Oral Cytidine 5'Diphosphate Choline Administration to Rats Increases Brain Phospholipid Levels (original) (raw)
Related papers
Journal of Neurochemistry, 2002
We examined the effects of orally administered 5'-cytidinediphosphocholine (CDP-choline) on arterial plasma choline and cytidine levels and on brain phospholipid composition in rats. Animals receiving a single oral dose of 100, 250, or 500 mg/kg showed peak plasma choline levels 6-8 h after drug administration (from 12 1 to 17 ± 2, 19 ± 2, and 24 ± 2 pM, respectively). The area under the plasma choline curve at >14 IiM, i.e ., at a concentration that induces a net influx of choline into the brain, was significantly correlated with CDP-choline dose. In rats receiving 500 mg/kg this area was 2 .3 times that of animals consuming 250 mg/kg, which in turn was 1 .8 times that of rats receiving 100 mg/kg. Plasma cytidine concentrations increased 5.4, 6.5, and 15 .1 times baseline levels, respectively, 8 h after each of the three doses. When the oral CDP-choline treatment was prolonged for 42 and 90 days, brain phosphatidylcholine concentrations increased significantly (by 22-25% ; p < 0.05) in rats consuming 500 mg/kg/day. Brain phosphatidylethanolamine and phosphatidylserine concentrations also increased significantly under some experimental conditions ; levels of other phospholipids were unchanged.
Choline-containing phospholipids: relevance to brain functional pathways
Clinical Chemistry and Laboratory Medicine, 2000
Choline participates in several relevant neurochemical processes. It is the precursor and metabolite of acetylcholine (ACh), plays a role in single-carbon metabolism and is an essential component of different membrane phospholipids (PLs). PLs are structural components of cell membranes involved in intraneuronal signal transduction. This paper reviews the roles of choline and of choline-containing phospholipids (CCPLs) on brain metabolism in health and disease followed by an analysis of the effects of exogenously administered CCPLs on the brain, a topic extensively investigated by literature. Based on the observation of decreased cholinergic neurotransmission in brain disorders characterized by cognitive impairment, cholinergic precursor loading therapy with CCPLs was the first approach used to attempt for relieving the cognitive symptoms of Alzheimer ' s disease. This therapeutic strategy was discontinued due to the negative clinical results obtained with choline or lecithin. Negative results obtained with some compounds cannot be generalized for all CCPLs, as CDP-choline (citicoline) and to a greater extent choline alphoscerate (GPC) displayed interesting effects documented in preclinical studies and limited clinical trials. We provide evidence in favor of CDP-choline and GPC activity in cerebrovascular or neurodegenerative disorders characterized by cholinergic neurotransmission impairment. Based on the results of the controlled clinical trials available, we suggest that due to the lack of novel therapeutic strategies, safe compounds developed a long time ago such as effective CCPLs could have still a place in pharmacotherapy. Therefore selected compounds of this class should be further investigated by new appropriate clinical studies.
Effect of Cytidine on Membrane Phospholipid Synthesis in Rat Striatal Slices
Journal of Neurochemistry, 2002
Using rat striatal slices, we examined the effect of cytidine on the conversion of [3H]choline to [3H]phosphatidylcholine ([ 3H]PC), and on net syntheses of PC, phosphatidylethanolamine (PE), and phosphatidylserine, when media did or did not also contain choline, ethanolamine, or serine. Incubation of striatal slices with cytidine (50-500 NM) caused dose-dependent increases in intracellular cytidine and cytidine triphosphate (CTP) levels and in the rate of incorporation of [3H]choline into membrane [ 3 H] PC. In pulse-chase experiments, cytidine (200 N,M) also increased significantly the conversion of [3H]choline to [3H]PC during the chase period. When slices were incubated with this concentration of cytidine for 1 h, small (7%) but significant elevations were observed in the absolute contents (nmol/mg of protein) of membrane PC and PE (p < 0 .05), but not phosphatidylserine, the synthesis of which is independent of cytidinecontaining CTP. Concurrent exposure to cytidine (200 NM) and choline (10 pM) caused an additional significant increase (p < 0.05) in tissue PC levels beyond that produced by cytidine alone. Exposure to choline alone at a higher concentration (40 N,M) increased the levels of all three membrane phospholipids (p < 0 .01) ; the addition of cytidine, however, did not cause further increases. Concurrent exposure to cytidine (200^and ethanolamine (20^also caused significantly greater elevations (p < 0.05) in tissue PE levels than those caused by cytidine alone. In contrast, the addition of serine (500 did not enhance cytidine's effects on any membrane phospholipid. Exposure to serine alone, however, like exposure to sufficient choline, increased levels of all three membrane phospholipids significantly (p < 0.01). These data show that exogenous cytidine, probably acting via CTP and the Kennedy cycle, can increase the synthesis and levels of membrane PC and PE in brain cells.
Biosynthesis of Rat Brain Phosphatidylcholines from Intracerebrally Injected Choline
Journal of Neurochemistry, 1976
Ab~tract-[Me-~H]Choline was injected intracerebrally into male rats and the brains immediately removed by particular procedures at regular intervals over the first 1200 s. The incorporation of radioactivity into brain phosphorylcholine, CDP-choline and phosphatidylcholines was examined and quantitated, in order to investigate the relative roles of net synthesis and base-exchange reactions for choline incorporation into lipid. The molecular subspecies of phosphatidylcholines were also examined after isotope administration. Phosphorylcholine, CDP-choline and phosphatidylcholines all became labelled as early as 5 s after the administration of labelled choline. The time course of incorporation of choline into brain lipid is biphasic with two flex points at about 20 and 120 s from the injection. The specific radioactivity of different phosphatidylcholines appears to be different at early and later intervals from injection. The suggestion is made that the base-exchange pathway for choline incorporation into lipid might be operative in viw in early periods after administration. GAIT1 A., DE MEDIO G. E., BRUNETTI M., AMADUCCI L.
Biosynthesis of Rat Brain Phosphatidylcholines from Intracerebrally Injected CHOLINE1
Journal of Neurochemistry, 1976
Ab~tract-[Me-~H]Choline was injected intracerebrally into male rats and the brains immediately removed by particular procedures at regular intervals over the first 1200 s. The incorporation of radioactivity into brain phosphorylcholine, CDP-choline and phosphatidylcholines was examined and quantitated, in order to investigate the relative roles of net synthesis and base-exchange reactions for choline incorporation into lipid. The molecular subspecies of phosphatidylcholines were also examined after isotope administration. Phosphorylcholine, CDP-choline and phosphatidylcholines all became labelled as early as 5 s after the administration of labelled choline. The time course of incorporation of choline into brain lipid is biphasic with two flex points at about 20 and 120 s from the injection. The specific radioactivity of different phosphatidylcholines appears to be different at early and later intervals from injection. The suggestion is made that the base-exchange pathway for choline incorporation into lipid might be operative in viw in early periods after administration. ' This work has been aided by a research grant from the Consiglio Nazionale delle Richerche, Rome (Contract n. 74.00259).
Phospholipid biosynthetic enzymes in human brain
Lipids, 1997
Growing evidence suggests an involvement of brain membrane phospholipid metabolism in a variety of neurodegenerative and psychiatric conditions. This has prompted the use of drugs (e.g., CDPcholine) aimed at elevating the rate of neural membrane synthesis. However, no information is available regarding the human brain enzymes of phospholipid synthesis which these drugs affect. Thus, the objective of our study was to characterize the enzymes involved, in particular, whether differences existed in the relative affinity of substrates for the enzymes of phosphatidylethanolamine (PE) compared to those of phosphatidylcholine (PC) synthesis. The concentration of choline in rapidly frozen human brain biopsies ranged from 32-186 nmol/g tissue, a concentration similar to that determined previously for ethanolamine. Since human brain ethanolamine kinase possessed a much lower affinity for ethanolamine (K m = 460 µM) than choline kinase did for choline (K m = 17 µM), the activity of ethanolamine kinase in vivo may be more dependent on substrate availability than that of choline kinase. In addition, whereas ethanolamine kinase was inhibited by choline, and to a lesser extent by phosphocholine, choline kinase activity was unaffected by the presence of ethanolamine, or phosphoethanolamine, and only weakly inhibited by phosphocholine. Phosphoethanolamine cytidylyltransferase (PECT) and phosphocholine cytidylyltransferase (PCCT) also displayed dissimilar characteristics, with PECT and PCCT being located predominantly in the cytosolic and particulate fractions, respectively. Both PECT and PCCT exhibited a low affinity for CTP (K m approximately 1.2 mM), suggesting that the activities of these enzymes, and by implication, the rate of phospholipid synthesis, are highly dependent upon the cellular concentration of CTP. In conclusion, our data indicate different regulatory properties of PE and PC synthesis in human brain, and suggest that the rate of PE synthesis may be more dependent upon substrate (ethanolamine) availability than that of PC synthesis.
Brain Research, 1999
. Ž . Brain levels of glycerophosphocholine GPC and glycerophosphoethanolamine GPE , abundant metabolites of phosphatidylcholine and phosphatidylethanolamine, are increased in several disorders of the human brain. To determine whether accumulation of these compounds may alter phospholipid metabolism, we assessed the ability of GPE and GPC to modulate the activities of phospholipase A , 2 lysophospholipase, and other enzymes involved in phospholipid metabolism, in preparations of human brain parietal cortex. GPC and GPE acted as competitive inhibitors of lysophospholipase activity, but failed to alter the activity of the other enzymes tested. Our results suggest that GPC and GPE may normally act to inhibit lysophospholipid hydrolysis, thereby reducing the rate of membrane phospholipid degradation. q 14 ated to lysophospholipase : 25 mM 1-C-palmitoyl-3-0006-8993r99r$ -see front matter q 1999 Elsevier Science B.V. All rights reserved.
Psychopharmacology, 1996
Phosphatidylcholine (PtdCho), which is essential for membrane integrity and repair, is reduced in brain cell membranes with age. Evidence from both animal and in vitro studies indicates that cytidine 5" diphosphate choline (CDP-choline) can increase the synthesis of PtdCho; however, the effect of CDPcholine on brain choline metabolism has not previously been studied in human subjects. In this study, in vivo proton magnetic resonance spectroscopy (IH-MRS) was used to measure brain levels of cytosolic, cholinecontaining compounds before and after single oral doses of CDP-choline. Three hours after dosing, plasma choline increased similarly in younger (mean age 25 years) and older subjects (mean age 59 years). However, while the choline resonance in brain increased by 18% on average in younger subjects, it decreased by almost 6% in older subjects (P = 0.028). These results may be explained by a previously observed decrease in brain choline uptake, but not cytidine uptake, in older subjects. Additional intracellular cytidine following the administration of CDP-choline should lead to the increased incorporation of choline already present in brain into membrane PtdCho, which is not MRSvisible, consequently lowering the brain choline resonance below that of pre-treatment values. These results suggest that the cytidine moiety of CDP-choline stimulates phosphatidylcholine synthesis in human brain cell membranes in older subjects.