This application requests continued support for a research program on brain membrane phosphatides (e.g., phosphatidylcholine [PC]); circulating compounds needed for the synthesis of PC (uridine in humans or cytidine in rats; choline; polyunsaturated fatty acids); and related compounds that interact with them in membranes (APP and other membrane proteins; DAG; cholesterol). It involves studies on humans, experimental animals, and cultured cells. Conceivably, the information generated by this program may lead to effective treatments for age-related cognitive impairments or for stroke and other types of brain injury. Research conducted in our laboratory since this program's last competitive review (June, 1997) has shown, among other things, that in humans, plasma uridine levels determine the production of CTP, a limiting intermediate in membrane synthesis. Moreover, plasma uridine is increased (along with choline) when people take oral citicoline (CDP-choline) in doses that affect cognition in the aged and reportedly diminish stroke size. One goal of our studies is to characterize the dietary constituents (RNA; insulin-secreting carbohydrates) that cause variations in plasma uridine, and the mechanisms that cause plasma uridine to fall below fasting levels several hours after it is elevated by giving oral citicoline. Another is to determine whether UMP, an approved constituent of infant formulas, can serve as an inexpensive and effective agent for raising plasma uridine levels in adults. Other studies will determine whether uridine - alone or with the other circulating PC precursors - can (like citicoline) ameliorate age-related memory impairments in humans and rats, and whether such effects can be correlated in rats with elevations in levels of brain UTP or CTP (or endogenous CDP-choline, or PC); whether systemic uridine administration enhances the release of particular neurotransmitters, and of uridine (or cytidine) itself, into CSF; the mechanisms by which uddine (and the other phosphatide precursors, or cholesterol) seems to enhance NGF-induced neurite outgrowth by PC-12 cells, and/or the synthesis/levels of APP and other membrane proteins in the cells; whether the polyunsaturated fatty acids and DAG formed from them are especially able to promote uridine-induced PC formation; and whether uridine's actions affect the production of platelet-activating factor (PAF) from CDPcholine.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Brain Disorders and Clinical Neuroscience 5 (BDCN)
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Nadler, Laurie S
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Massachusetts Institute of Technology
Other Basic Sciences
Schools of Arts and Sciences
United States
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Wurtman, Richard J; Cansev, Mehmet; Sakamoto, Toshimasa et al. (2010) Nutritional modifiers of aging brain function: use of uridine and other phosphatide precursors to increase formation of brain synapses. Nutr Rev 68 Suppl 2:S88-101
Wurtman, Richard J; Cansev, Mehmet; Sakamoto, Toshimasa et al. (2009) Administration of docosahexaenoic acid, uridine and choline increases levels of synaptic membranes and dendritic spines in rodent brain. World Rev Nutr Diet 99:71-96
Cansev, Mehmet; Marzloff, George; Sakamoto, Toshimasa et al. (2009) Giving uridine and/or docosahexaenoic acid orally to rat dams during gestation and nursing increases synaptic elements in brains of weanling pups. Dev Neurosci 31:181-92
Wurtman, R J; Cansev, M; Ulus, I H (2009) Synapse formation is enhanced by oral administration of uridine and DHA, the circulating precursors of brain phosphatides. J Nutr Health Aging 13:189-97
Holguin, Sarah; Huang, Yi; Liu, Jenny et al. (2008) Chronic administration of DHA and UMP improves the impaired memory of environmentally impoverished rats. Behav Brain Res 191:11-6
Cansev, Mehmet; Ulus, Ismail H; Wang, Lei et al. (2008) Restorative effects of uridine plus docosahexaenoic acid in a rat model of Parkinson's disease. Neurosci Res 62:206-9
Wurtman, Richard J (2008) Synapse formation and cognitive brain development: effect of docosahexaenoic acid and other dietary constituents. Metabolism 57 Suppl 2:S6-10
Cansev, Mehmet; Wurtman, Richard J; Sakamoto, Toshimasa et al. (2008) Oral administration of circulating precursors for membrane phosphatides can promote the synthesis of new brain synapses. Alzheimers Dement 4:S153-68
Cansev, M; Wurtman, R J (2007) 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 148:421-31
Wang, Lei; Albrecht, Meredith A; Wurtman, Richard J (2007) Dietary supplementation with uridine-5'-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat. Brain Res 1133:42-8

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