Short-term administration of uridine increases brain membrane phospholipid precursors in healthy adults: a 31-phosphorus magnetic resonance spectroscopy study at 4T

Abstract

Objectives: Altered metabolism of membrane phospholipids has been implicated in bipolar disorder. In humans, uridine is an important precursor of cytidine diphosphate (CDP)-choline, which plays a critical role in phospholipid synthesis and is currently being evaluated as a potential treatment for bipolar depression.

Methods: A total of 17 healthy males (mean age ± SD: 32.73 ± 7.2 years; range: 21.8-46.4 years) were enrolled in this study. Subjects underwent a 31-phosphorus magnetic resonance spectroscopy ((31) P-MRS) acquisition at baseline and then again after seven days of either 2 g of uridine or placebo administration. A two-dimensional chemical shift imaging (31) P-MRS acquisition collected spectral data from a 4 × 4 cluster of voxels acquired in the axial plane encompassing the subcortical structures as well as frontal-temporal cortical gray and white matter. The slab thickness was 3 cm and the approximate total volume of brain sampled was 432 cm(3) . The spectra obtained were analyzed using a fully automated in-house fitting algorithm. A population-averaged generalized estimating equation was used to evaluate changes both in phosphomonoesters (PME) [phosphocholine (PCho) and phosphoethanolamine (PEtn)] and phosphodiesters (PDE) [glycerophosphocholine (GPCho) and glycerophosphethanolamine (GPEtn)]. Metabolite ratios were reported with respect to the total integrated (31) P resonance area.

Results: The uridine group had significantly increased total PME and PEtn levels over the one-week period [6.32 and 7.17% for PME and PEtn, respectively (p<0.001)]. Other metabolite levels such as PCho, PDE, GPEtn and GPCho showed no significant changes following either uridine or placebo (all p>0.05).

Conclusions: This is the first study to report a direct effect of uridine on membrane phospholipid precursors in healthy adults using (31) P-MRS. Sustained administration of uridine appears to increase PME in healthy subjects. Further investigation is required to clarify the effects of uridine in disorders with altered phospholipid metabolism such as bipolar disorder.

© 2010 John Wiley and Sons A/S.

Figures

Fig.1

Magnetic resonance images depicting 3 cm chemical shift imaging slab placement and grid alignment and an in vivo human brain sample phosphorus spectrum acquired from a single voxel at 4.0 Tesla. Spectrum (B) is displayed with 5 Hz exponential filtering for display, as well as residual (A), and fitted curve (C). The main metabolites are clearly visible, including the phosphomonoesters (PME) and the phosphodiesters (PDE). PEtn = phosphoethanolamine; PCho = phosphocholine; Pi = inorganic phosphate; GPEtn = glycerophosphoethanolamine; GPCho = glycerophosphocholine; MP = membrane phospholipid; PCr = phosphocreatine; ATP = adenosine triphosphate; NAD = nicotinamide adenine dinucleotide.

Fig. 2

Synthesis of phosphatidylcholine via the Kennedy Cycle. Uridine is the major circulating pyrimidine that is converted to cytidine triphosphate (CTP) in humans. Specific transporters facilitate the entry of uridine across the blood-brain barrier, where it is phosphorylated to uridine triphosphate (UTP) and CTP. CTP reacts with phosphocholine to form cytidine diphosphate (CDP)-choline in a rate-determining step (CTP:phosphocholine cytidylyl transferase). CDP-choline and diacylglycerol then form phosphatidylcholine. (Reprinted with permission from Cansev M. Uridine and cytidine in the brain: their transport and utilization. Brain Res Rev 2006; 52: 389-397).

Fig. 3

Changes in metabolite levels at baseline and following one week of uridine intake in (A) total PME, (B) PEtn, and (C) PCho. The black bars represent the placebo group and the white bars represent the uridine group. Vertical bars denote 95% confidence intervals. Each mean value (y-axis) represents percentage of metabolite levels over total phosphorus. TP = total 31P; PME = phosphomonoesters; PEtn = phosphoethanolamine; PCho = phosphocholine. *p < 0.001.