New perspectives on the roles of pyrimidines in the central nervous system.

Since 1956, when exogenous uridine and cytidine were found to be necessary for the maintenance of perfused rat brain function, the co-existence of de novo synthesis, salvage pathways and removal of pyrimidine bases in the CNS has been a controversial subject. Here, we review studies on metabolites and enzymes of pyrimidine metabolism through more than 60 years. In view of known and newly-described inherited pyrimidine and purine disorders - some with complex clinical profiles of neurological impairments - we underline the necessity to investigate how the different pathways work together in the developing brain and then sustain plasticity, regeneration and neuro-transmission in the adult CNS. Experimentally, early incorporation studies in animal brain slices and homogenates with radio-labelled nucleosides or precursors demonstrated salvage activity or de novo synthesis. Later, the nucleoside transporters and organic anionic transporters underlying uptake of metabolites and anti-pyrimidine drugs in the CNS were identified. Recently, the expression of de novo enzymes in glial cells and neurons was verified using (immuno) histochemical and in-situ-hybridization techniques. Adult brain was shown to take up or produce all pyrimidine (deoxy) ribonucleosides or, after uptake and phosphorolysis of nucleosides, to make use of ribose for different purposes, including energy. More recently, non-canonical pyrimidine bases (5mC, 5hmC) have been found most notably in brain, pointing to considerable postreplicative DNA metabolism, with the need for pyrimidine-specific enzymes. Even more perspectives are emerging, with advances in genome analysis and in the manipulation of expression from the gene.