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PubMed1994

Retinal cholinergic system: characterization of rat retinal acetyltransferases using specific inhibitors of choline- and carnitine-acetyltransferases.

Choline acetyltransferase catalyzes the synthesis of acetylcholine from choline and acetylcoenzyme A (ACoA) in both nervous and non-nervous tissues. Carnitine acetyltransferase occurs in several tissues and transfers acetyl groups from ACoA to carnitine forming acetylcarnitine and exhibits weak choline acetyltransferase activity. Several haloacetylcholines and haloacetylcarnitines were synthesized to develop selective inhibitors of choline acetyltransferase and carnitine acetyltransferase. Acetylcholine is a transmitter for some presynaptic neurons and/or amacrine cells in retina. Selective inhibitors of choline acetyltransferase and carnitine acetyltransferase were used in the evaluation of choline acetyltransferase and carnitine acetyltransferase activities in the rat retina. Choline acetyltransferase and carnitine acetyltransferase activities were assayed by transferring of [14C]acetyl group from [14C]ACoA to choline or carnitine and estimating [14C]-acetylcholine or [14C]acetylcarnitine. This study gave the following results: (a) Bromoacetylcholine (BrACh) was a selective inhibitor of purified choline acetyltransferase (I50, 2.2 microM); (b) (R)-bromoacetylcarnitine [(R)-BrACa] was more potent for inhibiting purified carnitine acetyltransferase (I50, 4 microM) than purified choline acetyltransferase (I50, 46 microM); (c) Rat retinal sonicate gave choline acetyltransferase activity of 98 +/- 6 nmol of ACh formed/mg/10 min. When the carnitine acetyltransferase was completely inhibited by (R)-BrACa, the activity for choline acetyltransferase decreased to 47 +/- 1 nmol, and this decrease was possibly due to the formation of some [14C]acetylcholine by carnitine acetyltransferase. The net retinal choline acetyltransferase activity was 51 nmol acetylcholine/mg protein/10 min; (d) Rat retinal sonicate contained carnitine acetyltransferase activity of 102 +/- 7 nmol acetylcarnitine formed/mg protein/10 min. This was not altered by inhibition of choline acetyltransferase with BrACh. This means that choline acetyltransferase did not use carnitine as a substrate. Choline acetyltransferase and carnitine acetyltransferase activities did not change after dialysis of retinal sonicates at 4 degrees C for 24 hrs. These observations suggest that BrACh and (R)-BrACa are useful for assessing the correct values for choline acetyltransferase and carnitine acetyltransferase activities in retinal tissues.

Acetylcarnitine↗
PubMed1993

Choline: its role in the growth of filamentous fungi and the regulation of mycelial morphology.

Choline is an essential metabolite for the growth of filamentous fungi. It occurs most notably as a component of the major membrane phospholipid, phosphatidyl choline (lecithin), and fulfills a major role in sulphate metabolism in the form of choline-o-sulphate in many species. Choline is usually synthesised endogenously, but exogenous choline can also be taken up, either to compensate for metabolic deficiencies in choline-requiring mutants such as those of Aspergillus nidulans and Neurospora crassa, or as a normal function by species such as Fusarium graminearum which do not require added choline for growth. F. graminearum has a highly specific constitutive uptake system for this purpose. Recent studies have begun to indicate that choline also plays an important role in hyphal and mycelial morphology. Over a wide range of concentrations, choline influences mycelial morphology, apparently by controlling branch initiation. At high concentrations of added choline, branching is inhibited but specific growth rate is unaffected, leading to the production of rapidly extending, sparsely branched mycelia. Reduction of choline concentration allows a progressive increase in branching. Additionally, in choline-requiring mutants which have a very reduced content of choline, multiple tip-formation and apical branching occurs. Just prior to cessation of growth in choline-starved cultures of A. nidulans choline-requiring mutants, hyphal morphology changes due to a brief phase of unpolarised growth to produce spherical swellings called balloons, at or near hyphal apices. The precise mechanism by which choline affects fungal morphology is not yet known, although in A. nidulans it appears to be at least partially due to the influence of membrane composition on the synthesis of the hyphal wall polymer chitin. Several hypotheses for the possible mode of action of choline in affecting fungal morphology are discussed here.

Cell Membrane↗
PubMed1968

Specificity and control of choline-O-sulfate transport in filamentous fungi.

Choline-O-sulfate uptake by Penicillium notatum showed the following characteristics. (i) Transport was mediated by a permease which is highly specific for choline-O-sulfate. No significant inhibition of transport was caused by choline, choline-O-phosphate, acetylcholine, ethanolamine-O-phosphate, ethanolamine-O-sulfate, methanesulfonyl choline, 2-aminoethane thiosulfate, or the monomethyl or dimethyl analogues of choline-O-sulfate. Similarly, no significant inhibition was caused by any common sulfur amino acid or inorganic sulfur compound. Mutants lacking the inorganic sulfate permease possessed the choline-O-sulfate permease at wild-type levels. (ii) Choline-O-sulfate transport obeyed saturation kinetics (K(m) = 10(-4) to 3 x 10(-4)m; V(max) = 1 to 6 mumoles per g per min). The kinetics of transport between 10(-9) and 10(-1)m external choline-O-sulfate showed that only one saturable mechanism is present. (iii) Transport was sensitive to 2,4-dinitrophenol, azide, N-ethylmaleimide, p-chloromercuribenzoate, and cyanide. Ouabain, phloridzin, and eserine had no effect. (iv) Transport was pH-dependent with an optimum at pH 6. Variations in the ionic strength of the incubation medium had no effect. (v) Transport was temperature-dependent with a Q(10) of greater than 2 between 3 and 40 C. Transport decreased rapidly above 40 C. (vi) Ethylenediaminetetraacetate (sodium salts, pH 6) had no effect, nor was there any stimulation by metal or nonmetal ions. Cu(++), Ag(+), and Hg(++) were inhibitory. (vii) The initial rate at which the ester is transported was independent of intracellular hydrolysis. After long periods of incubation (> 10 min), a significant proportion of the transported choline-O-sulfate was hydrolyzed intracellulary. In the presence of 5 x 10(-3)m external choline-O-sulfate, the mycelia accumulated choline-O-sulfate to an apparent intracellular concentration of 0.075 m by 3 hr. Transport was unidirectional. No efflux or exchange of (35)S-choline-O-sulfate was observed when preloaded mycelia were suspended in buffer alone or in buffer containing a large excess of unlabeled choline-O-sulfate. (viii) The specific transport activity of the mycelium depended on the sulfur source used for growth. (ix) Sulfur starvation of sulfur-sufficient mycelium resulted in an increase in the specific transport activity of the mycelium. This increase was prevented by cycloheximide, occurred only when a metabolizable carbon source was present, and resulted from an increase in the V(max) of the permease, rather than from a decrease in K(m). The increase could be partially reversed by refeeding the mycelia with unlabeled choline-O-sulfate, sulfide, sulfite, l-homocysteine, l-cysteine, or compounds easily converted to cysteine. The results strongly suggested that the choline-O-sulfate permease is regulated primarily by repression-derepression, but that intracellular choline-O-sulfate and cysteine can act as feedback inhibitors.

Antimetabolites↗
PubMed2000

Changes in plasma free and phospholipid-bound choline concentrations in chronic hemodialysis patients.

BACKGROUND: Choline deficiency may develop in malnourished patients, those with cirrhosis, and those who require total parenteral nutrition. Previous data has suggested an important role for the kidneys in the maintenance of choline homeostasis. OBJECTIVE: This study was undertaken to determine the change in plasma choline during hemodialysis and to determine if it was lost in the dialysate. DESIGN: Thirteen adult patients (10 men, 3 women) who had required hemodialysis for a mean of 10.8 years were studied. Dialysis was performed 3 times weekly for 4 hours using either a cellulose acetate or polysulfone dialyzer membrane. Venous and arterial blood, and dialysate samples were taken for measurement of plasma free and phospholipid-bound choline concentration before beginning dialysis and after each hour of dialysis. An in vitro system was devised to determine if choline could bind to a significant degree to the dialysis membrane. RESULTS: Plasma free choline concentration was increased above normal (11.7 +/- 3.7 nmol/mL) at baseline and declined progressively during dialysis. In contrast, plasma phospholipid-bound choline concentration increased progressively during dialysis. The decrease in plasma free choline (-1.8 +/- 0.3 nmol/mL(-1)/h(-1); P = 1.6 x 10(-6)) was almost entirely related to that which was removed during dialysis, although the magnitude of the loss was not correlated with the increase in plasma phospholipid-bound choline concentration (125 +/- 20.5 nmol/mL(-1)/h(-1); P < 1.2 x 10(-6)). Patients lost a mean of 246 pmol of free choline during hemodialysis. Choline did not bind to the dialysis membrane. CONCLUSION: Plasma free choline concentration is elevated before dialysis, and choline is lost to a significant degree in the dialysate. Further investigation is necessary to determine whether a transient, dialysis-induced choline deficiency develops, and whether there is a role for choline supplementation in these patients. The choline homeostatic mechanism requires further investigation in renal failure patients.

Adult↗
PubMed1993

Characterization of choline metabolism and secretion by human placental trophoblasts in culture.

Choline is an essential nutrient for fetal development and may be utilized to form phospholipids such as phosphatidylcholine and sphingomyelin; to synthesize the neurotransmitter, acetylcholine; and to donate methyl groups after being oxidized to betaine. Since the majority of choline required for fetal growth must be transported by the placenta from the maternal circulation, we examined the ability of isolated human trophoblasts to metabolize choline and to release choline and its metabolites into culture medium. Cytotrophoblasts were isolated from normal, full-term human placentas and incubated with [14C]choline for 3 h; the cells were washed to remove extracellular radiolabel, and the changes in intracellular and medium choline pools were followed for an additional 24 h. During the incubation, choline rapidly reached steady state intracellularly and label was incorporated into betaine, phosphocholine, cytidylyldiphosphocholine, phosphatidylcholine, glycerophosphocholine, lysophosphatidylcholine, and sphingomyelin. All labeled choline metabolites in cells, except glycerophosphocholine, decreased at 6 and 27 h of incubation (3 and 24 h, respectively, after labeled choline was removed), and labeled metabolites appeared in media. By 24 h after labeled choline was removed, the major labeled metabolites in the media were choline (82%), betaine (11%), and glycerophosphocholine (5%). Small amounts of phosphatidylcholine (1%), and lysophosphatidylcholine (1%) were found. Acetylcholine was a very minor choline metabolite in these cells. When placental cells were incubated for 66 h after isolation, they formed syncytiotrophoblasts, which incorporated labeled choline into metabolites in a similar pattern to cytotrophoblasts. These data indicate that isolated trophoblast cells can metabolize choline to form all of its major metabolites and that several metabolites are released to the medium in significant amounts. Thus, our data suggest that the major metabolite supplied to the fetus may be choline, but that betaine and glycerophosphocholine may also be vehicles for transfer of choline equivalents from mother to fetus.

Betaine↗
PubMed1997

Apoptosis is induced by choline deficiency in fetal brain and in PC12 cells.

Treatment of rats with choline during critical periods in brain development results in long-lasting enhancement of spatial memory in their offspring. Apoptosis is a normal process during brain development, and, in some tissues, is modulated by the availability of the nutrient choline. In these studies, we examined whether availability of choline influences apoptosis in fetal brain and in the PC12 cell line derived from a rat pheochromocytoma. Timed-bred Sprague Dawley rats were fed a choline-deficient (CD), choline-control, or choline-supplemented (CS) diet for 6 days and, on embryonic day 18, fetal brain slices were prepared and apoptosis was assessed using terminal dUTP nucleotide end labeling (TUNEL) to detect DNA strand breaks and by counting of apoptotic bodies. TUNEL-positive cells were detected in 15.9% (P < 0.01), 8.7% and 7.2% of hippocampal cells from fetuses of dams fed the CD, control or CS diets, respectively. A similar inverse relationship between dietary intake of choline and TUNEL positive cells was detected in an area of cerebral cortex from these fetal brain slices. Counts of apoptotic bodies in fetal brain slices correlated inversely with choline intake of the mothers (6.2% (P < 0.01), 2.5% and 1.9% of hippocampal cells had apoptotic bodies in fetuses of dams fed the CD, control and CS diets, respectively). PC12 cells were grown in DMEM/F12 media supplemented with 70 microM choline or with 0 microM choline. The number of apoptotic bodies in PC12 cells increased when cells were grown in 0 microM choline medium (1.5%; P < 0.05) compared to 70 microM choline medium (0.55%). In PC12 cells, TUNEL labeling (DNA strand breaks) increased in choline deficient (13.5%, P < 0.05) compared to sufficient medium (5.0%). In addition, cleavage of genomic DNA-into 200 bp internucleosomal fragments was detected in choline-deficient cells. These results show that choline deficiency induces-apoptotic cell death in neuronal-type cells and in whole brain. We suggest that variations in choline availability to brain modulate apoptosis rates during development.

Animals↗
PubMed2001

Hemicholinium-3 mustard reveals two populations of cycling choline cotransporters in Limulus.

Cholinergic neurons have both a low-affinity and a high-affinity choline transport process. The high-affinity choline transport is sodium dependent and thus it can be referred to as choline cotransport. Choline cotransport has been shown to be up-regulated by neuronal activity. Protein kinase C has also been shown to regulate choline cotransport. Both forms of regulation appear to modulate transport by altering the numbers of choline cotransporters in the nerve terminal membrane. The present study centers on choline cotransporter trafficking in Limulus brain hemi-slice preparations. The competitive, reversible, non-permeant ligand, [3H]hemicholinium-3, was used in binding studies to estimate the relative number of choline cotransporters in plasma membranes. The hemicholinium-3 mustard derivative has been shown to be an irreversible, highly selective, non-permeant ligand for the choline cotransporter, and was also used. Hemicholinium-3 mustard binding to the choline cotransporter blocked [3H]choline transport and [3H]hemicholinium-3 binding. Antecedent elevated potassium exposure of cholinergic tissues has been shown to up-regulate choline transport by the recruitment of additional choline cotransporters to surface membranes. This treatment was also effective in the recruitment of cotransporters following maximal inhibition by hemicholinium-3 mustard of brain hemi-slices. Long-term washout of hemicholinium-3 mustard in hemi-slices resulted in a time-dependent restoration of choline cotransport. Full recovery occurred within 2h. In uninhibited slice preparations, both staurosporine and chelerythrine, protein kinase C inhibitors, stimulated choline uptake. However, within a 1-h washout recovery of uptake following hemicholinium-3 mustard inhibition, the staurosporine responsive but not chelerythrine responsive transport had returned. On the basis of these findings, we hypothesize the existence of two distinct populations of cycling choline cotransporters, which includes inactive or "silent" transporters.

Alkaloids↗
PubMed1999

Plasma free, phospholipid-bound and urinary free choline all decrease during a marathon run and may be associated with impaired performance.

BACKGROUND: Previous investigations have shown that plasma free choline decreases during long distance running. OBJECTIVE: This study was undertaken to determine if body choline status changes during a marathon run and whether performance is thereby adversely affected. DESIGN: Twenty-three accomplished marathon runners 25 to 49 years of age were studied before and after the 1997 Houston-Methodist Marathon. Fasting blood and five-hour urine samples were obtained in the morning, 14 days prior to the race, immediately after the race and approximately 48 hours after completion of the race. Runners were asked to predict their finish times two weeks prior to the race. Performance was indicated by the ratio of predicted to actual time. RESULTS: Both plasma free and phospholipid-bound choline concentrations as well as urinary free choline concentration decreased immediately following the race (19.2+/-4.5 to 14.6+/-4.2 nmol/mL, p=0.005, and 2565.2+/-516.4 to 2403.4+/-643.0 nmol/mL, p=0.068, respectively) and, except for the phospholipid-bound choline, rebounded towards baseline after 48 hours (15.6+/-3.2 and 2299.9+/-426.7 nmol/mL), although plasma concentrations remained significantly below baseline. Plasma free and phospholipid-bound choline concentrations were significantly correlated (r=0.46, p=0.0001), although urinary free choline concentration was not correlated with either. There was no correlation between plasma free, phospholipid-bound or urinary free choline concentration and actual finish time or the ratio of predicted to actual finish time. However, the percent decrease in urinary free choline concentration was significantly correlated with the ratio of predicted to actual time (r=0.47, p=0.036). No relationship was seen between this ratio and the percent decrease in either plasma free or phospholipid-bound choline concentrations immediately after the race. CONCLUSION: Our finding of both decreased free and phospholipid-bound choline suggests the decrease in choline status is related to accelerated choline metabolism or enhanced choline uptake by tissues rather than decreased hepatic choline release. The role of choline supplementation during endurance running requires further investigation.

Adult↗
PubMed1994

Competitive inhibition of the nickel-induced response to choline by calcium ions in single water fibers of the frog glossopharyngeal nerve.

NiCl2 induces a response to choline Cl and enhances the response to CaCl2 in water-sensitive fibers (water fibers) of the frog glossopharyngeal nerve. The Ni(2+)-induced choline+ response was inhibited by Ca2+ ions and, conversely, the enhanced Ca2+ response by Ni2+ ions was inhibited by choline+ ions. Hence, there exists a mutual antagonism between Ca2+ and choline+ ions. In the present study, the inhibition of the Ni(2+)-induced choline+ response by Ca2+ ions was investigated quantitatively. The assumption was made that receptors for choline (XCh) exist and that binding of a choline+ ion to XCh brings about a neural response. It was further assumed that the magnitude of the neural response is proportional to the amount of choline-XCh complex minus some constant (the threshold concentration of the choline-XCh complex). The results from analysis of double-reciprocal plot were consistent with the hypothesis that Ca2+ ions compete with choline+ ions for XCh. The dissociation constants for the choline-XCh complex and the CaXCh complex were obtained to be 0.6 M and 7.4 x 10(-5) M, respectively. This result indicates that the affinities of XCh for choline+ and Ca2+ ions are very different. Furthermore, Mg2+ ions did not affect the Ni(2+)-induced choline+ response, an indication that the affinity of XCh is not charge-specific, but is chemically specific. The identification of a competitive inhibitor of the choline+ response provides evidence for existence of a choline-specific receptor at the surface of taste cells that are innervated by the water fibers of the frog glossopharyngeal nerve. Differences between the features of the response to choline Cl in the chorda tympani nerve of the rat and those in the frog glossopharyngeal nerve are discussed.

Animals↗
PubMed2005

Molecular and functional characterization of an Na+-independent choline transporter in rat astrocytes.

In this study, we examined the molecular and functional characterization of choline uptake into cultured rat cortical astrocytes. Choline uptake into astrocytes showed little dependence on extracellular Na+. Na+-independent choline uptake was saturable and mediated by a single transport system, with an apparent Michaelis-Menten constant (Km) of 35.7 +/- 4.1 microm and a maximal velocity (Vmax) of 49.1 +/- 2.0 pmol/mg protein/min. Choline uptake was significantly decreased by acidification of the extracellular medium and by membrane depolarization. Na+-independent choline uptake was inhibited by unlabeled choline, acetylcholine and the choline analogue hemicholinium-3. The prototypical organic cation tetrahexylammonium (TEA), and other n-tetraalkylammonium compounds such as tetrabutylammonium (TBA) and tetrahexylammonium (THA), inhibited Na+-independent choline uptake, and their inhibitory potencies were in the order THA > TBA > TEA. Various organic cations, such as 1-methyl-4-tetrahydropyridinium (MPP+), clonidine, quinine, quinidine, guanidine, N-methylnicotinamide, cimetidine, desipramine, diphenhydramine and verapamil, also interacted with the Na+-independent choline transport system. Corticosterone and 17beta-estradiol, known inhibitors of organic cation transporter 3 (OCT3), did not cause any significant inhibition. However, decynium22, which inhibits OCTs, markedly inhibited Na+-independent choline uptake. RT-PCR demonstrated that astrocytes expressed low levels of OCT1, OCT2 and OCT3 mRNA, but the functional characteristics of choline uptake are very different from the known properties of these OCTs. The high-affinity Na+-dependent choline transporter, CHT1, is not expressed in astrocytes as evidenced by RT-PCR. Furthermore, mRNA for choline transporter-like protein 1 (CTL1), and its splice variants CTL1a and CTL1b, was expressed in rat astrocytes, and the inhibition of CTL1 expression by RNA interference completely inhibited Na+-independent choline uptake. We conclude that rat astrocytes express an intermediate-affinity Na+-independent choline transport system. This system seems to occur through a CTL1 and is responsible for the uptake of choline and organic cations in these cells.

Animals↗
PubMed1986

Neurochemical effects of choline supplementation.

Whether or not the brain can use supplemental choline to enhance the synthesis of acetylcholine (ACh) is an important consideration for assessing the merits of using choline or phosphatidylcholine (lecithin) for the treatment of neuropsychiatric disorders postulated to involve hypocholinergic activity. While it is well documented that administered choline is incorporated into ACh, the ability of supplemental choline to increase the synthesis and release of ACh has been questionable. Studies in my laboratory have demonstrated that acute or chronic choline supplementation does not, by itself, enhance the levels of ACh in brain under normal biochemical and physiological conditions. However, supplemental choline prevents the depletion of ACh in brain induced by numerous pharmacological agents that increase the firing of cholinergic neurons. Since the levels of free choline in brains from supplemented rats were not different from controls prior to drug challenge, evidence suggested that the observed effects of choline were mediated by alterations in the mobilization of choline from choline-containing compounds. Studies investigating the release of choline from brain indicated that more choline was released per unit time in tissues from choline-supplemented rats than from controls. In addition, brain tissue from choline-supplemented rats had increased concentrations of total lipid phosphorus as compared with controls. Hence, although choline supplementation does not alter the levels of ACh in brain under normal conditions, it does appear to support ACh synthesis during drug-induced increases in neuronal activity, an effect most likely mediated by alterations in the metabolism of choline-containing phospholipids.

Acetylcholine↗
PubMed1991

Choline, an essential nutrient for humans.

Choline is required to make essential membrane phospholipids. It is a precursor for the biosynthesis of the neurotransmitter acetylcholine and also is an important source of labile methyl groups. Mammals fed a choline-deficient diet develop liver dysfunction; however, choline is not considered an essential nutrient in humans. Healthy male volunteers were hospitalized and fed a semisynthetic diet devoid of choline supplemented with 500 mg/day choline for 1 wk. Subjects were randomly divided into two groups, one that continued to receive choline (control), and the other that received no choline (deficient) for three additional wk. During the 5th wk of the study all subjects received choline. The semisynthetic diet contained adequate, but no excess, methionine. In the choline-deficient group, plasma choline and phosphatidylcholine concentrations decreased an average of 30% during the 3-wk period when a choline-deficient diet was ingested; plasma and erthrocyte phosphatidylcholine decreased 15%; no such changes occurred in the control group. In the choline-deficient group, serum alanine aminotransferase activity increased steadily from a mean of 0.42 mukat/liter to a mean of 0.62 mukat/liter during the 3-wk period when a choline-deficient diet was ingested; no such change occurred in the control group. Other tests of liver and renal function were unchanged in both groups during the study. Serum cholesterol decreased an average of 15% in the deficient group and did not change in the control group. Healthy humans consuming a choline-deficient diet for 3 wk had depleted stores of choline in tissues and developed signs of incipient liver dysfunction. Our observations support the conclusion and choline is an essential nutrient for humans when excess methionine and folate are not available in the diet.

Choline↗
PubMed1995

CDP-choline: pharmacological and clinical review.

Cytidine 5'-diphosphocholine, CDP-choline or citicoline, is an essential intermediate in the biosynthetic pathway of the structural phospholipids of cell membranes, especially in that of phosphatidylcholine. Upon oral or parenteral administration, CDP-choline releases its two principle components, cytidine and choline. When administered orally, it is absorbed almost completely, and its bioavailability is approximately the same as when administered intravenously. Once absorbed, the cytidine and choline disperse widely throughout the organism, cross the blood-brain barrier and reach the central nervous system (CNS), where they are incorporated into the phospholipid fraction of the membrane and microsomes. CDP-choline activates the biosynthesis of structural phospholipids in the neuronal membranes, increases cerebral metabolism and acts on the levels of various neurotransmitters. Thus, it has been experimentally proven that CDP-choline increases noradrenaline and dopamine levels in the CNS. Due to these pharmacological activities, CDP-choline has a neuroprotective effect in situations of hypoxia and ischemia, as well as improved learning and memory performance in animal models of brain aging. Furthermore, it has been demonstrated that CDP-choline restores the activity of mitochondrial ATPase and of membranal Na+/K+ ATPase, inhibits the activation of phospholipase A2 and accelerates the reabsorption of cerebral edema in various experimental models. CDP-choline is a safe drug, as toxicological tests have shown; it has no serious effects on the cholinergic system and it is perfectly tolerated. These pharmacological characteristics, combined with CDP-choline's mechanisms of action, suggest that this drug may be suitable for the treatment of cerebral vascular disease, head trauma of varying severity and cognitive disorders of diverse etiology. In studies carried out on the treatment of patients with head trauma, CDP-choline accelerated the recovery from post-traumatic coma and the recuperation of walking ability, achieved a better final functional result and reduced the hospital stay of these patients, in addition to improving the cognitive and memory disturbances which are observed after a head trauma of lesser severity and which constitute the disorder known as postconcussion syndrome. In the treatment of patients with acute cerebral vascular disease of the ischemic type, CDP-choline accelerated the recovery of consciousness and motor deficit, attaining a better final result and facilitating the rehabilitation of these patients. The other important use for CDP-choline is in the treatment of senile cognitive impairment, which is secondary to degenerative diseases (e.g., Alzheimer's disease) and to chronic cerebral vascular disease. In patients with chronic cerebral ischemia, CDP-choline improves scores on cognitive evaluation scales, while in patients with senile dementia of the Alzheimer's type, it slows the disease's evolution. Beneficial neuroendocrine, neuroimmunomodulatory and neurophysiological effects have been described. CDP-choline has also been shown to be effective as co-therapy for Parkinson's disease. No serious side effects have been found in any of the groups of patients treated with CDP-choline, which demonstrates the safety of the treatment.

Animals↗
PubMed1999

Enhancement of free fatty acid incorporation into phospholipids by choline plus cytidine.

Cytidine and choline, present in cytidine 5'-diphosphate choline (CDP-choline), are major precursors of the phosphatidylcholine found in cell membranes and important regulatory elements in phosphatide biosynthesis. Administration of CDP-choline to rats increases blood and brain cytidine and choline levels; this enhances the production of endogenous CDP-choline which then combines with fatty acids (as diacylglycerol), to yield phosphatidylcholine. We examined the effect of providing cytidine and choline on incorporation of free fatty acids into phosphatidylcholine and other major phospholipids in PC12 cells. Addition of equimolar cytidine and choline (100-500 microM) to [3H]-arachidonic acid (50 microM, 0.2 microCi, bound to bovine serum albumin) dose-dependently increased the accumulations of [3H]-phosphatidylcholine (PtdCho), [3H]-phosphatidylinositol (PtdIno) and [3H]-phosphatidylethanolamine (PtdEtn) (by up to 27+/-3%, 16+/-3% and 11+/-3%, respectively, means+/-S.E.M.). This effect was seen with 8-18 h of incubation. The incorporation of [3H]-oleic acid into [3H]-PtdCho was even more enhanced (by up to 42+/-3%) as were the incorporations of [14C]-choline and [3H]-glycerol. The effects of choline and cytidine were enhanced by 12-O-tetradecanoylphorbol-13-acetate (TPA, 1 microM), which activates CTP:phosphocholine cytidylyltransferase (CT) and facilitates choline uptake. Replacing choline by ethanolamine also enhanced the incorporation of [3H]-arachidonic acid into [3H]-PtdEtn, [3H]-PtdIno and [3H]-PtdCho. Arachidonic acid (10-200 microM) alone failed to affect the incorporation of [14C]-choline into phosphatidylcholine. We suggest that the increases in phospholipid synthesis caused by concurrent cytidine and choline supplementation enhance the incorporation of arachidonic acid and certain other fatty acids into the major glycerophospholipids. Removing these fatty acids as source of potentially toxic oxidation products could contribute to the beneficial effects of CDP-choline in treating stroke or other brain damage.

Animals↗
PubMed1992

Effects of amino acids and ethanolamine on choline uptake and phosphatidylcholine biosynthesis in baby hamster kidney-21 cells.

The effects of amino acids and ethanolamine on choline uptake and phosphatidylcholine biosynthesis in baby hamster kidney (BHK-21) cells were investigated. The cells were incubated with labelled choline in the presence of an amino acid or ethanolamine. The uptake of labelled choline was noncompetitively inhibited by amino acids. Glycine, L-alanine, L-serine, L-leucine, L-aspartate, and L-arginine were effective inhibitors and a maximum of 22% inhibition of choline uptake was obtained with 5 mM glycine. Analyses of the labelings in the choline-containing metabolites revealed that the conversion of choline to CDP-choline and subsequently phosphatidylcholine was not affected by the presence of amino acids. The uptake of choline was also inhibited by ethanolamine in a concentration-dependent manner. Kinetic studies on the uptake of choline indicated that the inhibition by ethanolamine was competitive in nature. Although ethanolamine is a potent inhibitor of choline kinase, analyses of the labelings in the choline-containing metabolites indicated that the conversion of choline to phosphocholine was not affected in the cells incubated with ethanolamine. Ethanolamine did not change the pool sizes of phosphocholine and CDP-choline. Based on the specific radioactivity of CDP-choline and the labeling of phosphatidylcholine, the rates of phosphatidylcholine biosynthesis were not significantly different between the control and the ethanolamine-treated cells. In view of the concentrations of amino acids (millimolar) and ethanolamine (micromolar) in most cell culture media, it appeared that only amino acids were important metabolites for the regulation of choline uptake in BHK-21 cells. We conclude that both amino acids and ethanolamine have no direct effect on the biosynthesis of phosphatidylcholine.

Amino Acids↗
PubMed1993

Sympathetic neurons expressing cholinergic properties are poised to allocate choline symmetrically between acetylcholine and the phosphatidylcholine-generating pathway in growing neurites.

We have examined the question of how regenerating sympathetic neurons that are concomitantly induced to become cholinergic regulate choline allocation between ACh and the phospholipid synthetic pathway. The allocation of choline into ACh increased parabolically with time in culture, and by 3 weeks, cultures with neurites of approximately 6 mm length were incorporating over 85% of the choline locally in the neurites into four major metabolites: ACh, phosphorylcholine, cytidine diphosphocholine, and phosphatidylcholine. The near-equivalent distribution of labeled choline between intracellular choline, ACh, and phosphorylcholine was independent of time (5 min to 6 hr) and choline concentration (0.125-30 microM), phosphatidylcholine being the sole metabolite whose level in the neurites increased steadily with incubation time. Relative choline distribution into ACh and phosphorylcholine was unaltered even after a brief depolarizing prepulse, which caused a two- to fourfold enhancement in the total choline incorporated. These observations, allied with the similar half-saturation constants and Vmax values of CAT and choline kinase for intracellular choline, suggest that growing sympathetic neurons are poised to allocate choline symmetrically between the synthesis of ACh and phosphatidylcholine in the neurites. When, however, the supply of choline was limited either by replacement of Na+ in the medium with N-methyl-D-glucamine, or by vesamicol, a 90-97% reduction in intracellular choline caused a similar decline in ACh levels but synthesis of metabolites of the phosphatidylcholine pathway was maintained unperturbed, as if no drug was present. We suggest that this can be accounted for by a 10-fold increase in choline kinase activity. Thus, growing sympathetic neurons that express cholinergic properties not only maintain their chief cellular phosphatidylcholine-synthesizing activity concomitantly with ACh synthesis in the neurites, but may also preserve phosphatidylcholine synthesis more effectively than ACh synthesis when the supply of choline is perturbed. Relinquishing ACh synthesis during growth may be one way of conserving and encouraging neurite regeneration.

Acetylcholine↗
PubMed2005

Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly.

BACKGROUND: CDP-choline (cytidine 5'-diphosphocholine) is a precursor essential for the synthesis of phosphatidylcholine, one of the cell membrane components that is degraded during cerebral ischaemia to free fatty acids and free radicals. Animal studies suggest that CDP-choline may protect cell membranes by accelerating resynthesis of phospholipids. CDP-choline may also attenuate the progression of ischaemic cell damage by suppressing the release of free fatty acids. CDP-choline is the endogenous compound normally produced by the organism. When the same substance is introduced as a drug it can be called citicoline.CDP-choline is mainly used in the treatment of disorders of a cerebrovascular nature. The many years of its presence in the clinical field have caused an evolution in dosage, method of administration, and selection criteria of patients to whom the treatments were given. Modalities of the clinical studies, including length of observation, severity of disturbance, and methodology of evaluation of the results were also heterogeneous. In spite of uncertainties about its efficacy due to these complexities, CDP-choline is a frequently prescribed drug for cognitive impairment in several European countries, especially when the clinical picture is predominantly one of cerebrovascular disease, hence the need for this review. Due to its effects on the adrenergic and dopaminergic activity of the CNS, CDP-choline has also been used as an adjuvant in the treatment of Parkinson's disease. OBJECTIVES: To assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and behavioural deficits associated with chronic cerebral disorders in the elderly. SEARCH STRATEGY: The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 22 April 2004 using the terms CDP-choline, CDP, citicoline, cytidine diphosphate choline or diphosphocholine. The Register contains records from all major health-care databases and many ongoing trials databases and is updated regularly. SELECTION CRITERIA: All relevant unconfounded, double-blind, placebo-controlled, randomized trials of CDP-choline for cognitive impairment due to chronic cerebral disorders were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed the included studies, extracted the data, and pooled it when appropriate and possible. The pooled odd ratios (95% Confidence Interval (CI)) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the studies included. MAIN RESULTS: Fourteen studies were included in this review. Some of the included studies did not present numerical data suitable for analysis. Description of participants varied over the years and by type of disorders and severity, and ranged from aged individuals with subjective memory disorders to patients with Vascular Cognitive Impairment (mild to moderate), Vascular Dementia or Senile Dementia (mild to moderate). Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, four studies used periods extending over 2 and 3 months, one study observed continuous administration over 3 months and one study was prolonged, with 12 months of observation. The studies were heterogeneous in dose, modalities of administration, inclusion criteria for subjects, and outcome measures. Results were reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There was no evidence of a beneficial effect of CDP-choline on attention. There was evidence of benefit of CDP-choline on memory function and behaviour. The drug was well tolerated. AUTHORS' CONCLUSIONS: There was some evidence that CDP-choline has a positive effect on memory and behaviour in at least the short to medium term. The evidence of benefit from global impression was stronger, but is still limited by the duration of the studies. Further research with CDP-choline should focus on longer term studies in subjects who have been diagnosed with currently accepted standardised criteria, especially Vascular Mild Cognitive Impairment (VaMCI) or vascular dementia.

Aged↗
PubMed1992

A choline transporter in renal brush-border membrane vesicles: energetics and structural specificity.

Choline is a quaternary ammonium compound that is normally reabsorbed by the renal proximal tubule, despite its acknowledged role as a substrate for the renal organic cation (OC) secretory pathway. The basis for choline reabsorption was examined in studies of transport in rabbit renal brush-border membrane vesicles (BBMV). Although an outwardly directed H+ gradient (pH 6.0in: 7.5out) stimulated uptake of tetraethylammonium (TEA), a model substrate of the OC/H+ exchanger in renal BBMV, it had no effect on uptake of 1 microM choline. A 5 mM trans concentration gradient of choline did, however, drive countertransport of both TEA and choline, although trans TEA had no effect on choline accumulation in BBMV. A 20 mM concentration of unlabeled choline blocked uptake of both choline and TEA by greater than 85%, whereas 20 mM TEA blocked only TEA uptake. The kinetics of choline uptake into vesicles preloaded with 1 mM unlabeled choline appeared to involve two, saturable transport processes, one of high affinity for choline (Kt of 97 microM) and a second of low affinity (Kt of approximately 10 mM), the latter presumably reflecting a weak interaction of choline with the OC/H+ exchanger. An inside-negative electrical PD stimulated the rate of uptake and supported the transient concentrative accumulation of choline in BBMV. The high affinity transporter showed a marked specificity for choline and closely related analogues. A model of the molecular determinants of substrate-transporter interaction is described. We conclude that the electrogenic high affinity pathway plays a central role in renal reabsorption of choline.

Animals↗