Nutritional modifiers of aging brain function: Use of uridine and other phosphatide precursors to increase formation of brain synapses

Nutrition Reviews

Volumn 68, Issue SUPPL. 2, 2010, Pages S88-S101

  Wurtman, Richard J ^a   Cansev, Mehmet ^b   Sakamoto, Toshimasa ^c   Ulus, Ismael ^d  

^a MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^b ULUDAG UNIVERSITY   (Turkey)

^c KOBE GAKUIN UNIVERSITY   (Japan)

^d ACIBADEM UNIVERSITY   (Turkey)

Author keywords

Aging brain function; Nutritional modifiers; Phosphatide precursors; Uridine

Indexed keywords

CHOLINE; DOCOSAHEXAENOIC ACID; OMEGA 3 FATTY ACID; URIDINE;

ALZHEIMER DISEASE; ARTICLE; BEHAVIOR; BRAIN CELL; BRAIN DEVELOPMENT; BRAIN FUNCTION; CLINICAL TRIAL; COGNITION; HUMAN; NERVE CELL NETWORK; NEURITE; NONHUMAN; PROTEIN SYNTHESIS; SYNAPSE; SYNAPTIC MEMBRANE; SYNAPTOGENESIS; VERBAL MEMORY;

ANIMALIA;

EID: 78649436932     PISSN: 00296643     EISSN: 17534887     Source Type: Journal    
DOI: 10.1111/j.1753-4887.2010.00344.x     Document Type: Article

References (124)

1. Terry RD. Alzheimer's disease and the aging brain. J Geriatr Psychiatry Neurol. 2006;19:125-128.
2. Selkoe DJ. Alzheimer's disease in a synaptic failure. Science. 2002;298:789-791.
3. Spires-Jones TL, Meyer-Luehmann M, Osetek JD, et al. Impaired spine stability underlies plaque-related spine loss in an Alzheimer's disease mouse model. Am J Pathol. 2007;171:1304-1311.
4. Cansev M, Wurtman RJ, Sakamoto T, Ulus IH. Oral administration of circulating precursors for membrane phosphatides can promote the synthesis of new brain synapses. Alzheimers Demen. 2008;4(Suppl 1):S153-S169.
5. Wurtman RJ. Use of phosphatide precursors to promote synaptogenesis. Ann Rev Nutr. 2009;29:59-87.
6. Scheltens P, Verhey FRJ, Olde Rikkert MGM, Kamphuis PJ, Wilkinson D, Kurz A. The efficacy of Souvenaid™ in mild Alzheimer's disease: a randomized, controlled, double-blind, parallel group, multi-centre, multi-country clinical trial. Alzheimers Demen. 2008;4(Suppl 2):T789.
7. 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.
8. Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological dependence on plasma tryptophan levels. Science. 1971;173:149-152.
9. Fernstrom JD, Wurtman RJ. Nutrition and the brain. Sci Am. 1974;230:84-91.
10. Schaechter JD, Wurtman RJ. Serotonin release varies with brain tryptophan levels. Brain Res. 1990;532:203-210.
11. Ulus IH, Wurtman RJ, Mauron C, Blusztajn JK. Choline increases acetylcholine release and protects against the stimulation-induced decrease in phosphatide levels within membranes of rat corpus striatum. Brain Res. 1989;484:217-227.
12. Schwartz JC, Lampart C, Rose C. Histamine formation in rat brain in vivo: effects of histidine loads. J Neurochem. 1972;19:801-810.
13. During MJ, Acworth IN, Wurtman RJ. Dopamine release in rat striatum: physiological coupling to tyrosine supply. J Neurochem. 1989;52:1449-1454.
14. Nimchinsky EA, Yasuda R, Oertner TG, Svoboda K. The number of glutamate receptors opened by synaptic stimulation in single hippocampal spines. J Neurosci. 2004;24:2054-2064.
15. Diano S, Farr SA, Benoit SC, et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci. 2006;9:381-388.
16. Alvarez VA, Sabatini BL. Anatomical and physiological plasticity of dendritic spines. Annu Rev Neurosci. 2007;30:79-97.
17. Arellano JI, Espinosa A, Fairen A, Yuste R, DeFelipe J. Non-synaptic dendritic spines in neocortex. Neuroscience. 2007;145:464-469.
18. Arikkath J, Reichardt LF. Cadherins and catenins at synapses: roles in synaptogenesis and synaptic plasticity. Trends Neurosci. 2008;31:487-494.
19. Barbosa AC, Kim MS, Ertunc M, et al. MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. Proc Natl Acad Sci U S A. 2008;105:9391-9396.
20. Di Maio V. Regulation of information passing by synaptic transmission: a short review. Brain Res. 2008;1225:26-38.
21. Harms KJ, Dunaevsky A. Dendritic spine plasticity: looking beyond development. Brain Res. 2007;1184:65-71.
22. Knott GW, Holtmaat A, Wilbrecht L, Welker E, Svoboda K. Spine growth precedes synapse formation in the adult neocortex in vivo. Nat Neurosci. 2006;9:1117-1124.
23. Toni N, Teng EM, Bushong EA, Aimone JB, Zhao C. Synapse formation on neurons born in the adult hippocampus. Nat Neurosci. 2007;10:727-734.
24. Lardi-Studler B, Fritschy JM. Matching of pre-and postsynaptic specializations during synaptogenesis. Neuroscientist. 2007;13:115-126.
25. Gelbard-Sagiv H, Mukamel R, Harel M, Malach R, Fried I. Internally generated reactivation of single neurons in human hippocampus during free recall. Science. 2008;322:96-101.
26. Mammen AL, Huganir RL, O'Brien RJ. Redistribution and stabilization of cell surface glutamate receptors during synapse formation. J Neurosci. 1997;17:7351-7358.
27. Verhage M, Maia AS, Plomp JJ, et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science. 2000;287:864-869.
28. Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER, Bourtchouladze R. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell. 1997;88:615-626.
29. Kaplan MP, Abel T. Genetic approaches to the study of synaptic plasticity and memory storage. CNS Spectr. 2003;8:597-610.
30. Lonze BE, Ginty DD. Function and regulation of CREB family transcription factors in the nervous system. Neuron. 2002;35:605-623.
31. Flavell SW, Cowan CW, Kim TK, et al. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science. 2006;311:1008-1012.
32. Kennedy EM, Weiss SB. The function of cytidine coenzymes in the biosynthesis of phospholipids. J Biol Chem. 1956;222:193-214.
33. 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.
34. Marszalek JR, Lodish HF. Docosahexaenoic acid, fatty acid-interacting proteins, and neuronal function: breastmilk and fish are good for you. Annu Rev Cell Dev Biol. 2005;21:633-657.
35. Millington WR, Wurtman RJ. Choline administration elevates brain phosphorylcholine levels. J Neurochem. 1982;38:1748-1752.
36. 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.
37. 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.
38. 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.
39. Ross BM, Moszczynska A, Blusztajn JK, Sherwin A, Lozano A, Kish SJ. Phospholipid biosynthetic enzymes in human brain. Lipids. 1997;32:351-358.
40. Stavinoha WB, Weintraub ST. Choline content of rat brain. Science. 1974;183:964-965.
41. Vance DE, Pelech SL. Enzyme translocation in the regulation of phosphatidylcholine biosynthesis. Trends Biochem Sci. 1984;9:17-20.
42. 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.
43. Araki W, Wurtman RJ. Control of membrane phosphatidylcholine synthesis by diacylglycerol levels in neuronal cells undergoing neurite outgrowth. Proc Natl Acad Sci U S A. 1997;94:11946-11950.
44. 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.
45. 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 proteins levels in gerbils. Neuroscience. 2007;148:421-431.
46. Pooler AM, Guez DH, Benedictus R, Wurtman RJ. Uridine enhances neurite outgrowth in NGF-differentiated PC12 cells. Neuroscience. 2005;134:207-214.
47. 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.
48. 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.
49. Teather LA, Wurtman RJ. Chronic administration of UMP ameliorates the impairment of hippocampal-dependent memory in impoverished rats. J Nutr. 2006;136:2834-2837.
50. 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. 2008;22:3938-3946.
51. 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.
52. 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.
53. Wilson TH, Wilson DW. Studies in vitro of digestion and absorption of pyrimidine nucleotides by the intestine. J Biol Chem. 1958;233:1544-1547.
54. Wilson TH, Wilson DW. Studies in vitro of the digestion and absorption of purine ribonucleotides by the intestine. J Biol Chem. 1962;237:1643-1647.
55. Bronk JR, Hastewell JG. The transport and metabolism of the uridine mononucleotides by rat jejunum in vitro. J Physiol. 1989;408:129-135.
56. Leach JL, Baxter JH, Molitor BE, Ramstack MB, Masor ML. Total potentially available nucleosides of human milk by stage of lactation. Am J Clin Nutr. 1995;61:1224-1230.
57. Thorell L, Sjoberg L-B, Hernell O. Nucleotides in human milk: sources and metabolism by the newborn infant. Pediatr Res. 1996;40:845-852.
58. Farghali H, Novotny L, Ryba M, Berank J, Janku I. Kinetics of transport and metabolism of 1-beta-D-arabinofuranosylcytosine and structural analogs by everted perfused rat jejunum. Biochem Pharmacol. 1984;33:655-662.
59. Novotny L, Farghali H, Ryba M, Berank J, Janku I. Structure-intestinal transport and structure-metabolism correlations of some potential cancerostatic pyrimidine nucleosides in isolated rat jejunum. Cancer Chemother Pharmacol. 1984;13:195-199.
60. Gray JH, Owen RP, Giacomini KM. The concentrative nucleoside transporter family, CLC28. Pflugers Arch. 2004;447:728-734.
61. Gasser T, Moyer JD, Handschumacher RE. Novel single-pass exchange of circulating uridine in rat liver. Science. 1981;213:777-778.
62. Cansev M. Uridine and cytidine in the brain: their transport and utilization. Brain Res Rev. 2006;52:389-397.
63. 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.
64. Orengo A. Regulation of enzymic activity by metabolites. I. Uridine-cytidine kinase of Novikoff ascites rat tumor. J Biol Chem. 1969;244:2204-2209.
65. Skold O. Uridine kinase from Erlich ascites tumor: purification and properties. J Biol Chem. 1960;235:3273-3279.
66. Ruffner BW, Anderson EP. Adenosine triphosphate: uridine monophosphate-cytidine monophosphate phosphotransferase from Tetrahymena pyriformis. J Biol Chem. 1969;244:5994-6002.
67. 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.
68. Parks RE Jr, Agarwal RP. Nucleoside diphosphokinases. In: Boyer PD, ed. The Enzymes. New York: Academic Press; 1973:307-333.
69. Wang TP, Sable HZ, Lampen JO. Enzymatic deamination of cytosine nucleosides. J Biol Chem. 1950;184:17-28.
70. 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.
71. Ropp PA, Traut TW. Uridine kinase: altered enzyme with decreased affinities for uridine and CTP. Arch Biochem Biophys. 1998;359:63-68.
72. Mascia L, Cotrufo C, Cappiello M, Ipata PL. Ribose 1-phosphate and inosine activate uracil salvage in rat brain. Biochim Biophys Acta. 1999;1472:93-98.
73. 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;97:161-167.
74. Ulus IH, Watkins CJ, Cansev M, Wurtman RJ. Cytidine and uridine increase striatal CDP-choline levels without decreasing acetylcholine synthesis or release. Cell Mol Neurobiol. 2006;26:563-577.
75. Cohen EL, Wurtman RJ. Brain acetylcholine: increase after systemic choline administration. Life Sci. 1975;16:1095-1102.
76. Hirsch MJ, Growdon JH, Wurtman RJ. Relations between dietary choline or lecithin intake, serum choline levels, and various metabolic indices. Metabolism. 1978;27:953-960.
77. 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 U S A. 1992;89:1671-1675.
78. Wurtman RJ, Cansev M, Ulus IH. Choline and its products acetylcholine and phosphatidylcholine. In: Lajtha A, ed. Neural Lipids: Handbook of Neurochemistry and Molecular Neurobiology. Vol. 8. Berlin-Heidelberg: Springer-Verlag; 2009;Part 3, Chapter 18:445-501.
79. Holmes-McNarry MQ, Cheng WL, Mar MH, Fussel S, Zeisel SH. Choline and choline esters in human and rat milk and in infant formulas. Am J Clin Nutr. 1996;64:572-576.
80. Zeisel SH, Da Costa K-A, Franklin PD, et al. Choline, an essential nutrient for humans. FASEB J. 1991;5:2093-2098.
81. Houtsmuller UMT. Metabolic fate of dietary lecithin. In: Wurtman RJ, Wurtman JJ, eds. Nutrition and the Brain. New York: Raven Press; 1979:83-94.
82. Fox JM, Betzing H, Lekim D. Pharmacokinetics of orally ingested phosphatidylcholine. In: Wurtman RJ, Wurtman JJ, eds. Nutrition and the Brain. New York: Raven Press; 1979:95-108.
83. Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington DC: National Academy Press; 1998:390-422.
84. Blusztajn JK, Wurtman RJ. Choline biosynthesis by a preparation enriched in synaptosomes from rat brain. Nature. 1981;290:417-418.
85. Crews FT, Hirata F, Axelrod J. Identification and properties of methyltransferases that synthesize phosphatidylcholine in rat brain synaptosomes. J Neurochem. 1980;34:1491-1498.
86. Blusztajn JK, Zeisel SH, Wurtman RJ. Synthesis of lecithin (phosphatidylcholine) from phosphatidylethanolamine in bovine brain. Brain Res. 1979;179:319-327.
87. Holbrook PG, Wurtman RJ. Presence of base-exchange activity in rat brain nerve endings: dependence on soluble substrate concentrations and effect of cations. J Neurochem. 1988;50:156-162.
88. Zeisel SH. Dietary choline: biochemistry, physiology and pharmacology. Annu Rev Nutr. 1981;1:95-121.
89. Tacconi M, Wurtman RJ. Phosphatidylcholine produced in rat synaptosomes by N-methylation is enriched in polyunsaturated fatty acids. Proc Natl Acad Sci U S A. 1985;82:4828-4831.
90. Friedrich A, George RL, Bridges CC, Prasad PD, Ganapathy V. Transport of choline and its relationship to the expression of the organic cation transporters in a rat brain microvessel endothelial cell line (RBE4). Biochim Biophys Acta. 2001;1512:299-307.
91. Cornford EM, Braun LD, Oldendorf WH. Carrier mediated blood-brain barrier transport of choline and certain choline analogs. J Neurochem. 1978;30:299-308.
92. Sweet DH, Miller DS, Pritchard JB. Ventricular choline transport. A role for organic cation transporter 2 expressed in choroid plexus. J Biol Chem. 2001;276:41611-41619.
93. Oldendorf WH, Braun LD. [H]Tryptamine and 3H-water as diffusible internal standards for measuring brain extraction of radio-labeled substances following carotid injection. Brain Res. 1976;113:219-224.
94. Mooradian AD. Blood-brain barrier transport of choline is reduced in the aged rat. Brain Res. 1988;440:328-332.
95. Klein J, Koppen A, Loffelholz K. Small rises in plasma choline reverse the negative arteriovenous difference of brain choline. J Neurochem. 1990;55:1231-1236.
96. Farber SA, Savci V, Wei A, Slack BE, Wurtman RJ. Choline's phosphorylation in rat striatal slices is regulated by the activity of cholinergic neurons. Brain Res. 1996;723:90-99.
97. Blusztajn JK, Holbrook PG, Lakher M, et al. "Autocannibalism" of membrane choline-phospholipids: physiology and pathology. Psychopharmacol Bull. 1986;22:781-786.
98. Simopoulos AP, Leaf A, Salem N Jr. Workshop on the essentiality of and recommended dietary intakes for omega-6 and omega-3 fatty acids. J Am Coll Nutr. 1999;18:487-489.
99. Kamp F, Westerhoff HV, Hamilton JA. Movement of fatty acids, fatty acid analogues, and bile acids across phospholipid bilayers. Biochemistry. 1993;32:11074-11086.
100. 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.
101. Chmurzynska A. The multigene family of fatty acid-binding proteins: function, structure and polymorphism. J Appl Genet. 2006;47:39-48.
102. 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 the Brain. New York: Raven Press; 1990:1-24.
103. 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.
104. 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.
105. 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.
106. Neufeld EJ, Wilson DB, Sprecher H, Majerus P. High affinity esterification of eicosanoid precursor fatty acids by platelets. J Clin Invest. 1983;72:214-220.
107. 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.
108. 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.
109. Breckenridge WC, Gombos G, Morgan IG. The lipid composition of adult rat brain synaptosomal plasma membranes. Biochim Biophys Acta. 1972;266:697-707.
110. Soderberg M, Edlund C, Kristensson K, Dallner G. Fatty acid composition of brain phospholipids in aging and in Alzheimer's disease. Lipids. 1991;26:421-425.
111. Svennerholm L. Distribution and fatty acid composition of phosphoglycerides in normal human brain. J Lipid Res. 1968;9:570-579.
112. Rapoport SI, Chang MCJ, Spector AA. Delivery and turnover of plasma-derived essential PUFAs in mammalian brain. J Lipid Res. 2001;42:678-685.
113. Burnstock G. Purine and pyrimidine receptors. Cell Mol Life Sci. 2007;64:1471-1483.
114. Arslan G, Filipeanu CM, Irenius E, et al. P2Y receptors contribute to ATP-induced increases in intracellular calcium in differentiated but not undifferentiated PC12 cells. Neuropharmacology. 2000;39:482-496.
115. Cansev M. Involvement of uridine-nucleotide-stimulated P2Y receptors in neuronal growth and function. Cent Nerv Syst Agents Med Chem. 2007;7:223-229.
116. Arthur DB, Akassoglou K, Insel PA. P2Y2 receptor activates nerve growth factor/TrkA signaling to enhance neuronal differentiation. Proc Natl Acad Sci U S A. 2005;102:19138-19143.
117. Lai MK, Tan MG, Kirvell S, Hobbs C, Lee J, et al. Selective loss of P2Y2 nucleotide receptor immunoreactivity is associated with Alzheimer's disease neuropathology. J Neural Transm. 2008;115:1165-1172.
118. Yen C-HE, Mar M-H, Meeker RB, Fernandes A, Zeisel SH. Choline deficiency induces apoptosis in primary cultures of fetal neurons. FASEB J. 2001;15:1704-1710.
119. Jacobsen JS, Wu CC, Redwine JM, et al. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA. 2006;103:5161-5166.
120. Knobloch M, Mansuy IM. Dendritic spine loss and synaptic alterations in Alzheimer's disease. Mol Neurobiol. 2008;37:73-82.
121. Engert F, Bonhoeffer T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature. 1999;399:66-70.
122. Toni N, Buchs PA, Nikonenko I, Bron CR, Muller D. LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature. 1999;402:421-425.
123. Cansev M, Marzloff G, Sakamoto T, Ulus IH, Wurtman RJ. Giving uridine and/or docosahexaenoic acid orally to rat dams during gestation and nursing increases synaptic elements in brains of weanling pups. Dev Neurosci. 2009;31:181-192.
124. Cansev M, Ulus IH, Wang L, Maher TJ, Wurtman RJ. Restorative effects of uridine plus docosahexaenoic acid in a rat model of Parkinson's disease. Neurosci Res. 2008;62:206-209.