU) decreases depressive symptoms and increases brain pH in bipolar patientsExp Clin Psychopharmacol.(2008 Jun)
95.^Nolan D, Hammond E, Martin A, Taylor L, Herrmann S, McKinnon E, Metcalf C, Latham B, Mallal SMitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapyAIDS.(2003 Jun 13)
96.^McComsey GA, Walker UA, Budhathoki CB, Su Z, Currier JS, Kosmiski L, Naini LG, Charles S, Medvik K, Aberg JA; AIDS Clinical Trials Group A5229 TeamUridine supplementation in the treatment of HIV lipoatrophy: results of ACTG 5229AIDS.(2010 Oct 23)
97.^McComsey GA, O'Riordan M, Choi J, Libutti D, Rowe D, Storer N, Harrill D, Gerschenson MMitochondrial function, inflammation, fat and bone in HIV lipoatrophy: randomized study of uridine supplementation or switch to tenofovirAntivir Ther.(2012)
98.^Sutinen J, Walker UA, Sevastianova K, Klinker H, Häkkinen AM, Ristola M, Yki-Järvinen HUridine supplementation for the treatment of antiretroviral therapy-associated lipoatrophy: a randomized, double-blind, placebo-controlled trialAntivir Ther.(2007)
104.^Dixon CJ, Bowler WB, Littlewood-Evans A, Dillon JP, Bilbe G, Sharpe GR, Gallagher JARegulation of epidermal homeostasis through P2Y2 receptorsBr J Pharmacol.(1999 Aug)
106.^Lee WK, Choi SW, Lee HR, Lee EJ, Lee KH, Kim HOPurinoceptor-mediated calcium mobilization and proliferation in HaCaT keratinocytesJ Dermatol Sci.(2001 Feb)
107.^Babb SM, Ke Y, Lange N, Kaufman MJ, Renshaw PF, Cohen BMOral choline increases choline metabolites in human brainPsychiatry Res.(2004 Jan 15)