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.
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