Research Notes: Choline

J Am Coll Nutr. 2004 Dec.
Nutritional importance of choline for brain development.
Zeisel SH.
Department of Nutrition, School of Public Health, The University of North Carolina, Chapel Hill, NC, USA.

Choline is a dietary component essential for normal function of all cells. In 1998 the National Academy of Sciences, USA, issued a report identifying choline as a required nutrient for humans and recommended daily intake amounts. In ongoing studies we are finding that men have a higher requirement than do postmenopausal women, who in turn need more than premenopausal women. Pregnancy and lactation are periods when maternal reserves of choline are depleted. At the same time, the availability of choline for normal development of brain is critical. When rat pups received choline supplements (in utero or during the second week of life), their brain function is changed, resulting in lifelong memory enhancement. This change in memory function appears to be due to changes in the development of the memory center (hippocampus) in brain. These changes are so important that investigators can pick out the groups of animals whose mothers had extra choline even when these animals are elderly. Thus, memory function in the aged is, in part, determined by what mother ate. Foods highest in total choline concentrations per 100 g were beef liver (418 mg), chicken liver (290 mg), and eggs (251 mg). We suggest that choline-rich foods are an important component of the diet and that especially during pregnancy it would be prudent to include them as part of a healthy diet.

Fundam Clin Pharmacol. 2004 Oct.
CDP-choline increases plasma ACTH and potentiates the stimulated release of GH, TSH and LH: the cholinergic involvement.
Cavun S, Savci V.
Department of Pharmacology and Clinical Pharmacology, Uludag University Medical Faculty, 16059 Bursa, Turkey.

In the present study, we investigated the effect of intracerebroventricular (i.c.v.) administration of cytidine-5'-diphosphate (CDP) choline on plasma adrenocorticotropin (ACTH), serum growth hormone (GH), thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels in conscious rats. The involvement of cholinergic mechanisms in these effects was also determined. In basal conditions, CDP-choline (0.5, 1.0 and 2.0 micromol, i.c.v.) increased plasma ACTH levels dose- and time-dependently, but it did not affect the TSH, GH, FSH and LH levels. In stimulated conditions, i.c.v. administration of CDP-choline (1 micromol, i.c.v.) produced an increase in clonidine-stimulated GH, thyrotyropin-releasing hormone (TRH)-stimulated TSH, LH-releasing hormone (LHRH)-stimulated LH, but not FSH levels. Injection of equimolar dose of choline (1 micromol, i.c.v.) produced similar effects on hormone levels, but cytidine (1 micromol, i.c.v.) failed to alter plasma levels of these hormones. Pretreatment with hemicholinium-3, a neuronal high affinity choline uptake inhibitor, (20 microg, i.c.v.) completely blocked the observed hormone responses to CDP-choline. The increase in plasma ACTH levels induced by CDP-choline (1 micromol, i.c.v.) was abolished by pretreatment with mecamylamine, a nicotinic receptor antagonist, (50 microg, i.c.v.) but not atropine, a muscarinic receptor antagonist, (10 microg, i.c.v.). The increase in stimulated levels of serum TSH by CDP-choline (1 micromol, i.c.v.) was blocked by atropine but not by mecamylamine pretreatment. However, CDP-choline induced increases in serum GH and LH levels were greatly attenuated by both atropine and mecamylamine pretreatments. The results show that CDP-choline can increase plasma ACTH and produce additional increases in serum levels of TSH, GH and LH stimulated by TRH, clonidine and LHRH, respectively. The activation of central cholinergic system, mainly through the presynaptic mechanisms, was involved in these effects. Central nicotinic receptors solely mediated the increase in plasma ACTH levels while the activation of central muscarinic receptors was involved in the increase in TSH levels. Both muscarinic and nicotinic receptor activations, separately, mediated the increases in serum GH and LH levels after CDP-choline.

Ann N Y Acad Sci. 2004 Jun.
Chronic treatment with a precursor of cellular phosphatidylcholine ameliorates morphological and behavioral effects of aging in the mouse hippocampus.
Crespo D, Megias M, Fernandez-Viadero C, Verduga R.
Department of Anatomy and Cell Biology, Faculty of Medicine, University of Cantabria, Santander, Spain.

Normal aging is commonly associated with a decline in memory, mainly for that related with newly acquired information. The hippocampal formation (HF) is a brain region that has been implicated in this dysfunction. Within the HF there are several cellular types, such as pyramidal cells, granule neurons of the dentate gyrus, and astrocytes. CDP-choline is a well-known intermediate in the biosynthesis of phosphatidylcholine, a phospholipid essential for neuronal membrane preservation and function; thus, this compound would attenuate the process of neuronal aging. To test this, three groups of male mice were used in this study. An adult 12-month-old group (ACG), a 24-month-old (OCG), and an old experimental group (OEG) were administered orally a solution of CDP-choline (150 mg/kg per day) from 12 up to 24 months. Experimental observations suggest that CDP-choline has a positive effect on memory (reference errors were attenuated), and hippocampal morphology resembled that of younger animals.

Altern Med Rev. 2004 Mar.
Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature.
Conant R, Schauss AG.
Technical and Regulatory Affairs, Life Sciences Division, American Institute for Biosocial and Medical Research, Inc. (AIBMR), Puyallup, WA, USA.
[ Free full text ]

Citicoline (CDP-choline; cytidine 5'-diphosphocholine), a form of the essential nutrient choline, shows promise of clinical efficacy in elderly patients with cognitive deficits, inefficient memory, and early-stage Alzheimer's disease. Citicoline has also been investigated as a therapy in stroke patients, although the results of trials to date are inconclusive. Produced endogenously, citicoline serves as a choline donor in the metabolic pathways for biosynthesis of acetylcholine and neuronal membrane phospholipids, chiefly phosphatidylcholine. The principal components of citicoline, choline and cytidine, are readily absorbed in the GI tract and easily cross the blood-brain barrier. Exogenous citicoline, as the sodium salt, has been researched in animal experiments and human clinical trials that provide evidence of its cholinergic and neuroprotective actions. As a dietary supplement, citicoline appears useful for improving both the structural integrity and functionality of the neuronal membrane that may assist in membrane repair. This review, while not intended to be exhaustive, highlights the published, peer-reviewed research on citicoline with brief discussions on toxicology and safety, mechanisms of action, and pharmacokinetics.

J Am Coll Nutr. 2000 Oct.
Choline: needed for normal development of memory.
Zeisel SH.
Department of Nutrition, School of Public Health, University of North Carolina at Chapel Hill, USA.
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Choline is a dietary component essential for normal function of all cells. It, or its metabolites, assures the structural integrity and signaling functions of cell membranes; it is the major source of methyl-groups in the diet (one of choline's metabolites, betaine, participates in the methylation of homocysteine to form methionine); and it directly affects nerve signaling, cell signaling and lipid transport/metabolism. In 1998, the National Academy of Sciences, USA, issued a report identifying choline as a required nutrient for humans and recommended daily intake amounts. Eggs are an excellent dietary source of choline. Pregnancy and lactation are periods when maternal reserves of choline are depleted. At the same time, the availability of choline for normal development of the brain is critical. When rat pups received choline supplements (in utero or during the second week of life), their brain function changed, resulting in the lifelong memory enhancement. This change in memory function appears to be due to changes in the development of the memory center (hippocampus) in the brain. The mother's dietary choline during a critical period in brain development of her infant influences the rate of birth and death of nerve cells in this center. These changes are so important that we can pick out the groups of animals whose mothers had extra choline even when these animals are elderly. Thus, memory function in the aged rat is, in part, determined by what the mother ate. This is not the first example of a critical nutrient that must be present at a specific time in brain development. If folate isn't available in the first few weeks of pregnancy, the brain does not form normally. Thus, we suggest that pregnancy is a period when special attention has to be paid to dietary intake.

Excerpt from the full text article:

Introduction

The Institute of Medicine (IOM) of the US National Academy of Sciences recently made recommendations for dietary choline requirements. Choline in the diet is important for many reasons: it is needed for synthesis of the phospholipids in cell membranes, methyl metabolism, cholinergic neurotransmission, transmembrane signaling, and lipid-cholesterol transport and metabolism. Most choline in the body is found in phospholipids such as phosphatidylcholine and sphingomyelin. Though representing a smaller proportion of the total choline pool, important metabolites of choline include platelet-activating factor, acetylcholine, choline plasmalogens, lysophosphatidylcholine, phosphocholine, glycerophosphocholine and betaine. There are several comprehensive reviews of the metabolism and functions of choline.

Male humans and many species of animals, including the baboon, fed a choline deficient diet deplete choline stores and develop liver dysfunction. Some humans (male and female) fed with total parenteral nutrition (TPN) solutions devoid of choline, but adequate for methionine and folate, develop fatty liver and liver damage that resolves when a source of dietary choline is provided. Fatty liver occurs because choline is required to make the phosphatidylcholine portion of the very-low-density lipoprotein (VLDL) particle that is needed to export triacylglycerol from the liver. Animals fed a choline deficient diet may also develop growth retardation, renal dysfunction and hemorrhage, or bone abnormalities [8,18,19]. There is no doubt that cells in culture absolutely require choline and die by programmed cell suicide when deprived of this nutrient. The exact amount of choline that the human diet must contain to sustain life is modulated by the pathway (most active in the liver) for the de novo biosynthesis of the choline moiety via the sequential methylation of phosphatidylethanolamine using S-adenosylmethionine as the methyl donor. This ability to form choline moiety de novo means that some of the demand for choline can, in part, be met by using methyl-groups derived from one carbon metabolism (via methyl-folate and methionine). Because of this metabolic interrelationship, choline deficiency depletes cells of methyl-folate and methionine, and increases intracellular S-adenosylhomocysteine and homocysteine concentrations. As our understanding of the importance of folate and homocysteine nutrition increases, there should be increased interest in how choline interacts with folate and homocysteine metabolism.

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Almost no information is available about the choline content of foods. Eggs have an especially high choline moiety content (about 300 mg choline/egg, mostly in the form of phosphatidylcholine). Both commercially available infant formulas and bovine milk contain choline and choline-containing compounds. Plasma choline concentration varies in response to diet and can rise as much as two-fold after a two-egg meal. Fasting plasma choline concentrations vary from 7 to 20 µM, with most subjects having concentrations of 10 µM. Individuals that have starved for up to seven days have diminished plasma choline, but levels never drop below approximately 50% of normal.

Pregnancy may be a time when dietary supplies of choline are especially limiting. Though female rats are resistant to choline deficiency, pregnant rats are as vulnerable to deficiency as are males. During pregnancy, large amounts of choline are delivered to the fetus across the placenta, and this depletes maternal stores of choline. At birth, humans and other mammals have plasma choline concentrations that are much higher than those in adults. The need for choline is likely to be increased during lactation because so much must be secreted into milk (human milk contains 1.5 to 2 mM choline moiety per liter). Lactating rats are more sensitive to choline deficiency than are non-lactating rats.

Ensured availability of choline appears to be important to infants because organ growth - extremely rapid in the neonate - requires large amounts of choline for membrane biosynthesis. During development, there is a progressive decline in blood choline concentration that begins in utero. In fact, plasma or serum choline concentrations are sevenfold higher in the fetus and neonate than they are in the adult. This decline in serum choline concentration occurs during the first weeks of life in the rat and the human. High levels of choline circulating in the fetus presumably ensure enhanced availability of choline to tissues. Neonatal rat brain efficiently extracts choline from blood. Supplementing choline during the perinatal period further increases blood and brain choline metabolite concentrations.

An interesting effect of dietary choline deficiency in rats has never been studied in humans. Choline availability during embryogenesis and perinatal development of the rat and mouse may be especially important. There are two sensitive periods in rodent brain development during which treatment with choline (about 1 mmol/day) produces long-lasting enhancement of spatial memory that is lifelong. The first occurs during embryonic days 12 to 17 (rats give birth on day 21), and the second during postnatal days 16 to 30. Choline supplementation during these critical periods elicits a major improvement in memory performance at all stages of training on a 12-arm radial maze. Though all animals were cross-fostered with untreated mothers, even when the rats are old these memory changes persist and can be used to easily identify which rats got more or less choline during the perinatal period; the normal age-associated decrement that occurs in rat memory seems to be delayed in the choline supplemented group (Warren Meck, personal communication). Pups from mothers fed a choline deficient diet during this same period of pregnancy have diminished memory function. During embryogenesis, progenitors of neurons and glia divide, many migrate to new locations, and unnecessary cells die by apoptosis. These early developmental events determine the future structure and function of the brain. The choline-induced spatial memory facilitation correlates with changes in the birth, death and migration of cells in the hippocampus during fetal brain development, with altered distribution and morphology of neurons involved in memory storage within the brain, with biochemical changes in the hippocampus and with electrophysiological changes in the hippocampus. Are these findings in rats likely to be true of humans? We do not know. Human and rat brains mature at different rates; the rat brain is comparatively more mature at birth than is the human brain, but in humans hippocampal development may continue for months or years after birth. A controlled human study is needed, but until then it seems prudent to ensure that dietary intake of choline is adequate during pregnancy. Two eggs per day contain approximately the dietary requirement for choline, and until more foods are analyzed for choline content, pregnant women might want to include eggs in their diets.

Life Sci. 1996.
Effects of dietary phosphatidylcholine on memory in memory deficient mice with low brain acetylcholine concentration.
Moriyama T, Uezu K, Matsumoto Y, Chung SY, Uezu E, Miyagi S, Uza M, Masuda Y, Kokubu T, Tanaka T, Yamamoto S.
Department of Biochemistry, University of the Ryukyus, Okinawa, Japan.

Data concerning the effect of phosphatidylcholine (PCh) administration on the improvement of memory in senile dementia of Alzheimer type are inconsistent, probably due to the different conditions under which studies were conducted. Animal studies provide a good model, but data on this is limited. We studied the effect of PCh on memory in memory deficient mice (Dull mice) with low brain acetylcholine (ACh) concentration and normal mice. Mice were fed 24% casein diet (control) or this diet supplemented with 2 or 8% egg yolk PCh from gestation (Experiment 1) and after weaning (Experiment 2). Memory acquisition and retention were studied by step-down type passive avoidance performance at 8 and 10 weeks old, respectively. Control group of Dull mice had poorer memories than that of the normal mice in Experiments 1 and 2. On the 2% PCh diet, Dull mice improved memory acquisition and retention in Experiment 1 and retention in Experiment 2. On the 8% PCh diet in Dull mice there was improvement of memory and retention in Experiment 1, but no effect was observed in Experiment 2 (P > 0.05). In the normal mice, the 2% PCh diet did not affect memory acquisition and retention, however on the 8% PCh diet, there was no or adverse effect. These results suggest that dietary supplementation of egg yolk PCh improves memory of Dull mice, particularly when given from gestation and that the 2% PCh diet elicits better response than the 8% PCh diet.

Methods Find Exp Clin Pharmacol. 1995 Oct.
CDP-choline: pharmacological and clinical review.
Secades JJ, Frontera G.
F.I.S.A. Medical Department, Barcelona.

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.