Disease relevance of cytidine diphosphate choline

• These findings indicate that Sec14p functions to alleviate a CDP-choline pathway-mediated toxicity to yeast Golgi secretory function [1].
• Selective accumulation of cytosol CDP-choline as an isolated erythrocyte defect in chronic hemolysis [2].
• Erythrocytes from a young woman with chronic hemolytic anemia were found to contain 0.31-0.45 mM CDP-choline, concentrations that are 15-25 times those in normal erythrocytes and equivalent to 20-30% of the total adenine nucleotide content [2].
• Taken together, these results suggest that CDP-choline significantly restores Ptd-Cho levels by differentially affecting sPLA2-IIA, PtdCho-PLC, and CCTalpha after transient focal cerebral ischemia [3].
• CDP-choline treatment significantly attenuated the infarction volume by 55 +/- 5% after 1 h of tMCAO and 1 day of reperfusion [3].

Psychiatry related information on cytidine diphosphate choline

• CDP-choline at two dosages (50 and 250 mg/kg) shortened the time required for recovery of spontaneous motor activity in a dose-related manner; recovery time was measured early after reperfusion [4].
• Citicoline may prove effective in treating age-related cognitive decline that may be the precursor of dementia [5].
• We have previously shown that chronic, but not acute, dietary supplementation with CDP-choline prevents the hippocampal-dependent memory deficits manifested by aged rats and by rats reared under impoverished environmental conditions [6].
• Citicoline is a neuroprotective agent used clinically to treat for instance Parkinson disease, stroke, Alzheimer's disease and brain ischemia [7].
• This randomized, double-blind clinical trial was conducted to determine whether daily citicoline treatment improves neurocognitive and neuroimaging outcome over 12 months among patients diagnosed with vascular dementia (VaD) [8].

High impact information on cytidine diphosphate choline

• The antagonistic action of the CKI gene product on SEC14p function revealed a previously unsuspected influence of biosynthetic activities of the CDP-choline pathway for PC biosynthesis on yeast Golgi function and indicated that SEC14p controls the phospholipid content of yeast Golgi membranes in vivo [9].
• These results indicate that Nir2 is involved in maintaining a critical DAG pool in the Golgi apparatus by regulating its consumption via the CDP-choline pathway, demonstrating the interface between secretion from the Golgi and lipid homeostasis [10].
• The proportion of radioactivity increased with time in cytidine-5'-diphosphate-choline and phosphorylcholine, which suggested reutilization of choline for PC synthesis [11].
• Lysine and aspartic acid appeared to modify the cholinephosphotransferase reaction in which cytidine 5'-diphosphocholine (CDP-choline) and 1,2-diacylglycerol react to form phosphatidylcholine, the major phospholipid of renal membranes [12].
• The enzyme CDP-choline diglyceride transferase was virtually absent from canaliculi relative to microsomes, indicating that canaliculi lack the capacity for de novo lecithin synthesis [13].

Chemical compound and disease context of cytidine diphosphate choline

• These results suggest that channeling of intermediates in the CDP-choline pathway of Ptd-choline biosynthesis in glioma cells is mediated by intracellular Ca2+ levels that may coordinately regulate the steps involved in conversion of choline to Ptd-choline [14].
• The effects of cytidine 5'-diphosphocholine (CDP-choline) on neurologic deficits and cerebral glucose metabolism were studied in a rat model of transient cerebral ischemia [4].
• These results indicate that CDP-choline has beneficial effects on brain dysfunction induced by cerebral ischemia, which may be due in part to the restorative effects of CDP-choline on disturbed cerebral glucose metabolism, probably by stimulating phospholipid biosynthesis [4].
• To evaluate potential synergistic neuroprotective effects of prolonged citicoline treatment and early N-methyl-D-aspartate (NMDA) antagonist therapy, suboptimal treatment regimens of citicoline and MK-801 were tested alone and in combination in a rat model of temporary focal ischemia [15].
• Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport [16].

Biological context of cytidine diphosphate choline

• The yeast phosphatidylinositol transfer protein (Sec14p) is required for biogenesis of Golgi-derived transport vesicles and cell viability, and this essential Sec14p requirement is abrogated by inactivation of the CDP-choline pathway for phosphatidylcholine biosynthesis [1].
• These results show that the stimulus-secretion coupling and secretion reactions studied are not dependent on phospholipid methylation and suggest that the activity of action potential Ca2+ channels and the rate of neurotransmitter secretion are functionally coupled to the rate of phosphatidylcholine synthesis via the CDP-choline pathway [17].
• Inhibitors of CDP-choline synthesis, action potential calcium channels, and stimulus-secretion coupling [17].
• These data show that CCTalpha expression is required for early embryonic development, but that a 50% reduction in enzyme activity has little detectable impact on the operation of the CDP-choline metabolic pathway in adult tissues [18].
• Choline kinase catalyzes the phosphorylation of choline by ATP, the first committed step in the CDP-choline pathway for phosphatidylcholine biosynthesis [19].

Anatomical context of cytidine diphosphate choline

• By contrast, selective accumulation of CDP-choline was the only abnormality demonstrable in proband erythrocytes [2].
• These data demonstrate that the CDP-choline pathway alone, but not the PEMT pathway alone, can account for physiological concentrations of PC in gallbladder bile [20].
• Remarkably, in light of widely held assumptions, the rate of phosphatidylcholine synthesis from the CDP-choline pathway was not decreased in CD hepatocytes [21].
• In agreement with previous studies, the incorporation of [3H]choline into phosphatidylcholine via the CDP-choline pathway was stimulated 5-fold in cultures of HeLa cells following treatment with phorbol ester for 1 h [22].
• CTP:phosphocholine cytidylyltransferase alpha is found immediately upstream cholinephosphotransferase, and it translocates from a soluble nuclear location to the nuclear membrane in response to activators of the CDP-choline pathway [23].

Associations of cytidine diphosphate choline with other chemical compounds

• Accumulation of CDP-choline has been reported only in erythrocytes from subjects with severe (homozygous) pyrimidine nucleotidase deficiency [2].
• Expression of phosphatidylethanolamine N-methyltransferase-2 cannot compensate for an impaired CDP-choline pathway in mutant Chinese hamster ovary cells [24].
• Multiple mechanisms of regulation in the CDP-choline pathway for phosphatidylcholine (PC) synthesis were revealed by exploring the effects of choline and inositol on this pathway in Saccharomyces cerevisiae [25].
• The results support the hypothesis that Golgi has the capacity to make certain phospholipids for lipoprotein secretion: phosphatidylcholine via the CDP-choline and methylation pathways, phosphatidylethanolamine by the CDP-ethanolamine pathway, and phosphatidylserine [26].
• In addition to the CDP-choline pathway for phosphatidylcholine (PC) synthesis, the liver has a unique phosphatidylethanolamine (PE) methyltransferase activity for PC synthesis via three methylations of the ethanolamine moiety of PE [27].

Gene context of cytidine diphosphate choline

• Abrogation of the CDP-choline (CDP-Cho) pathway for phosphatidylcholine (PC) synthesis allows for life in the absence of the otherwise essential Sec14p [28].
• Only chimeras expressing the CDP-aminoalcohol specificity region of CPT1 were capable of PC synthesis via the CDP-choline pathway in vivo [29].
• Phosphorylation of Saccharomyces cerevisiae CTP synthetase at Ser424 by protein kinases A and C regulates phosphatidylcholine synthesis by the CDP-choline pathway [30].
• These cells (ept1-delta 1::URA3) also displayed an identical mode of regulation in response to inositol as did cells containing an intact EPT1 gene (wild type) indicating there is no requirement for an alternate functional CDP-amino-alcohol pathway for inositol to regulate PC synthesis via the CDP-choline pathway [25].
• Thus, the PLD1 gene product appears to play an essential role in the suppression of the sec14(ts) defect by CDP-choline pathway mutations, indicating a role for phospholipase D1 in growth and secretion [31].

Analytical, diagnostic and therapeutic context of cytidine diphosphate choline

• Activity of cytidylyltransferase (CT), a major regulatory enzyme in the CDP-choline pathway of PC synthesis, was raised in both microsomal and cytosolic fractions (226% and 150% of controls), and there was an increase to 187% in the mass of active enzyme as determined by Western blot of microsomal protein using an antibody specific to CT [32].
• These immunoelectron microscopy studies strongly suggest that the cellular organization of ET differs considerably from that reported recently for the corresponding enzyme in the CDP-choline pathway, CTP:phosphocholine cytidylyltransferase (Wang, Y., Sweiter, T. D., Weinhold, P. A., and Kent, C. (1993) J. Biol. Chem. 268, 5899-5904) [33].
• Using a novel combination of stable-isotope labeling and tandem mass spectrometry, we demonstrated for the first time that choline contributed to phosphatidylcholine (PC) synthesis both as an intact choline moiety via the CDP-choline pathway and as a methyl donor via PE methylation pathway [34].
• BACKGROUND AND PURPOSE: Citicoline, a naturally occurring precursor of phosphatidylcholine, is neuroprotective and is currently being assessed in clinical trials [15].
• CONCLUSIONS: In this animal model of ICH, treatment with citicoline significantly improved functional outcome and reduced the volume of ischemic injury surrounding the hematoma [35].

References