Oral cytidine 5'-diphosphate choline administration to rats increases brain phospholipid levels.

Exogenous cytidine 5'diphosphocholine (CDP-choline) is completely metabolized to circulating cytidine and choline. Both compounds enter the brain and can be used in phosphatidylcholine (PC) synthesis via the Kennedy (CDP-choline) cycle. We administered oral CDP-choline to 12 month-old rats (500 mg/kg/day) for 21, 42, or 90 days to determine whether this treatment would alter brain levels of PC and the other structural phospholipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE). After 42 days, brain PC levels increased significantly (p < 0.01) by 23.3%; after 90 days PC increased by 30% (p < 0.01), PS by 37.2% (p < 0.01), and PE by 13% (not significant). The ratios of each of the phospholipids to total membrane phospholipids were unchanged. These data demonstrate that repeated oral CDP-choline administration can increase the amounts of phospholipids in brain membranes, thus providing a rationale for using this compound in brain diseases that damage neurons.

Effects of orally administered cytidine 5'-diphosphate choline on brain phospholipid content.

Cytidine, as cytidine 5'-diphosphate choline (CDP-choline), is important for the synthesis of phosphatidylcholine in cell membranes. To investigate whether exogenous CDP-choline could affect brain phospholipid composition, we supplemented the diet of mice with this drug (500 mg/kg/day) for 27 months in 3-month-old mice and for 90, 42, and 3 days in 12-month-old mice, and measured their levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), and the content of phosphatidylinositol plus phosphatidic acid in the cerebral cortex. After 27 months of treatment, PC and PE increased significantly by 19% (P < 0.05) and by 20% (P < 0.01), respectively. PS levels increased by 18% (not statistically significant). Similar elevations in PC and PE levels were obtained when older mice were treated for only 3 months (P < 0.05). No changes were observed with shorter treatment periods. These results suggest that chronic administration of CDP-choline can have effects on brain phospholipid composition that may underlie its reported utility in various neurologic disorders.

Melatonin and its precursors in Y79 human retinoblastoma cells: effect of sodium butyrate.

We studied the release of melatonin and the production of its precursors, 5-hydroxytryptophan and serotonin, in cultured Y79 human retinoblastoma cells. This biosynthetic capability was found to be dependent on cell differentiation, which was initiated by culturing Y79 cells for 7 days in dishes coated with poly-D-lysine to promote cell adhesion to the surface of the culture dishes. Differentiation was further induced by exposing the cell monolayer to sodium butyrate (3 mM) for 3 days. This protocol dramatically increased the release of melatonin and the syntheses of 5-hydroxytryptophan and serotonin in response to forskolin stimulation. Exposure to dopamine (10 microM) or L-DOPA (100 microM) markedly diminished the forskolin-stimulated release of melatonin, as well as the production of 5-hydroxytryptophan and serotonin. These observations indicate that Y79 cells represent a primitive cell line which, following appropriate differentiation (e.g. treatment with sodium butyrate) can display biochemical characteristics similar to those of the human retina. Moreover, serotonin synthesis and melatonin release appear to be coupled in Y79 cells. The inhibition of melatonin release by dopamine supports the hypothesis that in these cells, melatonin and dopamine are components of a retinal feedback loop.

Effects of running the Boston marathon on plasma concentrations of large neutral amino acids.

Plasma large neutral amino acid concentrations were measured in thirty-seven subjects before and after completing the Boston Marathon. Concentrations of tyrosine, phenylalanine, and methionine increased, as did their "plasma ratios" (i.e., the ratio of each amino acid's concentration to the summed plasma concentrations of the other large neutral amino acids which compete with it for brain uptake). No changes were noted in the plasma concentrations of tryptophan, leucine, isoleucine, nor valine; however, the "plasma ratios" of acid patterns may influence neurotransmitter synthesis.

Metabolism of cytidine (5?)-diphosphocholine (cdp-choline) following oral and intravenous administration to the human and the rat.

We examined the effects of cytidine (5?)-diphosphocholine (CDP-choline) on plasma levels of cytidine, choline, and unchanged CDP-choline among normal volunteers receiving the substance orally or intravenously, and rats receiving it intravenously. Two hours after a single oral dose (2g), plasma choline levels were increased by 48% and plasma cytidine by 136%. Among subjects receiving three doses (2g each) at two-hour intervals, plasma choline peaked (30% over baseline) 4 h after the initial CDP-choline dose, while plasma cytidine levels continued to increase for at lest 6 h, at which time they were five times basal levels (P < 0.01). Intravenously-administered CDP-choline was rapidly hydrolysed, in both the human and the rat. In humans given the CDP-choline by infusion over 30 min, plasma CDP-choline fell to undetectable levels almost immediately after the end of the infusion period; plasma choline and cytidine peaked at that time, but their concentrations remained significantly elevated for at least 6 h. In rats given a bolus injection of CDP-choline, five minutes earlier, the unchanged compound was also undetectable in plasma, while plasma cytidine levels increased markedly and remained elevated for at least 60 min. These observations show that CDP-choline is converted to at least two major circulating metabolites, choline and cytidine. Since both of these compounds are used in the biosynthesis of phosphatidylcholine, both may be involved in the long-term effects of the CDP-choline.