The pyrimidines cytidine (as CTP) and uridine (which is converted to UTP and then CTP) contribute to brain phosphatidylcholine and phosphatidylethanolamine synthesis via the Kennedy pathway. Their uptake into brain from the circulation is initiated by nucleoside transporters located at the blood-brain barrier (BBB), and the rate at which uptake occurs is a major factor determining phosphatide synthesis. Two such transporters have been described: a low-affinity equilibrative system and a high-affinity concentrative system. It is unlikely that the low-affinity transporter contributes to brain uridine or cytidine uptake except when plasma concentrations of these compounds are increased several-fold experimentally. CNT2 proteins, the high-affinity transporters for purines like adenosine as well as for uridine, have been found in cells comprising the BBB of rats. However, to date, no comparable high-affinity carrier protein for cytidine, such as CNT1, has been detected at this location. Thus, uridine may be more available to brain than cytidine and may be the major precursor in brain for both the salvage pathway of pyrimidine nucleotides and the Kennedy pathway of phosphatide synthesis. This recognition may bear on the effects of cytidine or uridine sources in neurodegenerative diseases. (c) 2006 Elsevier B.V. All rights reserved.