Skip to main content
SpringerLink
Log in

Synapse formation is enhanced by oral administration of uridine and DHA, the circulating precursors of brain phosphatides

  • JNHA: Clinical Neurosciences
  • Published:
JNHA - The Journal of Nutrition, Health and Aging

Abstract

Objective

The loss of cortical and hippocampal synapses is a universal hallmark of Alzheimer’s disease, and probably underlies its effects on cognition. Synapses are formed from the interaction of neurites projecting from “presynaptic” neurons with dendritic spines projecting from “postsynaptic” neurons. Both of these structures are vulnerable to the toxic effects of nearby amyloid plaques, and their loss contributes to the decreased number of synapses that characterize the disease. A treatment that increased the formation of neurites and dendritic spines might reverse this loss, thereby increasing the number of synapses and slowing the decline in cognition.

Design setting, Participants, Intervention, Measurements and Results

We observe that giving normal rodents uridine and the omega-3 fatty acid docosahexaenoic acid (DHA) orally can enhance dendritic spine levels (3), and cognitive functions (32). Moreover this treatment also increases levels of biochemical markers for neurites (i.e., neurofilament-M and neurofilament-70) (2) in vivo, and uridine alone increases both these markers and the outgrowth of visible neurites by cultured PC-12 cells (9). A phase 2 clinical trial, performed in Europe, is described briefly.

Discussion and Conclusion

Uridine and DHA are circulating precursors for the phosphatides in synaptic membranes, and act in part by increasing the substrate-saturation of enzymes that synthesize phosphatidylcholine from CTP (formed from the uridine, via UTP) and from diacylglycerol species that contain DHA: the enzymes have poor affinities for these substrates, and thus are unsaturated with them, and only partially active, under basal conditions. The enhancement by uridine of neurite outgrowth is also mediated in part by UTP serving as a ligand for neuronal P2Y receptors. Moreover administration of uridine with DHA activates many brain genes, among them the gene for the m-1 metabotropic glutamate receptor [Cansev, et al, submitted]. This activation, in turn, increases brain levels of that gene’s protein product and of such other synaptic proteins as PSD-95, synapsin-1, syntaxin-3 and F-actin, but not levels of non-synaptic brain proteins like beta-tubulin. Hence it is possible that giving uridine plus DHA triggers a neuronal program that, by accelerating phosphatide and synaptic protein synthesis, controls synaptogenesis. If administering this mix of phosphatide precursors also increases synaptic elements in brains of patients with Alzheimer ’s disease, as it does in normal rodents, then this treatment may ameliorate some of the manifestations of the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science 2002;298:789–791.

    Article  PubMed  CAS  Google Scholar 

  2. Wurtman RJ, Ulus IH, Cansev M, Watkins CJ, Wang L, Marzloff G. Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Res 2006;1088:83–92.

    Article  PubMed  CAS  Google Scholar 

  3. Sakamoto T, Cansev M, Wurtman RJ. Oral supplementation with docosahexaenoic acid and uridine 5′-monophosphate increases dendritic spine density in adult gerbil hippocampus. Brain Res. 2007;1182:50–59.

    Article  PubMed  CAS  Google Scholar 

  4. Barbosa AC, Kim M-S, Ertunc M, Adachi M, Nelson ED, McAnally J, Richardson JA, Kavalali ET, Mongeggia, Bassel-Duby R, Olson EN. MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. PNAS 2008;105:9391–9396.

    Article  PubMed  CAS  Google Scholar 

  5. Toni N, Teng EM, Bushong EA, Aimone JB, Zhao C, Consiglio A, van Praag H, Martone ME, Ellisman MH, Gage FH. Synapse formation on neurons born in the adult hippocampus. Nat Neurosci. 2007;10:727–734.

    Article  PubMed  CAS  Google Scholar 

  6. Alvarez VA, Sabatini BL. Anatomical and physiological plasticity of dendritic spines. 2007;30:79–97.

    CAS  Google Scholar 

  7. Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschop MH, Horvath TH. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci. 2006;9:381–388.

    Article  PubMed  CAS  Google Scholar 

  8. Sastry PS. Lipids of nervous tissue: composition and metabolism. Prog Lipid Res 1985;24:69–176.

    Article  PubMed  CAS  Google Scholar 

  9. Pooler AM, Guez DH, Benedictus R, Wurtman RJ. Uridine enhances neurite outgrowth in nerve growth factor-differentiated pheochromocytoma cells. Neuroscience 2005;134:207–214.

    Article  PubMed  CAS  Google Scholar 

  10. Darios F, Davletov B. Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3. Nature 2006;440:813–817.

    Article  PubMed  CAS  Google Scholar 

  11. Cansev M, Wurtman RJ. Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils. Neuroscience 2007;148:421–431.

    Article  PubMed  CAS  Google Scholar 

  12. Kennedy EM, Weiss SB. The function of cytidine coenzymes in the biosynthesis of phospholipids. J Biol Chem 1956;222:193–214.

    PubMed  CAS  Google Scholar 

  13. Wurtman RJ, Regan M, Ulus I, Yu L. Effect of oral CDP-choline on plasma choline and uridine levels in humans. Biochem Pharmacol 2000;60:989–992.

    Article  PubMed  CAS  Google Scholar 

  14. Cansev M. Uridine and cytidine in the brain: Their transport and utilization. Brain Res Brain Res Rev 2006;52:389–397.

    Article  CAS  Google Scholar 

  15. Pardridge, W.M., Oldendorf, W.H. Transport of metabolic substrates through the blood-brain barrier. J. Neurochem. 1977;28:5–12.

    Article  PubMed  CAS  Google Scholar 

  16. Kamp F, Westerhoff HV, Hamilton JA. Movement of fatty acids, fatty acid analogues, and bile acids across phospholipid bilayers. Biochemistry 1993;32:11074–11086.

    Article  PubMed  CAS  Google Scholar 

  17. Abumrad NA, Park JH, Park CR. Permeation of long-chain fatty acid into adipocytes. Kinetics, specificity, and evidence for involvement of a membrane protein. J Biol Chem 1984;259:8945–8953.

    PubMed  CAS  Google Scholar 

  18. Cansev M, Watkins CJ, van der Beek EM, Wurtman RJ. Oral Uridine 5′ monophosphate (UMP) increases brain CDP-choline levels in gerbils. Brain Res 2005;1058:101–108.

    Article  PubMed  CAS  Google Scholar 

  19. Millington WR, Wurtman RJ. Choline administration elevates brain phosphorylcholine levels. J Neurochem 1982;38:1748–1752.

    Article  PubMed  CAS  Google Scholar 

  20. Babb SM, Ke Y, Lange N, Kaufman MJ, Renshaw PF, Cohen BM. Oral choline increases choline metabolites in human brain. Psychiatry Res 2004;130:1–9.

    Article  PubMed  CAS  Google Scholar 

  21. Spanner S, Ansell GB. Choline kinase and ethanolamine kinase activity in the cytosol of nerve endings from rat forebrain. Biochem J 1979;178:753–760.

    PubMed  CAS  Google Scholar 

  22. Stavinoha WB, Weintraub ST. Choline content of rat brain. Science 1974;183:964–965.

    Article  PubMed  CAS  Google Scholar 

  23. Klein J, Gonzales R, Koppen A, Loffelholz K. Free choline and choline metabolites in rat brain and body fluids: sensitive determination and implications for choline supply to the brain. Neurochem Int 1993;22:293–300.

    Article  PubMed  CAS  Google Scholar 

  24. Ross BM, Moszczynska A, Blusztajn JK, Sherwin A, Lozano A, Kish SJ. Phospholipid biosynthetic enzymes in human brain. Lipids 1997;32:351–358.

    Article  PubMed  CAS  Google Scholar 

  25. Vance DE, Pelech SL. Enzyme translocation in the regulation of phosphatidylcholine biosynthesis. Trends Biochem Sci 1984;9:17–20.

    Article  CAS  Google Scholar 

  26. Lim P, Cornell R, Vance DE. The supply of both CDP-choline and diacylglycerol can regulate the rate of phosphatidylcholine synthesis in HeLa cells. Biochem Cell Biol 1986;64:692–698.

    Article  PubMed  CAS  Google Scholar 

  27. Araki W, Wurtman RJ. Control of membrane phosphatidylcholine synthesis by diacylglycerol levels in neuronal cells undergoing neurite outgrowth. Proc Natl Acad Sci USA 1997;94:11946–11950.

    Article  PubMed  CAS  Google Scholar 

  28. Marszalek JR, Lodish HF. Docosahexaenoic acid, fatty acid-interacting proteins, and neuronal function: breastmilk and fish are good for you. Ann Rev Cell Dev Biol 2005;21:633–657.

    Article  CAS  Google Scholar 

  29. Ferreira A, Rapoport M. The synapsins: beyond the regulation of neurotransmitter release. Cell Mol Life Sci 2002;59:589–595.

    Article  PubMed  CAS  Google Scholar 

  30. Fujita A, Kurachi Y. SAP family proteins. Biochem Biophys Res Commun 2000;269:1–6.

    Article  PubMed  CAS  Google Scholar 

  31. Holguin S, Huang Y, Liu J, Wurtman R. Chronic administration of DHA and UMP improves the impaired memory of environmentally impoverished rats. Behav Brain Res. 2008;191:11–16.

    Article  PubMed  CAS  Google Scholar 

  32. Holguin S, Martinez J, Chow C, Wurtman R. Dietary uridine enhances the improvement in learning and memory produced by administering DHA to gerbils. FASEB J. FASEB fj.08-112425, published online July 7, 2008.

  33. Wang L, Pooler AM, Albrecht MA, Wurtman RJ. Dietary uridine-5′-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. J Mol Neurosci 2005;27:137–145.

    Article  PubMed  Google Scholar 

  34. Wang L, Albrecht MA, Wurtman RJ. Dietary supplementation with uridine-5′-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat. Brain Res 2007;1133:42–48.

    Article  PubMed  CAS  Google Scholar 

  35. Hersh LB. Kinetic studies of the choline acetyltransferase reaction using isotope exchange at equilibrium. J Biol Chem 1982;257:12820–12834.

    PubMed  CAS  Google Scholar 

  36. Tucek S. The synthesis of acetylcholine: Twenty years of progress. Prog Brain Res 1990;84:467–477.

    Article  PubMed  CAS  Google Scholar 

  37. Wilgram GF, Kennedy EP. Intracellular distribution of some enzymes catalyzing reactions in the biosynthesis of complex lipids. J Biol Chem 1963;238:2615–2619.

    PubMed  CAS  Google Scholar 

  38. Tronchere H, Record M, Terce F, Chap H. Phosphatidylcholine cycle and regulation of phosphatidylcholine biosynthesis by enzyme translocation. Biochim Biophys Acta 1994;1212:137–151.

    PubMed  CAS  Google Scholar 

  39. Sleight R, Kent C. Regulation of phosphatidylcholine biosynthesis in cultured chick embryonic muscle treated with phospholipase C. J Biol Chem 1980;255:10644–10650.

    PubMed  CAS  Google Scholar 

  40. Sleight R, Kent C. Regulation of phosphatidylcholine biosynthesis in mammalian cells. I. Effects of phospholipase C treatment on phosphatidylcholine metabolism in Chinese hamster ovary cells and LM mouse fibroblasts. J Biol Chem 1983;258:824–830.

    PubMed  CAS  Google Scholar 

  41. Pelech SL, Cook HW, Paddon HB, Vance DE. Membrane-bound CTP:phosphocholine cytidylyltransferase regulates the rate of phosphatidylcholine synthesis in HeLa cells treated with unsaturated fatty acids. Biochim Biophys Acta 1984;795:433–440.

    PubMed  CAS  Google Scholar 

  42. Cornell RB, Northwood IC. Regulation of CTP:phosphocholine cytidylyltransferase by amphitropism and relocalization. Trends Biochem Sci 2000;25:441–447.

    Article  PubMed  CAS  Google Scholar 

  43. Utal AK, Jamil H, Vance DE. Diacylglycerol signals the translocation of CTP:choline-phosphate cytidylyltransferase in HeLa cells treated with 12-O-tetradecanoylphorbol-13-acetate. J Biol Chem 1991;266:24084–24091.

    PubMed  CAS  Google Scholar 

  44. Weinhold PA, Charles L, Rounsifer ME, Feldman DA. Control of phosphatidylcholine synthesis in Hep G2 cells. Effect of fatty acids on the activity and immunoreactive content of choline phosphate cytidylyltransferase. J Biol Chem 1991;266:6093–6100.

    PubMed  CAS  Google Scholar 

  45. Watkins JD, Kent C. Regulation of CTP:phosphocholine cytidylyltransferase activity and subcellular location by phosphorylation in Chinese hamster ovary cells. The effect of phospholipase C treatment. J Biol Chem 1991;266:21113–21117.

    PubMed  CAS  Google Scholar 

  46. Mages F, Rey C, Fonlupt P, Pacheco H. Kinetic and biochemical properties of CTP:choline-phosphate cytidylyltransferase from the rat brain. Eur J Biochem 1988;178:367–372.

    Article  PubMed  CAS  Google Scholar 

  47. Mandel P, Edel-Harth S. Free nucleotides in the rat brain during post-natal development. J Neurochem 1966;13:591–595.

    Article  PubMed  CAS  Google Scholar 

  48. Abe K, Koqure K, Yamomoto H, Imazawa M, Miyamoto K. Mechanism of arachidonic acid liberation during ischemia in gerbil cerebral cortex. J Neurochem 1987;48:503–509.

    Article  PubMed  CAS  Google Scholar 

  49. Nitsch RM, Blusztajn JK, Pittas AG, Slack BE, Growdon JH, Wurtman RJ. Evidence for a membrane defect in Alzheimer disease brain. Proc Natl Acad Sci USA 1992;89:1671–1675.

    Article  PubMed  CAS  Google Scholar 

  50. Choy PC, Paddon HB, Vance DE. An increase in cytoplasmic CTP accelerates the reaction catalyzed by CTP:phosphocholine cytidylyltransferase in poliovirus-infected HeLa cells. J Biol Chem 1980;255:1070–1073.

    PubMed  CAS  Google Scholar 

  51. Lopez G-Coviella I, Wurtman RJ. Enhancement by cytidine of membrane phospholipid synthesis. J Neurochem 1992;59:338–343.

    Article  CAS  Google Scholar 

  52. Richardson UI, Watkins CJ, Pierre C, Ulus IH, Wurtman RJ. Stimulation of CDP-choline synthesis by uridine or cytidine in PC12 rat pheochromocytoma cells. Brain Res 2003;971:161–167.

    Article  PubMed  CAS  Google Scholar 

  53. Savci V, Wurtman RJ. Effect of cytidine on membrane phospholipid synthesis in rat striatal slices. J Neurochem 1995;64:378–384.

    Article  PubMed  CAS  Google Scholar 

  54. Cornell RB. Cholinephosphotransferase from mammalian sources. Methods Enzymol 1992;209:267–272.

    Article  PubMed  CAS  Google Scholar 

  55. Korniat EK, Beeler DA. Water-soluble phospholipid precursor pool-sizes in quick-frozen and unfrozen rat livers. Anal Biochem 1975;69:300–305.

    Article  PubMed  CAS  Google Scholar 

  56. Turinsky J, Bayly BP, O’sullivan DM. 1,2-diacylglycerol and ceramide levels in rat liver and skeletal muscle in vivo. Am J Physiol 1991;261:E620–E627.

    PubMed  CAS  Google Scholar 

  57. Alberghina M, Viola M, Giuffrida AM. Pool size of CDP-choline in the brain, heart, and lung of normal hypoxic guinea pigs. J Neurosci Res 1981;6:719–722.

    Article  PubMed  CAS  Google Scholar 

  58. Baldwin SA, Beal PR, Yao SYM, King AE, Cass CE, Young JD. The equilibrative nucleoside transporter family, SLC29. Pflugers Arch 2004;447:735–743.

    Article  PubMed  CAS  Google Scholar 

  59. Gray JH, Owen RP, Giacomini KM. The concentrative nucleoside transporter family, SLC28. Pflugers Arch 2004;447:728–734.

    Article  PubMed  CAS  Google Scholar 

  60. Redzic ZB, Biringer J, Barnes K, Baldwin SA, Al-Sarraf H, Nicola PA, Young JD, Cass CE, Barrand MA, Hlandky SB. Polarized distribution of nucleoside transporters in rat brain endothelial and choroid plexus epithelial cells. J Neurochem 2005;94:1420–1426.

    Article  PubMed  CAS  Google Scholar 

  61. Murakami H, Ohkura A, Takanaga H, Matsuo H, Koyabu N, Naito M, Tsuruo T, Ohtani H, Sawada Y. Functional characterization of adenosine transport across the BBB in mice. Int J Pharm 2005;290:37–44.

    Article  PubMed  CAS  Google Scholar 

  62. Pastor-Anglada M, Felipe A, Casado FJ. Transport and mode of action of nucleoside derivatives used in chemical and antiviral therapies. Trends Pharmacol Sci 1998;19:424–430.

    Article  PubMed  CAS  Google Scholar 

  63. Li JY, Boado RJ, Pardridge WM. Cloned blood-brain barrier adenosine transporter is identical to the rat concentrative Na+ nucleoside cotransporter CNT2. J Cereb Blood Flow Metab 2001;21:929–936.

    Article  PubMed  CAS  Google Scholar 

  64. Griffith DA, Jarvis SM. Nucleoside and nucleobase transport systems of mammalian cells. Biochim Biophys Acta 1996;1286:153–181.

    PubMed  CAS  Google Scholar 

  65. Traut TW. Physiological concentrations of purines and pyrimidines. Mol Cell Biochem 1994;140:1–22.

    Article  PubMed  CAS  Google Scholar 

  66. Larrayoz IM, Fernandez-Nistal A, Garces A, Gorraitz E, Lostao MP. Characterization of the rat Na+/nucleoside cotransporter 2 (rCNT2) and transport of nucleoside-derived drugs using electrophysiological methods. Am J Physiol Cell Physiol 2006;291:C1395–C1404.

    Article  PubMed  CAS  Google Scholar 

  67. Nagai K, Nagasawa K, Koma M, Hotta A, Fujimoto S. Cytidine is a novel substrate for wild-type concentrative nucleoside transporter 2. Biochem Biophys Res Commun 2006;347:439–443.

    Article  PubMed  CAS  Google Scholar 

  68. Nagai K, Nagasawa K, Koma M, Kihara Y, Fujimoto S. Contribution of an unidentified sodium-dependent nucleoside transport system to the uptake and cytotoxicity of anthracycline in mouse M5076 ovarian sarcoma cells. Biochem Pharmacol 2006;71:565–573.

    Article  PubMed  CAS  Google Scholar 

  69. Cansev, M, Wurtman RJ. Exogenous cytidine-5′-diphosphocholine increases brain cytidine-5′-diphosphocholine levels in gerbils. J Neurochem 2005;94(Supp. 2):105–106.

    Google Scholar 

  70. Anderson CM, Xiong W, Geiger JD, Young JD, Cass CE, Baldwin SA, Parkinson FE. Distribution of equilibrative, nitrobenzylthioinosine-insensitive nucleoside transporters (ENT1) in rat brain. J Neurochem 1999;73:867–873.

    Article  PubMed  CAS  Google Scholar 

  71. Anderson CM, Baldwin SA, Young JD, Cass CE, Parkinson FE. Distribution of mRNA encoding a nitrobenzylthioinosine-insensitive nucleoside transporter (ENT2) in rat brain. Brain Res Mol Brain Res 1999;70:293–297.

    Article  PubMed  CAS  Google Scholar 

  72. Wu X, Yuan G, Brett CM, Hui AC, Giacomini KM. Sodium-dependent nucleoside transport in choroid plexus from rabbit. Evidence for a single transporter for purine and pyrimidine nucleosides. J Biol Chem 1992;267:8813–8818.

    PubMed  CAS  Google Scholar 

  73. Wu X, Gutierrez MM, Giacomini KM. Further characterization of the sodium-dependent nucleoside transporter (N3) in choroid plexus from rabbit. Biochim Biophys Acta 1994;1191:190–196.

    Article  PubMed  CAS  Google Scholar 

  74. Pardridge WM. Invasive brain drug delivery; in Pardridge WM (ed): Brain Drug Targeting: The Future of Brain Drug Development. Cambridge, Cambridge University Press, UK, 2001, pp 13–35.

    Google Scholar 

  75. Canellakis ES. Pyrimidine metabolism. II. Enzymatic pathways of uracil anabolism. J Biol Chem 1957;227:329–338.

    PubMed  CAS  Google Scholar 

  76. Skold O. Uridine kinase from Erlich ascites tumor: Purification and properties. J Biol Chem 1960;235:3273–3279.

    CAS  Google Scholar 

  77. Orengo A. Regulation of enzymic activity by metabolites. I. Uridine-cytidine kinase of Novikoff ascites rat tumor. J Biol Chem 1969;244:2204–2209.

    PubMed  CAS  Google Scholar 

  78. Balestri F, Barsotti C, Lutzemberger L, Camici M, Ipata PL. Key role of uridine kinase and uridine phosphorylase in the homeostatic regulation of purine and pyrimidine salvage in brain. Neurochem Int In Press.

  79. Krystal G, Webb TE. Multiple forms of uridine kinase in normal and neoplastic rat liver. Biochem J 1971;124:943–947.

    PubMed  CAS  Google Scholar 

  80. Absil J, Tuilie M, Roux J-M. Electrophoretically distinct forms of uridine kinase in the rat. Tissue distribution and age-dependence. Biochem J 1980;185:273–276.

    PubMed  CAS  Google Scholar 

  81. Koizumi K, Shimamoto Y, Azuma A, Wataya Y, Matsuda A, Sasaki T, Fukushima M. Cloning and expression of uridine/cytidine kinase cDNA from human fibrosarcoma cells. Int J Mol Med 2001;8:273–278.

    PubMed  CAS  Google Scholar 

  82. Van Rompay AR, Norda A, Linden K, Johansson M, Karlsson A. Phosphorylation of uridine and cytidine analogs by two human uridine-cytidine kinases. Mol Pharmacol 2001;59:1181–1186.

    PubMed  Google Scholar 

  83. Hurwitz J. The enzymatic incorporation of ribonucleotides into polydeoxynucleotide material. J Biol Chem 1959;234:2351–2358.

    PubMed  CAS  Google Scholar 

  84. Sugino Y, Teraoka H, Shimono H. Metabolism of deoxyribonucleotides. I. Purification and properties of deoxycytidine monophosphokinase of calf thymus. J Biol Chem 1966;241:961–969.

    PubMed  CAS  Google Scholar 

  85. Ruffner BW, Anderson EP. Adenosine triphosphate: uridine monophosphate-cytidine monophosphate phosphotransferase from Tetrahymena pyriformis. J Biol Chem 1969;244:5994–6002.

    PubMed  CAS  Google Scholar 

  86. Wang TP, Sable HZ, Lampen JO. Enzymatic deamination of cytosine nucleosides. J Biol Chem 1950;184:17–28.

    PubMed  CAS  Google Scholar 

  87. Lieberman I: Enzymatic amination of uridine triphosphate to cytidine triphosphate. J Biol Chem 1956;222:765–775.

    PubMed  CAS  Google Scholar 

  88. Hurlbert RB, Kammen HO. Formation of cytidine nucleotides from uridine nucleotides by soluble mammalian enzymes: Requirements for glutamine and guanosine nucleotides. J Biol Chem 1960;235:443–449.

    CAS  Google Scholar 

  89. Zalkin H. CTP synthase. Methods Enzymol 1985;113:282–287.

    Article  PubMed  CAS  Google Scholar 

  90. Genchev DD, Mandel P. CTP synthetase activity in neonatal and adult rat brain. J Neurochem 1974;22:1027–1030.

    Article  PubMed  CAS  Google Scholar 

  91. Anderson EP. Nucleoside and nucleotide kinases; in Boyer PD (ed.): The Enzymes. New York, Academic Press, 1973, pp 49–96.

    Google Scholar 

  92. Greenberg N, Schumm DE, Webb TE. Uridine kinase activities and pyrimidine nucleoside phosphorylation in fluoropyrimidine-sensitive and -resistant cell lines of the Novikoff hepatoma. Biochem J 1977;164:379–387.

    PubMed  CAS  Google Scholar 

  93. Ropp PA, Traut TW. Cloning and expression of a cDNA encoding uridine kinase from mouse brain. Arch Biochem Biophys 1996;336:105–112.

    Article  PubMed  CAS  Google Scholar 

  94. Ropp PA, Traut TW. Uridine kinase: Altered enzyme with decreased affinities for uridine and CTP. Arch Biochem Biophys 1998;359:63–68.

    Article  PubMed  CAS  Google Scholar 

  95. Mascia L, Cotrufo T, Cappiello M, Ipata PL. Ribose 1-phosphate and inosine activate uracil salvage in rat brain. Biochim Biophys Acta 1999;1472:93–98.

    PubMed  CAS  Google Scholar 

  96. Peters GJ, van Groeningen CJ, Laurensse EJ, Lankelma J, Leyva A, Pinedo HM. Uridine-induced hypothermia in mice and rats in relation to plasma and tissue levels of uridine and its metabolites. Cancer Chemother Pharmacol 1987;20:101–108.

    Article  PubMed  CAS  Google Scholar 

  97. Chmurzynska A. The multigene family of fatty acid-binding proteins: Function, structure and polymorphism. J Appl Genet 2006;47:39–48.

    PubMed  Google Scholar 

  98. Shimizu F, Watanabe TK, Shinomiya H, Nakamura Y, Fujiwara T. Isolation and expression of a cDNA for human brain fatty acid-binding protein (B-FABP). Biochim Biophys Acta 1997;1354:24–28.

    PubMed  CAS  Google Scholar 

  99. Robinson PJ, Noronha J, DeGeorge JJ, Freed LM, Nariai T, Rapoport SI. A quantitative method for measuring regional in vivo fatty-acid incorporation into and turnover within brain phospholipids: review and critical analysis. Brain Res Brain Res Rev 1992;17:187–214.

    Article  PubMed  CAS  Google Scholar 

  100. Bazan NG. Supply of n-3 polyunsaturated fatty acids and their significance in the central nervous system; in Wurtman RJ, Wurtman JJ (eds): Nutrition and the Brain. New York, NY, Raven Press, 1990, vol 8, pp 1–24.

    Google Scholar 

  101. Thies F, Pillon C, Moliere P, Lagarde M, Lecerf J. Preferential incorporation of sn-2 lysoPC DHA over unesterified DHA in the young rat brain. Am J Physiol 1994;267:R1273–R1279.

    PubMed  CAS  Google Scholar 

  102. Marszalek JR, Kitidis C, DiRusso CC, Lodish HF. Long-chain acyl-CoA synthetase 6 preferentially promotes DHA metabolism. J Biol Chem 2005;280:10817–10826.

    Article  PubMed  CAS  Google Scholar 

  103. Reddy TS, Sprecher P, Bazan NG. Long-chain acyl-coenzyme A synthetase from rat brain microsomes. Kinetic studies using (1–14C)docosahexaenoic acid substrate. Eur J Biochem 1984;145:21–29.

    Article  PubMed  CAS  Google Scholar 

  104. Contreras MA, Greiner RS, Chang MC, Myers CS, Salem N Jr, Rapoport SI. Nutritional deprivation of alpha-linolenic acid decreases but does not abolish turnover and availability of unacylated docosahexaenoic acid and docosahexaenoyl-CoA in rat brain. J Neurochem 2000;75:2392–2400.

    Article  PubMed  CAS  Google Scholar 

  105. Neufeld EJ, Wilson DB, Sprecher H, Majerus PW. High affinity esterification of eicosanoid precursor fatty acids by platelets. J Clin Invest 1983;72:214–220.

    Article  PubMed  CAS  Google Scholar 

  106. Moore SA, Yoder A, Murphy S, Dutton GR, Spector AA. Astrocytes, not neurons, produce docosahexaenoic acid (22:6w-3) and arachidonic acid (20:4w-6). J Neurochem 1991;56:518–524.

    Article  PubMed  CAS  Google Scholar 

  107. DeGeorge JJ, Nariai T, Yamazaki S, Williams WM, Rapoport SI. Arecoline-stimulated brain incorporation of intravenously administered fatty acids in unanesthetized rats. J Neurochem 1991;56:352–355.

    Article  PubMed  CAS  Google Scholar 

  108. Sarda N, Gharib A, Moliere P, Grange E, Bobillier P, Lagarde M. Docosahexaenoic acid (cervonic acid) incorporation into different brain regions in the awake rat. Neurosci Lett 1991;123:57–60.

    Article  PubMed  CAS  Google Scholar 

  109. Farooqui AA, Horrocks LA. Plasmalogens, phospholipase A2, and docosahexaenoic acid turnover in brain tissue. J Mol Neurosci 2001;16:263–272.

    Article  CAS  Google Scholar 

  110. Nagan N, Zoeller RA. Plasmalogens: biosynthesis and functions. Prog Lipid Res 2001;40:199–229.

    Article  PubMed  CAS  Google Scholar 

  111. O’Brien JS, Sampson EL. Fatty acid and fatty aldehyde composition of the major brain lipids in normal human gray matter, white matter, and myelin. J Lipid Res 1965;6:545–551.

    PubMed  Google Scholar 

  112. Breckenridge WC, Gombos G, Morgan IG. The lipid composition of adult rat brain synaptosomal plasma membranes. Biochim Biophys Acta 1972;266:695–707.

    Article  PubMed  CAS  Google Scholar 

  113. Svennerholm L. Distribution and fatty acid composition of phosphoglycerides in normal human brain. J Lipid Res 1968;9:570–579.

    PubMed  CAS  Google Scholar 

  114. Hicks AM, DeLong CJ, Thomas MJ, Samuel M, Cui Z. Unique molecular signatures of glycerophospholipid species in different rat tissues analyzed by tandem mass spectrometry. Biochim Biophys Acta 2006;1761:1022–1029.

    PubMed  CAS  Google Scholar 

  115. Carlier H, Bernard A, Caselli C. Digestion and absorption of polyunsaturated fatty acids. Reprod Nutr Dev 1991;31:475–500.

    Article  PubMed  CAS  Google Scholar 

  116. Bezard J, Blond JP, Bernard A, Clouet P. The metabolism and availability of essential fatty acids in animal and human tissues. Reprod Nutr Dev 1994;34:539–568.

    Article  PubMed  CAS  Google Scholar 

  117. Rapoport SI, Chang MCJ, Spector AA. Delivery and turnover of plasma-derived essential PUFAs in mammalian brain. J Lipid Res 2001;42:678–685.

    PubMed  CAS  Google Scholar 

  118. Pawlosky RJ, Hibbeln JR, Novotny JA, Salem N Jr. Physiological compartmental analysis of a-linolenic acid metabolism in adult humans. J Lipid Res 2001;42:1257–1265.

    PubMed  CAS  Google Scholar 

  119. Zhou L, Vessby B, Nilsson A. Quantitative role of plasma free fatty acids in the supply of arachidonic acid to extrahepatic tissues in rats. J Nutr 2002;132:2626–2631.

    PubMed  CAS  Google Scholar 

  120. Rapoport SI. In vivo approaches and rationale for quantifying kinetics and imaging brain lipid metabolic pathways. Prostaglandins Other Lipid Mediat 2005;77:185–196.

    Article  PubMed  CAS  Google Scholar 

  121. Strokin M, Sergeeva M, Reiser G. Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A2 and is differently regulated by cyclic AMP and Ca2+. British J Pharmacol 2003;139:1014–1022.

    Article  CAS  Google Scholar 

  122. Lai MKP, Tan MGK, Kirvell S, Hobbs C, Lee J, Esiri MM, Chen CP, Francis PT. Selective loss of P2Y2 nucleotide receptor immunoreactivity is associated with Alzheimer’s disease neuropathology. J Neural Transm, 2008;115:1165–1172.

    Article  PubMed  CAS  Google Scholar 

  123. Teng FYH, Wang Y, Tang BL. The syntaxins. Genome Biol 2001;2:3012–3017.

    Article  Google Scholar 

  124. Kothapalli KSD, Anthony JC, Pan BS, Hsieh AT, Nathanielsz PW, Brenna JT. Differential cerebral cortex transcriptomes of baboon neonates consuming moderate and high docosahexaenoic acid formulas. PLoS ONE 2007;2:e370

    Article  PubMed  CAS  Google Scholar 

  125. Lands WEM, Inoue M, Sugiura Y, Okuyama H. Selective incorporation of polyunsaturated fatty acids into phosphatidylcholine by rat liver microsomes. J Biol Chem 1982;257:14968–14972.

    PubMed  CAS  Google Scholar 

  126. Matus A. Actin-based plasticity in dendritic spines. Science 2000;290:754–758.

    Article  PubMed  CAS  Google Scholar 

  127. Hering H, Sheng M. Dendritic spines: structure, dynamics and regulation. Nat Rev Neurosci 2001;2:880–888.

    Article  PubMed  CAS  Google Scholar 

  128. Nimchinsky EA, Sabatini BL, Svoboda K. Structure and function of dendritic spines. Annu Rev Physiol 2002;64:313–353.

    Article  PubMed  CAS  Google Scholar 

  129. El-Husseini AE, Schnell E, Chetkovich DM, Nicoll RA, Bredt DS. PSD-95 involvement in maturation of excitatory synapses. Science 2000;290:1364–1368.

    PubMed  CAS  Google Scholar 

  130. Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, Nakahara H. Structure-stability-function relationships of dendritic spines. Trends Neurosci 2003;26:360–368.

    Article  PubMed  CAS  Google Scholar 

  131. Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature 2004;429:761–766.

    Article  PubMed  CAS  Google Scholar 

  132. Greengard P, Valtorta F, Czernik AJ Benfenati F. Synaptic vesicle phosphoproteins and regulation of synaptic function. Science 1993;259:780–785.

    Article  PubMed  CAS  Google Scholar 

  133. Ziv NE, Garner CC. Cellular and molecular mechanisms of presynaptic assembly. Nat Rev Neurosci 2004;5:385–399.

    Article  PubMed  CAS  Google Scholar 

  134. Matus A. Growth of dendritic spines: a continuing story. Curr Opin Neurobiol 2005;15:67–72.

    Article  PubMed  CAS  Google Scholar 

  135. Williams JH, Errington ML, Lynch MA, Bliss TVP. Arachidonic acid induces a long-term activity-dependent enhancement of synaptic transmission in the hippocampus. Nature 1989;341:739–742.

    Article  PubMed  CAS  Google Scholar 

  136. Ramakers GM, Storm JFA. Postsynaptic transient K(+) current modulated by arachidonic acid regulates synaptic integration and threshold for LTP induction in hippocampal pyramidal cells. Proc Natl Acad Sci USA 2002;99:10144–10149.

    Article  PubMed  CAS  Google Scholar 

  137. Feinmark SJ, Begum R, Tsvetkov E, Goussakov I, Funk CD, Siegelbaum SA, Bolshakov VY. 12-lipoxygenase metabolites of arachidonic acid mediate metabotropic glutamate receptor-dependent long-term depression at hippocampal CA3-CA1 synapses. J Neurosci 2003;23:11427–11435.

    PubMed  CAS  Google Scholar 

  138. Ikemoto A, Kobayashi T, Watanabe S, Okuyama H. Membrane fatty acid modifications of PC12 cells by arachidonate or docosahexaenoate affect neurite outgrowth but not norepinephrine release. Neurochem Res 1997;22:671–678.

    Article  PubMed  CAS  Google Scholar 

  139. Calderon F, Kim H-Y. Docosahexaenoic acid promotes neurite growth in hippocampal neurons. J Neurochem 2004;90:979–988.

    Article  PubMed  CAS  Google Scholar 

  140. Abbracchio MP, Burnstock G, Boeynaems J-M, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA, Weisman GA. International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev 2006;58:281–341.

    Article  PubMed  CAS  Google Scholar 

  141. Price GD, Robertson SJ, Edwards FA. Long-term potentiation of glutamatergic synaptic transmission induced by activation of presynaptic P2Y receptors in the rat medial habenula nucleus. Eur J Neurosci 2003;17:844–850.

    Article  PubMed  Google Scholar 

  142. Yuste R, Bonhoeffer T. Genesis of dendritic spines: insights from ultrastructural and imaging studies. Nat Rev Neurosci 2004;5:24–34.

    Article  PubMed  CAS  Google Scholar 

  143. Teather LA, Wurtman RJ. Chronic administration of UMP ameliorates the impairment of hippocampal-dependent memory in impoverished rats. J Nutr 2006;136:2834–2837.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Clinical Pharmacology, Uludag University, Medical School, Bursa, 16059, Turkey

    M. Cansev & I. H. Ulus

  2. Department of Brain and Cognitive Sciences Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Richard J. Wurtman

  3. MIT, 77 Massachusetts Ave., Room l46-5023, Cambridge, MA, 02139, USA

    Richard J. Wurtman

Authors
  1. Richard J. Wurtman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Cansev
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. H. Ulus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard J. Wurtman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wurtman, R.J., Cansev, M. & Ulus, I.H. Synapse formation is enhanced by oral administration of uridine and DHA, the circulating precursors of brain phosphatides. J Nutr Health Aging 13, 189–197 (2009). https://doi.org/10.1007/s12603-009-0056-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12603-009-0056-3

Keywords

Search

Navigation