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PubMed1993

A rapid high performance liquid chromatographic method for the analysis of choline in human plasma and peritoneal dialysis effluent: application in the assessment of choline loss in continuous ambulatory peritoneal dialysis.

Mesothelial cells lining the peritoneal cavity utilize choline in the synthesis of a phosphatidylcholine-rich material thought to play a role in peritoneal homeostasis. This function is particularly important for patients undergoing continuous ambulatory peritoneal dialysis (CAPD). To assess choline loss in these patients, we measured choline in plasma and peritoneal dialysis effluent (PDE) by a rapid high performance liquid chromatography (HPLC) procedure that combined electrochemical detection with an immobilized enzyme reactor. Chromatography was performed directly on plasma and PDE ultrafiltrates. In 30 patients, the amount of choline lost to the dialysate was 129 +/- 49 mumol per day and 32 +/- 8 mumol per dwell (mean +/- SD). The average plasma choline concentration was 22.5 mumol/L, a value somewhat higher than the mean value reported for normal adults (9 mumol/L). The average PDE choline concentration was 14 mumol/L. There was a positive correlation between daily choline loss of dialysate and plasma choline concentrations (r = 0.826).

Choline↗

PubMed1993

The choline transporter is the major site of control of choline oxidation in isolated rat liver mitochondria.

The degree of control exerted by the mitochondrial choline transporter over the oxidation pathway was measured in isolated rat liver mitochondria. Choline transporter activity was titrated with hemicholinium-3, a known competitive inhibitor of the transporter. It was shown that the rate of betaine efflux from mitochondria was an accurate measure of choline oxidation. The relative rate of choline oxidation was measured as a function of the relative degree of inhibition of the transporter. The resulting data gave a flux control coefficient over choline oxidation of 0.9 for the choline transporter. It is concluded that the choline transporter is the major site for control of choline oxidation in isolated rat liver mitochondria.

Animals↗

PubMed2002

Assessment of choline uptake for the synthesis and release of acetylcholine in brain slices by a dynamic autoradiographic technique using [11C]choline.

The uptake of choline for the synthesis and release of acetylcholine was investigated in brain slices by dynamic positron autoradiography using [11C]choline. Brain slices (330 microm) were incubated with [11C]choline in oxygenated Krebs-Ringer medium at 34 degrees C and serial two-dimensional time-resolved images of the uptake and release of radioactivity were recorded on Storage Phosphor screens. [11C]choline uptake increased with the period of incubation and was 1.9 times higher in the striatum than cerebral cortex. The uptake in the striatum was significantly diminished by hemicholinium-3 (HC-3), an inhibitor of high-affinity choline uptake. Pretreatment of brain slices with 50 mM K(+) for 20 min enhanced the uptake in striatum. The uptake of [11C]choline in brain slices was saturable using nonlabeled choline. Two uptake systems, a high-affinity and a low-affinity system, were confirmed to exist by kinetic analysis using Lineweaver-Burk plots. The 11C radioactivity that had accumulated in the striatum disappeared on treatment with veratridine, a depolarization agent, in the presence of HC-3. This pattern of disappearance was consistent with that of the appearance of unlabeled and labeled acetylcholine in the medium. These results indicate that this method is useful for obtaining information regarding the uptake of choline for the synthesis and release of acetylcholine in live brain tissues.

Acetylcholine↗

PubMed1976

Arterio-venous differences of choline and choline lipids across the brain of rat and rabbit.

The concentration of unesterified choline in the plasma in the jugular vein of the rat (0.85 nmol/ml) was found to be three times that of the arterial supply to the brain (0.25 nmol/ml), indicating a higher efflux than uptake of unesterified choline by the brain. No such difference was found for the rabbit and no arterio-venous difference for phosphatidylcholine or lysophosphatidylcholine was observed in either species. No arterio-venous difference was found for choline in blood cells. The infusion of [Me-3H]choline into the circulation of the rat or rabbit indicated an uptake of radioactive choline by the brain and an efflux of non-radioactive choline. In the rabbit such an infusion produced a steady rise in the labelling of phosphatidylcholine and lysophosphatidylcholine in the plasma. When [14C2]ethanolamine was injected intraperitoneally into the rat there was a labelling of phosphatidylcholine, lysophosphatidylcholine and sphingomyelin in the plasma and cells of blood from the jugular vein and the arterial supply, as well as in the brain tissue. However, no labelling of unesterified choline in these tissues could be detected. Unesterified choline was shown to be liberated into the plasma when whole blood from the rat or man, but not the rabbit, was incubated for short periods at 30 degrees C.

Animals↗

PubMed1980

Regulation of phospholipid metabolism in differentiating cells from rat brain cerebral hemispheres in culture: ontogenesis of carrier-specific transport of choline and N-methyl-substituted choline analogs.

Dimethylaminoethanol was studied both as a substrate and as an inhibitor of choline uptake in long-term cultures of foetal rat cerebral hemispheres. A saturable component with an apparent Km of 28 microM and Vmax of 11 pmol/min/microgram DNA for dimethylaminoethanol, was observed. Like choline, dimethylaminoethanol was also taken up by a second, low-affinity component, the apparent Vmax of which was about 102 pmol/min/microgram DNA. Dimethylaminoethanol inhibited the high-affinity but not the low-affinity choline uptake in a competitive manner with an apparent inhibition constant of 6.0 microM. Monomethylaminoethanol (Ki approximately 60 microM) competitively inhibited high-affinity choline transport. At low concentrations hemicholinium-3, but not ethanolamine, effectively inhibited high-affinity uptake of choline and to a lesser degree the uptake of the dimethylaminoethanol. While the high-affinity uptake of both substrates was inhibited by high concentrations of hemicholinium-3 or ethanolamine, the low-affinity system was not affected by hemicholinium-3. From the kinetics of uptake and inhibition patterns of choline and its related analogs, the methyl group seems to play a major role in determining the affinity rate constants for these substrates. The maximum rate of choline uptake via the high-affinity component increases about sixfold during a period of 2 weeks. In the absence of serum the maximum velocity of the high-affinity component is greatly reduced. These observations suggest that the high-affinity choline uptake component is an integral property, and a useful marker, of the developing cerebral cells.

Animals↗

PubMed2005

Impaired trafficking of choline transporter-like protein-1 at plasma membrane and inhibition of choline transport in THP-1 monocyte-derived macrophages.

The present study investigates choline transport processes and regulation of choline transporter-like protein-1 (CTL1) in human THP-1 monocytic cells and phorbol myristate 13-acetate (PMA)-differentiated macrophages. Choline uptake is saturable and therefore protein-mediated in both cell types, but its transport characteristics change soon after treatments with PMA. The maximal rate of choline uptake intrinsic to monocytic cells is greatly diminished in differentiated macrophages as demonstrated by alterations in V(max) values from 1,973 +/- 118 to 380 +/- 18 nmol x mg(-1) x min(-1), when the binding affinity did not change significantly (K(m) values 56 +/- 8 and 53 +/- 6 microM, respectively). Treatments with hemicholinim-3 effectively inhibit most of the choline uptake, establishing that a choline-specific transport protein rather than a general transporter is responsible for the observed kinetic parameters. mRNA screening for the expression of various transporters reveals that CTL1 is the most plausible candidate that possesses the described kinetic and inhibitory properties. Fluorescence-activated cell sorting analyses at various times after PMA treatments further demonstrate that the disappearance of CTL1 protein from the cell surface follows the same trend as the reduction in choline uptake. Importantly, the loss of functional CTL1 from the cell surface occurs without significant changes in total CTL1 protein or its mRNA level indicating that an impaired CTL1 trafficking is the key contributing factor to the reduced choline uptake, subsequent to the PMA-induced THP-1 differentiation to macrophages.

Animals↗

PubMed1981

Effect of cytidine diphosphate choline (CDP-choline) on ischemia-induced alterations of brain lipid in the gerbil.

Brain ischemia was produced in gerbils (Meriones unguiculatus) by the bilateral ligation of the carotid arteries. Definite changes in the energy status of brain demonstrated that carotid occlusion was effective. Five minutes before ligation, an intraventricular injection of either saline or cytidine disphosphate choline (CDP-choline, 0.6 micromol/brain, 3 microliter) was given to groups of animals. Control animals, with and without CDP-choline, together with the ischemic groups, were decapitated directly into liquid nitrogen; 10 min after arterial ligation. Brain free fatty acids, neutral lipids and phospholipids, which were labeled in vivo by the intraventricular injection of [1-14C]arachidonic acid (0.4-0.6 micro Ci, 6-9 nmol) 2 hr prior to ligation, were extracted, purified, and separated by thin-layer chromatographic procedures. The CDP-choline treatment noticeably corrected the increase of total and individual fatty acids due to ischemia and the increase of their radioactivity content. The changes in neutral lipids, particularly in the diacyl glycerol fraction, were also corrected by the injection of the nucleotide. CDP-choline partially reversed the decreased of brain phosphatidylcholine and of its labeling, which was due to ischemia. All the data indicate that the prior injection of CDP-choline stimulates the choline phosphotransferase reaction of brain towards synthesis of phosphatidylcholine and prevents the release of free fatty acids, particularly of arachidonic acid, associated with ischemia.

Animals↗

PubMed2005

CDP-choline liposomes provide significant reduction in infarction over free CDP-choline in stroke.

Cytidine-5'-diphosphocholine (CDP-choline, Citicoline, Somazina) is in clinical use (intravenous administration) for stroke treatment in Europe and Japan, while USA phase III stroke clinical trials (oral administration) were disappointing. Others showed that CDP-choline liposomes significantly increased brain uptake over the free drug in cerebral ischemia models. Liposomes were formulated as DPPC, DPPS, cholesterol, GM(1) ganglioside; 7/4/7/1.57 molar ratio or 35.8/20.4/35.8/8.0 mol%. GM(1) ganglioside confers long-circulating properties to the liposomes by suppressing phagocytosis. CDP-choline liposomes deliver the agent intact to the brain, circumventing the rate-limiting, cytidine triphosphate:phosphocholine cytidylyltransferase in phosphatidylcholine synthesis. Our data show that CDP-choline liposomes significantly ( P < 0.01) decreased cerebral infarction (by 62%) compared to the equivalent dose of free CDP-choline (by 26%) after 1 h focal cerebral ischemia and 24 h reperfusion in spontaneously hypertensive rats. Beneficial effects of CDP-choline liposomes in stroke may derive from a synergistic effect between the phospholipid components of the liposomes and the encapsulated CDP-choline.

Animals↗

PubMed1980

Choline high-affinity uptake and metabolism and choline acetyltransferase activity in the striatum of rats chronically treated with neuroleptics.

High-affinity uptake of choline and choline acetyltransferase activity (ChAT) were measured in the striatum of rats treated for 45-60 days with haloperidol (1 mg/kg per os) and pimozide (1 mg/kg per os) daily and with fluspirilene (1 mg/kg i.m.) twice a week. Haloperidol and fluspirilene caused a 20%, and pimozide a 38%, increase in high-affinity uptake of choline. They also caused a significant decrease in ChAT activity: haloperidol, 20%; pimozide, 27%; and fluspirilene, 42%. In rats treated with fluspirilene for 65-80 days the metabolism of [3H] choline taken up by striatal synaptosomes was investigated. A 33% increase in total radioactivity, a significant increase in labelled acetylcholine (ACh), a relative decrease in labelled choline, and no change in labelled phosphorylcholine and betaine were found. It is concluded that the increase in high-affinity choline uptake caused by chronic administration of neuroleptic drugs is associated with a parallel increase in choline utilization for ACh formation. On the other hand, the decrease in ChAT activity does not appear to influence ACh formation.

Animals↗

PubMed1986

Determination of free choline in plasma and erythrocyte samples and choline derived from membrane phosphatidylcholine by a chemiluminescence method.

A sensitive chemiluminescence method for assay of choline which has been developed for analysis of erythrocyte and plasma levels of choline is reported here. This method includes a charcoal purification step which yields consistent results with plasma and erythrocyte extracts. Further, choline derived from membrane phosphatidylcholine may also be measured by an extension of this method following digestion with phospholipase D. This method has been used to study abnormal levels of erythrocyte choline that occur in cluster headache patients compared to control subjects and migraine patients. In addition, the time course of changes in plasma and erythrocyte choline following a fatty meal have been monitored. Plasma choline levels rise to a maximum between 1 and 3 h after the meal and this is followed by a rise in erythrocyte choline levels which are maximal 3 h after the meal.

Cholesterol↗

PubMed1995

Structural changes induced by cytidine-5'-diphosphate choline (CDP-choline) chronic treatment in neurosecretory neurons of the supraoptic nucleus of aged CFW-mice.

The influence of chronic administration of cytidine-5'-diphosphate choline (CDP-choline), a precursor of the membrane lipid phosphatidylcholine, was studied in neurosecretory neurons (NSNs) of the supraoptic nucleus (SON) of aged mouse hypothalamus. Animals were treated with CDP-choline from 12 months of age until 26 months. They were studied for both morphologic and morphometric features. The results obtained were compared to those of an age-matched control group. There was evidence of differences between NSNs of the control group and those of the CDP-choline group which showed neuronal hypertrophy. This size increase was mainly attributed to the increment of cellular protein synthesis machinery, rough endoplasmic reticulum (RER) and Golgi complexes. Furthermore there was an increase in the number of neurosecretory granules (NSGs) in the CDP-choline group. In addition, there was no tertiary lysosomes in the treated animals. Moreover, the percentage of NSN membrane that was not covered by glial prolongations, increased from about 2% in the control group to 12% in the CDP-Choline treated group. These changes suggested an activation of the cellular processes for neurohormone synthesis in the experimental group. Furthermore, these NSNs displayed lipid droplets in their cytoplasm. The possible relationship between CDP-choline and NSNs activity is discussed.

Aging↗

PubMedDate not supplied

Differences in red blood cell choline and lipid-bound choline between patients with Alzheimer disease and control subjects.

The concentrations of red blood cell choline, glycerophosphocholine, phosphocholine and lipid-bound choline were measured in patients with Alzheimer disease (AD) and in normal elderly controls. Red blood cell choline in the Alzheimer group (41.4 +/- 9.2 nmol/ml) was significantly higher (p less than 0.023) than in the elderly controls (18.7 +/- 2.3 nmol/ml). Red blood cell lipid-bound choline (1387 +/- 58 nmol/ml) in the AD group was significantly lower (p less than 0.0022) than in the age-matched controls (1667 +/- 65), while there were no significant differences in glycerophosphocholine or phosphocholine. Plasma choline and lipid-bound choline did not differ significantly between the groups. The mechanisms for these changes still need further study, although the finding of decreased lipid-bound choline supports the concept of altered phospholipid metabolism in patients with AD.

Alzheimer Disease↗

PubMed1984

Choline production from choline-containing phospholipids: a hypothetical role in Alzheimer's disease and aging.

Deficits in certain long-axon cholinergic brain neurons have been demonstrated both in senile dementia of the Alzheimer type (SDAT) and, to a lesser degree, in association with the cognitive and memory impairments sometimes seen with normal aging. Our studies support a hypothesis concerning the selective vulnerability of these neurons. In our superfused brain slice system, acetylcholine (ACh) release was dependent on the concentration of exogenous choline, at rest and during electrical stimulation. Decreases in intracellular levels of ACh and choline accounted for only a small fraction of the quantities of these compounds released into the superfusates, suggesting that some tissue pool of bound choline, such as the phospholipids (PL), might have liberated choline. In choline-free medium, the release and tissue content of ACh were sustained; thus, choline released from the putative endogenous pool can be utilized for ACh synthesis. We hypothesize that the use, by cholinergic neurons, of choline originating from the breakdown of membrane PL, may result in an impoverishment in certain PL. Since only cholinergic neurons use their membrane PL as a reservoir for their neurotransmitter's precursor, this relationship might explain the major deficits in long-axon cholinergic nerve terminals seen in SDAT and other age-related memory disorders.

Acetylcholine↗

PubMed2006

On the contribution of the positively charged headgroup of choline to substrate binding and catalysis in the reaction catalyzed by choline oxidase.

Recent kinetic studies established that the positive charge on the trimethylammonium group of choline plays an important role in substrate binding and specificity in the reaction catalyzed by choline oxidase. In the present study, pH and solvent viscosity effects with the isosteric analogue of choline 3,3-dimethyl-butan-1-ol have been used to further dissect the contribution of the substrate positive charge to substrate binding and catalysis in the reaction catalyzed by choline oxidase. Both the kcat and kcat/Km values with 3,3-dimethyl-butan-1-ol increased to limiting values that were approximately 3- and approximately 400-times lower than those observed with choline, defining pKa values that were similar to the thermodynamic pKa value of approximately 7.5 previously determined. No effects of increased solvent viscosity were observed on the kcat and kcat/Km values with the substrate analogue at pH 8, suggesting that the chemical step of substrate oxidation is fully rate-limiting for the overall turnover and the reductive half-reaction in which the alcohol substrate is oxidized to the aldehyde. The kcat/Km value for oxygen determined with the substrate analogue was pH-independent in the pH range from 6 to 10, with an average value that was approximately 75-times lower than that previously determined with choline as substrate. These data are consistent with the positive charge headgroup of choline playing important roles for substrate binding and flavin oxidation, with minimal contribution to substrate oxidation.

Alcohol Oxidoreductases↗

PubMed1991

Neurochemistry of aging. 2. Design, synthesis, and biological evaluation of halomethyl analogues of choline with high affinity choline transport inhibitory activity.

The design, synthesis, and testing of several halomethyl analogues of choline and acetylcholine as potential cholinotoxins is described. The compounds were evaluated for their ability to inhibit high-affinity choline transport and their affinity toward postsynaptic muscarinic receptors. Among the analogues tested, bromomethyl and iodomethyl analogues of choline were found to be the most potent inhibitors of the high affinity choline transport system. Introduction of a beta-methyl group in the halomethyl analogues drastically reduced their potencies. The bromomethyl and iodomethyl analogues were further investigated for their effects on choline acetyltransferase activity, acetylcholinesterase activity and QNB binding. Neither compound possesses significant ability to alter any of the above cholinergic markers, except at very high concentrations. These results suggest that the bromomethyl and iodomethyl choline analogues may be used as specific inhibitors of the presynaptic high-affinity choline transport system.

Acetylcholinesterase↗

PubMedDate not supplied

Inhibition of acetylcholinesterase by hemicholiniums, conformationally constrained choline analogues. Evaluation of aryl and alkyl substituents. Comparisons with choline and (3-hydroxyphenyl)trimethylammonium.

2-Substituted-2-hydroxy-4,4-dimethylmorpholiniums (hemicholiniums) inhibit acetylcholinesterase (EC 3.1.1.7)-catalyzed hydrolysis of acetylthiocholine (ATCh). The 4-substituted arenes [NH2, NHC(O)CH3, Cl, CN, and NO2] have values of inhibition constants (Ki) that range from 220 to 3690 microM, which correlate with Hammett sigma, rho approximately 0.8. The alkyl compounds, hydrogen, methyl, tert-butyl, and trifluoromethyl, have values of Ki of 550, 560, 1200, and 1200 microM, respectively. These values compare favorably with Ki = 960 microM for choline. The conformation of AChE-bound choline must be gauche to support our suggestion that hemicholiniums are conformationally constrained analogues of choline. (3-Hydroxyphenyl)trimethylammonium (5) inhibits most strongly, Ki = 0.21 microM, of the compounds examined in this study. The solvent isotope effect (H2OKi/D2OKi = 0.83 +/- 0.04) suggests that inhibition by 5 involves hydrogen bonding. The binding by AChE of the hemicholiniums of various sizes and the strong binding of 5 support an earlier proposal [Schowen, K. B., Smissman, E. E., and Stephen, W. F., Jr. (1975) J. Med. Chem. 18, 292-300] that the active site of AChE has ample space for rotation about the C-C bond in choline. Compound 5, which has one more carbon between the hydroxy and trimethylammonium than does choline, inhibits much more potently than either choline or the hemicholiniums. Compound 5 provides a correct spacer to span the trimethylammonium recognition site and the esteratic site of AChE. This aromatic spacer interacts favorably with the hydrophobic active site, and the phenolic hydroxyl probably hydrogen bonds to the histidine in the esteratic site. Choline in any conformation and the hemicholiniums are too short to make a strong hydrogen bond.

Animals↗

PubMed1981

Induction of choline transport and its role in the stimulation of the incorporation of choline into phosphatidylcholine by polyamines in a polyamine auxotroph of Saccharomyces cerevisiae.

1. A mutant of Saccharomyces cerevisiae, defective in ornithine decarboxylase, was isolated. A prolonged culture of the mutant in a polyamine-free medium resulted in a great decrease in the polyamine content and in cessation of growth. The addition of polyamines to the culture induced the growth after a lag period of 5--6.5 h. The growth rate in the presence of polyamine was comparable to that of the wild-type strain. The effectiveness of polyamines was as follows: spermidine greater than putrescine approximately equal to spermine. 2. Phosphatidylcholine-synthesizing activity during the lag phase of growth was determined by measuring the rate of incorporation of [14C]choline into phosphatidylcholine. The incorporation rate was markedly increased with time by polyamine prior to the initiation of cell division. Polyamines were effective in the following order: spermidine greater than putrescine approximately equal to spermine. Experiments with methylglyoxal bis(guanylhydrazone), an inhibitor of S-adenosylmethionine decarboxylase, showed that putrescine stimulates cell growth and choline incorporation into phosphatidylcholine after it has been converted into spermidine in the cell. 3. The induction of the choline transport system was shown to be responsible for the increase in the rate of incorporation of [14C]choline into phosphatidylcholine effected by polyamines. A low concentration of cycloheximide completely prevented the induction of choline transport by polyamines. The levels of the CDP-choline pathway enzymes such as choline kinase, cholinephosphate cytidyltransferase and cholinephosphotransferase were not significantly changed.

Biological Transport↗

PubMed1984

The relationship between dietary intake of choline, choline serum levels, and cognitive function in healthy elderly persons.

This study was designed to obtain information on normal dietary intake and serum levels of choline in a healthy elderly population and to observe the relationship between blood levels of choline and cognitive function. Two hundred fifty-eight healthy volunteers with a mean age of 72 years were recruited, and blood samples and dietary histories were obtained. All subjects were ambulatory, living at home, free of serious medical illnesses, and taking no prescription medications. Cognitive abilities were assessed by the Halstead Category Test, a nonverbal test measuring abstract thinking, and the Wechsler Memory Scale, using the multiple scoring method, which measures both long- and short-term memory. The mean value for serum choline was 13.16 micron with a standard deviation of 3.31. Serum choline levels were found to increase with age, but no difference was found between serum choline levels for men and women. There was no association between dietary intake and serum choline levels, nor could a relationship be found between serum choline levels and cognitive function.

Age Factors↗