5'-Uridylic acid (UMP), which is present at high concentrations in cow's colostrum, has been shown to cause a reduction in increased plasma levels of insulin and glucose after ingestion of milk replacer in pre-weaning calves. However, the precise mechanisms of UMP action have not been investigated, and its action has not been investigated in other pre-weaning ruminants. In order to demonstrate whether UMP causes changes in postprandial metabolic and hormonal parameters in pre-weaning goats, 11 Saanen kids were given milk replacer (twice a day) without (n = 5) or with (n = 6) UMP (1 g for each meal, 2 g/day for each head) for 14 days. Analysis of blood samples taken in the morning of day 14 demonstrated that the feeding of milk replacer with UMP abolished the significant changes in postprandial plasma glucose, NEFA, GH and insulin concentrations induced by feeding of milk replacer alone, and demonstrated a tendency to increase IGF-I levels. However, there was no significant difference between the two groups at any sampling time. We conclude that UMP feeding with milk replacer showed a tendency to blunt the postprandial changes in levels of some plasma metabolites and hormones that are induced by replacer alone in pre-weaning goats.

Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, is an essential component of membrane phosphatides and has been implicated in cognitive functions. Low levels of circulating or brain DHA are associated with various neurocognitive disorders including Alzheimer's disease (AD), while laboratory animals, including animal models of AD, can exhibit improved cognitive ability with a diet enriched in DHA. Various cellular mechanisms have been proposed for DHA's behavioral effects, including increases in cellular membrane fluidity, promotion of neurite extension and inhibition of apoptosis. However, there is little direct evidence that DHA affects synaptic structure in living animals. Here we show that oral supplementation with DHA substantially increases the number of dendritic spines in adult gerbil hippocampus, particularly when animals are co-supplemented with a uridine source, uridine-5'-monophosphate (UMP), which increases brain levels of the rate-limiting phosphatide precursor CTP. The increase in dendritic spines (>30%) is accompanied by parallel increases in membrane phosphatides and in pre- and post-synaptic proteins within the hippocampus. Hence, oral DHA may promote neuronal membrane synthesis to increase the number of synapses, particularly when co-administered with UMP. Our findings provide a possible explanation for the effects of DHA on behavior and also suggest a strategy to treat cognitive disorders resulting from synapse loss.

Membrane phospholipids like phosphatidylcholine (PC) are required for cellular growth and repair, and specifically for synaptic function. PC synthesis is controlled by cellular levels of its precursor, cytidine-5'-diphosphate choline (CDP-choline), which is produced from cytidine triphosphate (CTP) and phosphocholine. In rat PC12 cells exogenous uridine was shown to elevate intracellular CDP-choline levels, by promoting the synthesis of uridine triphosphate (UTP), which was partly converted to CTP. In such cells uridine also enhanced the neurite outgrowth produced by nerve growth factor (NGF). The present study assessed the effect of dietary supplementation with uridine-5'-monophosphate disodium (UMP-2Na+, an additive in infant milk formulas) on striatal dopamine (DA) release in aged rats. Male Fischer 344 rats consumed either a control diet or one fortified with 2.5% UMP for 6 wk, ad libitum. In vivo microdialysis was then used to measure spontaneous and potassium (K+)-evoked DA release in the right striatum. Potassium (K+)-evoked DA release was significantly greater among UMP-treated rats, i.e., 341+/-21% of basal levels vs. 283+/-9% of basal levels in control rats (p<0.05); basal DA release was unchanged. In general, each animal's K+-evoked DA release correlated with its striatal DA content, measured postmortem. The levels of neurofilament-70 and neurofilament-M proteins, biomarkers of neurite outgrowth, increased to 182+/-25%(p<0.05) and 221+/-34%(p<0.01) of control values, respectively, with UMP consumption. Hence, UMP treatment not only enhances membrane phosphatide production but also can modulate two membrane-dependent processes, neurotransmitter release and neurite outgrowth, in vivo.

Dietary nucleotides seem to play a number of physiologic roles during early life. They are improved in the maintenance of the immune system, intestinal maturation, and lipid metabolism. Nucleotides affect the conversion of essential fatty acids into their long-chain polyunsaturated (PUFA) derivatives in both preterm and at-term newborn infants. This work examines the effect of postnatal age and dietary nucleotides on the fatty acid composition of total plasma lipids and lipid fractions in the rat. Weanling rats (21 days old) were divided into three groups. The first group was killed, and the other two groups were fed a standard semipurified diet, and the same diet supplemented with 250 mg each of CMP, UMP, AMP, GMP, and IMP per 100 g of diet for 4 weeks. Advancing postnatal age led to an increase of total plasma fatty acids, especially saturated, and PUFA of the n-6 series, whereas PUFA of the n-3 series decreased. The fatty acid profile of plasma phospholipids (PL) exhibited minor changes, although there was a tendency to show lower levels of saturates and PUFA of the n-3 series and increased levels of PUFA of the n-6 series. Cholesteryl esters showed a response similar to that of PL, although the increase in arachidonic acid (20:4n-6) was significant. For triglycerides, linoleic acid (18:2n-6) and monounsaturates increased their levels, whereas saturates decreased. Dietary nucleotides mediated a significant increase in total plasma fatty acids, namely monounsaturated fatty acids and PUFA of both n-6 and n-3 series as compared with the control group. The relative fatty acid composition of PL and cholesteryl esters was mostly unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Postprandial changes in plasma concentrations of GH, insulin, IGF-I, leptin and metabolites were compared between young Holstein bull calves fed with milk alone (control group) and with milk+5'-uridylic acid (UMP)(UMP group). UMP (2 g/day) was given with milk at 0830 h and 1530 h for 11 days from the 4th to the 14th day after birth. The perirenal fat weight was significantly lower in the UMP group than in the control group, but there was no significant difference in the weights of the liver, spleen and heart between the groups. Basal GH concentrations in the UMP group were slightly higher, but the postprandial increase in plasma insulin level and the area under the curve for insulin in the UMP group were significantly lower than those in the control group. There was no significant difference in IGF-I levels between the groups. In addition, the postprandial glucose concentrations were lower in the UMP group as reflected by the insulin level, and nonesterified fatty acid concentrations were not different. In the muscle (M. longissimus thoracis) sampled at 14 days of age, the triacylglycerol (TAG) content was significantly greater but glycogen content was significantly lower in the UMP group than in the control group. From these results, we have concluded that feeding 5'-UMP at 2 g/day for 11 days significantly alters TAG accumulation in the body and plasma concentrations of GH and insulin in young bull calves.

We present an in vivo model for specific protection of normal hepatocytes from damage by the highly specific hepatotoxin galactosamine. The idea is based on the fact that normal, unlike malignant, hepatocytes possess unique cell-surface receptors that can bind and internalize galactose terminal (asialo)glycoproteins by receptor-mediated endocytosis. A targetable carrier-antagonist conjugate was formed by coupling asialofetuin to the galactosamine antagonist uridine monophosphate. Intravenous injection of the antagonist conjugate resulted in specific uptake by the liver. Rats treated with carrier-antagonist conjugate together with a toxic dose of galactosamine developed significantly less hepatotoxicity than did controls. We conclude that a galactosamine antagonist can be targeted to liver, resulting in specific protection of hepatocytes from galactosamine toxicity in vivo. Because hepatoma cells lack asialoglycoprotein receptor activity, this "targeted rescue" may be of value in the differential protection of normal cells in the treatment of hepatocellular carcinoma.

Young healthy volunteers received a purine-free, isoenergetic formula diet over a period of 28 to 32 days. After a short time under formula diet alone 400 mg allopurinol were administered daily. After a further 10 days each volunteer received daily, in addition, either 4 g RNA, 4 g RNA-hydrolysate, 1 g guanosine-5-monophosphate (GMP), 1 or 3 g adenosine-5-monophosphate (AMP), uridine-5-monophosphate (UMP), cytidine-5-monophosphate (CMP) or adenosine, guanosine, uridine, cytidine, guanine, hypoxanthine, xanthine, cytosine and uracil. Finally the allopurinol was omitted. The renal excretion of total orotic acid (orotic acid and orotidine), uric acid and creatinine was determined daily; serum uric acid concentrations and the enzyme activities of orotidine-5-phosphate-decarboxylase (ODCase) and hypoxanthine-guanine-phosphoribosyltransferase (HGPRTase) from erythrocytes were determined every other day. The results show that RNA, RNA-hydrolysate, purine- and pyrimidine-nucleotides and -nucleotides as well as hypoxanthine, and to a lesser extent adenine, diminish allopurinol-induced orotaciduria. This is compatible with an influence of dietary purines and pyrimidines on human pyrimidine biosynthesis.

This study aimed to demonstrate the effect of uridine monophosphate (UMP) on the consolidation of a brightness-discrimination reaction after topical application of this RNA precursor into the hippocampus, the neocortex or the mesencephalic reticular formation (MRF). Thirty minutes before the rats started their training in a Y-chamber, UMP was injected into each animal through cannula implanted into the particular brain area. When injected into hippocampus or MRF UMP exerted no influence on acquisition, but after epidural UMP injection an impairment of acquisition was observed. After intrahippocampal or epidural UMP application the retention test carried out 48 hour after training showed a significant improvement in retention performance, whereas UMP injection into MRF showed no influence on retention. Consequently, the retention-improving effect of UMP is probably not induced by activation of ascending neuronal systems.