Misplaced Pages

#301698

57-405: Citicoline is available as a supplement in over 70 countries under a variety of brand names: CereBleu, Cebroton, Ceraxon, Cidilin, Citifar, Cognizin, Difosfocin, Hipercol, NeurAxon, Nicholin, Sinkron, Somazina, Synapsine, Startonyl, Trausan, Xerenoos, etc. When taken as a supplement, citicoline is hydrolyzed into choline and cytidine in the intestine . Once these cross the blood–brain barrier it

114-590: A tissue extract or dead organism. This is not to be confused with experiments done in vitro ("within the glass"), i.e., in a laboratory environment using test tubes , Petri dishes , etc. Examples of investigations in vivo include: the pathogenesis of disease by comparing the effects of bacterial infection with the effects of purified bacterial toxins ; the development of non-antibiotics, antiviral drugs, and new drugs generally; and new surgical procedures. Consequently, animal testing and clinical trials are major elements of in vivo research. In vivo testing

171-437: A major impact on studies of the pathogenesis of infectious disease. The maxim in vivo veritas ("in a living thing [there is] truth") is a play on in vino veritas , ("in wine [there is] truth"), a well-known proverb. In microbiology , in vivo is often used to refer to experimentation done in a whole organism , rather than in live isolated cells , for example, cultured cells derived from biopsies . In this situation,

228-486: A precursor for other essential cell components and signaling molecules, such as phospholipids that form cell membranes, the neurotransmitter acetylcholine, and the osmoregulator trimethylglycine ( betaine ). Trimethylglycine in turn serves as a source of methyl groups by participating in the biosynthesis of S -adenosylmethionine . Choline is transformed to diverse phospholipids, like phosphatidylcholines and sphingomyelins. These are found in all cell membranes and

285-419: A result of rapid catabolism in the liver). The English microbiologist Professor Harry Smith and his colleagues in the mid-1950s found that sterile filtrates of serum from animals infected with Bacillus anthracis were lethal for other animals, whereas extracts of culture fluid from the same organism grown in vitro were not. This discovery of anthrax toxin through the use of in vivo experiments had

342-679: A side product. In humans and most other animals, de novo synthesis of choline proceeds via the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, but biosynthesis is not enough to meet human requirements. In the hepatic PEMT route, 3-phosphoglycerate (3PG) receives 2 acyl groups from acyl-CoA forming a phosphatidic acid . It reacts with cytidine triphosphate to form cytidine diphosphate-diacylglycerol. Its hydroxyl group reacts with serine to form phosphatidylserine which decarboxylates to ethanolamine and phosphatidylethanolamine (PE) forms. A PEMT enzyme moves three methyl groups from three S -adenosyl methionines (SAM) donors to

399-669: A single smooth exponential decrease over time. However, the elimination half-life for citicholine has been reported as approximately 50 hours for citicholine removed via respiration and approximately 70 hours for citicholine removed via urine. Plasma levels of choline peak about four hours after ingestion. Citicoline has a very low toxicity profile in animals and humans. Clinically, doses of 2000 mg per day have been observed and approved. Minor transient adverse effects are rare and most commonly include stomach pain and diarrhea. A 2020 study reported that concerns had emerged that chronic citicoline use may have adverse psychiatric effects, however,

456-441: Is hygroscopic and thus often encountered as a colorless viscous hydrated syrup that smells of trimethylamine (TMA). Aqueous solutions of choline are stable, but the compound slowly breaks down to ethylene glycol , polyethylene glycols , and TMA. Choline chloride can be made by treating TMA with 2-chloroethanol : Choline has historically been produced from natural sources, such as via hydrolysis of lecithin . Choline

513-452: Is oxidized irreversibly in liver mitochondria to glycine betaine aldehyde by choline oxidases . This is oxidized by mitochondrial or cytosolic betaine-aldehyde dehydrogenases to trimethylglycine. Trimethylglycine is a necessary osmoregulator. It also works as a substrate for the BHMT -enzyme, which methylates homocysteine to methionine . This is a S -adenosylmethionine (SAM) precursor. SAM

570-459: Is 550 mg for adults and children age 4 years and older. The FDA does not require food labels to list choline content unless choline has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet. The U.S. Department of Agriculture's (USDA's) FoodData Central lists

627-454: Is 7–20  micromoles per liter (μmol/L) and 10 μmol/L on average. Levels are regulated, but choline intake and deficiency alters these levels. Levels are elevated for about 3 hours after choline consumption. Phosphatidylcholine levels in the plasma of fasting adults is 1.5–2.5 mmol/L. Its consumption elevates the free choline levels for about 8–12 hours, but does not affect phosphatidylcholine levels significantly. Choline

SECTION 10

#1733092274302

684-428: Is a cation with the chemical formula [(CH 3 ) 3 NCH 2 CH 2 OH] . Choline forms various salts , such as choline chloride and choline bitartrate . It is an essential nutrient for humans and many other animals, and is a structural part of phospholipids and cell membranes . Choline is used to synthesize acetylcholine , a neurotransmitter involved in muscle control and numerous functions of

741-429: Is a common reagent in biological methylation reactions. For example, it methylates guanidines of DNA and certain lysines of histones . Thus it is part of gene expression and epigenetic regulation . Choline deficiency thus leads to elevated homocysteine levels and decreased SAM levels in blood. Choline occurs in foods as a free cation and in the form of phospholipids, especially as phosphatidylcholines. Choline

798-421: Is a water-soluble ion and thus requires transporters to pass through fat-soluble cell membranes . Three types of choline transporters are known: SLC5A7s are sodium - (Na ) and ATP-dependent transporters. They have high binding affinity for choline, transport it primarily to neurons and are indirectly associated with the acetylcholine production. Their deficient function causes hereditary weakness in

855-501: Is associated with an increased risk of neural tube defects . Higher maternal intake of choline is likely associated with better neurocognition/neurodevelopment in children. Choline and folate, interacting with vitamin B 12 , act as methyl donors to homocysteine to form methionine, which can then go on to form SAM ( S -adenosylmethionine). SAM is the substrate for almost all methylation reactions in mammals. It has been suggested that disturbed methylation via SAM could be responsible for

912-410: Is catalyzed by a serine decarboxylase . The synthesis of choline from ethanolamine may take place in three parallel pathways, where three consecutive N -methylation steps catalyzed by a methyl transferase are carried out on either the free-base, phospho-bases, or phosphatidyl-bases. The source of the methyl group is S -adenosyl- L -methionine and S -adenosyl- L -homocysteine is generated as

969-405: Is due to trimethylamine (TMA) formed by the gut microbes from the unabsorbed choline (see trimethylaminuria ). The liver oxidizes TMA to trimethylamine N -oxide (TMAO). Elevated levels of TMA and TMAO in the body have been linked to increased risk of atherosclerosis and mortality. Thus, excessive choline intake has been hypothetized to increase these risks in addition to carnitine , which also

1026-417: Is excreted into urine in humans. Excretion happens via transporters that occur within kidneys (see transport ). Trimethylglycine is demethylated in the liver and kidneys to dimethylglycine ( tetrahydrofolate receives one of the methyl groups). Methylglycine forms, is excreted into urine, or is demethylated to glycine . Choline and its derivatives have many biological functions. Notably choline serves as

1083-702: Is formed into TMA and TMAO by gut bacteria. However, choline intake has not been shown to increase the risk of dying from cardiovascular diseases . It is plausible that elevated TMA and TMAO levels are just a symptom of other underlying illnesses or genetic factors that predispose individuals for increased mortality. Such factors may have not been properly accounted for in certain studies observing TMA and TMAO level related mortality. Causality may be reverse or confounding and large choline intake might not increase mortality in humans. For example, kidney dysfunction predisposes for cardiovascular diseases, but can also decrease TMA and TMAO excretion. Low maternal intake of choline

1140-526: Is highest in organ meats and egg yolks though it is found to a lesser degree in non-organ meats, grains, vegetables, fruit and dairy products . Cooking oils and other food fats have about 5 mg/100 g of total choline. In the United States, food labels express the amount of choline in a serving as a percentage of Daily Value (%DV) based on the Adequate Intake of 550 mg/day. 100% of

1197-429: Is often employed over in vitro because it is better suited for observing the overall effects of an experiment on a living subject. In drug discovery , for example, verification of efficacy in vivo is crucial, because in vitro assays can sometimes yield misleading results with drug candidate molecules that are irrelevant in vivo (e.g., because such molecules cannot reach their site of in vivo action, for example as

SECTION 20

#1733092274302

1254-415: Is present in breast milk and is commonly added as an ingredient to baby foods . Choline is a quaternary ammonium cation . The cholines are a family of water-soluble quaternary ammonium compounds . Choline is the parent compound of the cholines class, consisting of ethanolamine residue having three methyl groups attached to the same nitrogen atom. Choline hydroxide is known as choline base. It

1311-1328: Is reformed into citicoline by the rate-limiting enzyme in phosphatidylcholine synthesis, CTP-phosphocholine cytidylyltransferase . Studies suggest, but have not confirmed, potential benefits of citicoline for cognitive impairments. Some preliminary research suggested that citicoline may reduce the rates of death and disability following an ischemic stroke . However, the largest citicoline clinical trial to date (a randomised, placebo-controlled, sequential trial of 2,298 patients with moderate-to-severe acute ischaemic stroke in Europe), found no benefit of administering citicoline on survival or recovery from stroke. A meta-analysis of seven trials reported no statistically significant benefit for long-term survival or recovery. The effect of citicoline on visual function has been studied in patients with glaucoma , with possible positive effect for protecting vision. Citicoline may have neuroprotective effects due to its preservation of cardiolipin and sphingomyelin , preservation of arachidonic acid content of phosphatidylcholine and phosphatidylethanolamine , partial restoration of phosphatidylcholine levels, and stimulation of glutathione synthesis and glutathione reductase activity. Citicoline's effects may also be explained by

1368-504: Is suggested that the neuroprotective effects of citicoline after a stroke are due in part to citicoline's ability to decrease levels of glutamate in the brain. Citicoline is water-soluble, with more than 90% oral bioavailability . Plasma levels of citicholine peak one hour after oral ingestion, and a majority of the citicoline is excreted as CO 2 in respiration with the remaining citicoline being excreted through urine . The pharmacokinetic profile of citicholine cannot be described by

1425-441: Is suspected to be due to deficiency of choline derived trimethylglycine, which functions as an osmoregulator. Estrogen production is a relevant factor which predisposes individuals to deficiency along with low dietary choline intake. Estrogens activate phosphatidylcholine producing PEMT enzymes. Women before menopause have lower dietary need for choline than men due to women's higher estrogen production. Without estrogen therapy ,

1482-436: Is used to create acetylcholine, which is a neurotransmitter in the human brain. Clinical trials have found that citicoline supplementation might improve focus and attention. Citicoline lowers increased glutamate concentrations and raises decreased ATP concentrations induced by ischemia . Citicoline also increases glutamate uptake by increasing expression of EAAT2 , a glutamate transporter , in vitro in rat astrocytes. It

1539-451: Is widespread in living beings. In most animals, choline phospholipids are necessary components in cell membranes , in the membranes of cell organelles , and in very low-density lipoproteins . Choline is an essential nutrient for humans and many other animals. Humans are capable of some de novo synthesis of choline but require additional choline in the diet to maintain health. Dietary requirements can be met by choline by itself or in

1596-455: The EU countries . The EFSA has not set any upper limits for intake. Individual EU countries may have more specific recommendations. The National Academy of Medicine (NAM) recommendations apply in the United States, Australia and New Zealand. Twelve surveys undertaken in 9 EU countries between 2000 and 2011 estimated choline intake of adults in these countries to be 269–468 milligrams per day. Intake

1653-431: The intestinal absorption of lipids . Choline is a precursor to acetylcholine , a neurotransmitter that plays a necessary role in muscle contraction , memory and neural development . Nonetheless, there is little acetylcholine in the human body relative to other forms of choline. Neurons also store choline in the form of phospholipids to their cell membranes for the production of acetylcholine. In humans, choline

1710-670: The EU and the US, it is mandatory to add at least 7 mg of choline per 100  kilocalories (kcal) to every infant formula. In the EU, levels above 50 mg/100 kcal are not allowed. Trimethylglycine is a functional metabolite of choline. It substitutes for choline nutritionally, but only partially. High amounts of trimethylglycine occur in wheat bran (1,339 mg/100 g), toasted wheat germ (1,240 mg/100 g) and spinach (600–645 mg/100 g), for example. The following table contains updated sources of choline to reflect

1767-539: The amount of choline available for acetylcholine synthesis and aid in rebuilding membrane phospholipid stores after depletion. Citicoline decreases phospholipase stimulation. This can lower levels of hydroxyl radicals produced after an ischemia and prevent cardiolipin from being catabolized by phospholipase A2 . It can also work to restore cardiolipin levels in the inner mitochondrial membrane . Citicoline may enhance cellular communication by increasing levels of neurotransmitters. The choline component of citicoline

Citicoline - Misplaced Pages Continue

1824-495: The blood side of the barrier, but also on the membranes of astrocytes and neurons. OCT1s and OCT2s are not associated with the acetylcholine production. They transport choline with low affinity. OCT1s transport choline primarily in the liver and kidneys; OCT2s in kidneys and the brain. Choline is stored in the cell membranes and organelles as phospholipids, and inside cells as phosphatidylcholines and glycerophosphocholines. Even at choline doses of 2–8 g, little choline

1881-449: The choline intake to be too low in some US subpopulations. Intake was 315.2–318.8 mg/d in 2+ year olds between this time period. Out of 2+ year olds, only 15.6 ± 0.8 % of males and 6.1 ± 0.6 % of females exceeded the adequate intake (AI). AI was exceeded by 62.9 ± 3.1 % of 2- to 3-year-olds, 45.4 ± 1.6 % of 4- to 8-year-olds, 9.0 ± 1.0 % of 9- to 13-year-olds, 1.8 ± 0.4 % of 14–18 and 6.6 ± 0.5 % of 19+ year olds. Upper intake level

1938-455: The choline needs of post-menopausal women are similar to men's. Some single-nucleotide polymorphisms (genetic factors) affecting choline and folate metabolism are also relevant. Certain gut microbes also degrade choline more efficiently than others, so they are also relevant. In deficiency, availability of phosphatidylcholines in the liver are decreased – these are needed for formation of VLDLs. Thus VLDL-mediated fatty acid transport out of

1995-511: The daily value means that a serving of food has 550 mg of choline. "Total choline" is defined as the sum of free choline and choline-containing phospholipids, without accounting for mass fraction. Human breast milk is rich in choline. Exclusive breastfeeding corresponds to about 120 mg of choline per day for the baby. Increase in a mother's choline intake raises the choline content of breast milk and low intake decreases it. Infant formulas may or may not contain enough choline. In

2052-432: The diet and are able to biosynthesize limited amounts of it via PEMT . Symptomatic deficiency is often caused by certain diseases or by other indirect causes. Severe deficiency causes muscle damage and non-alcoholic fatty liver disease , which may develop into cirrhosis . Besides humans, fatty liver is also a typical sign of choline deficiency in other animals. Bleeding in the kidneys can also occur in some species. This

2109-559: The dietary need for choline. In rodents, 70% of phosphatidylcholines are formed via the PEMT route and only 30% via the CDP-choline route. In knockout mice , PEMT inactivation makes them completely dependent on dietary choline. In humans, choline is absorbed from the intestines via the SLC44A1 (CTL1) membrane protein via facilitated diffusion governed by the choline concentration gradient and

2166-513: The electrical potential across the enterocyte membranes. SLC44A1 has limited ability to transport choline: at high concentrations part of it is left unabsorbed. Absorbed choline leaves the enterocytes via the portal vein , passes the liver and enters systemic circulation . Gut microbes degrade the unabsorbed choline to trimethylamine, which is oxidized in the liver to trimethylamine N -oxide . Phosphocholine and glycerophosphocholines are hydrolyzed via phospholipases to choline, which enters

2223-937: The ethanolamine group of the phosphatidylethanolamine to form choline in the form of a phosphatidylcholine. Three S -adenosylhomocysteines (SAHs) are formed as a byproduct. Choline can also be released from more complex precursors. For example, phosphatidylcholines (PC) can be hydrolyzed to choline (Chol) in most cell types. Choline can also be produced by the CDP-choline route, cytosolic choline kinases (CK) phosphorylate choline with ATP to phosphocholine (PChol). This happens in some cell types like liver and kidney. Choline-phosphate cytidylyltransferases (CPCT) transform PChol to CDP-choline (CDP-Chol) with cytidine triphosphate (CTP). CDP-choline and diglyceride are transformed to PC by diacylglycerol cholinephosphotransferase (CPT). In humans, certain PEMT-enzyme mutations and estrogen deficiency (often due to menopause ) increase

2280-699: The form of choline phospholipids , such as phosphatidylcholine . Choline is not formally classified as a vitamin despite being an essential nutrient with an amino acid –like structure and metabolism. Choline is required to produce acetylcholine – a neurotransmitter – and S -adenosylmethionine (SAM), a universal methyl donor. Upon methylation SAM is transformed into S-adenosyl homocysteine . Symptomatic choline deficiency causes non-alcoholic fatty liver disease and muscle damage. Excessive consumption of choline (greater than 7.5 grams per day) can cause low blood pressure , sweating , diarrhea , and fish-like body smell due to trimethylamine , which forms in

2337-706: The liver decreases leading to fat accumulation in the liver. Other simultaneously occurring mechanisms explaining the observed liver damage have also been suggested. For example, choline phospholipids are also needed in mitochondrial membranes. Their unavailability leads to the inability of mitochondrial membranes to maintain proper electrochemical gradient , which, among other things, is needed for degrading fatty acids via β-oxidation . Fat metabolism within liver therefore decreases. Excessive doses of choline can have adverse effects. Daily 8–20 g doses of choline, for example, have been found to cause low blood pressure , nausea , diarrhea and fish-like body odor . The odor

Citicoline - Misplaced Pages Continue

2394-429: The membranes of most cell organelles. Phosphatidylcholines are structurally important part of the cell membranes. In humans, 40–50% of their phospholipids are phosphatidylcholines. Choline phospholipids also form lipid rafts in the cell membranes along with cholesterol . The rafts are centers, for example for cholinergic receptors and receptor signal transduction enzymes. Phosphatidylcholines are needed for

2451-466: The metabolism of choline. Rich dietary sources of choline and choline phospholipids include organ meats , egg yolks , dairy products , peanuts , certain beans , nuts and seeds . Vegetables with pasta and rice also contribute to choline intake in the American diet . In plants, the first step in de novo biosynthesis of choline is the decarboxylation of serine into ethanolamine , which

2508-413: The mitochondria in the tongue, kidneys, muscles and heart. They are associated with the mitochondrial oxidation of choline to trimethylglycine. CTL1s and CTL2s are not associated with the acetylcholine production, but transport choline together via the blood–brain barrier . Only CTL2s occur on the brain side of the barrier. They also remove excess choline from the neurons back to blood. CTL1s occur only on

2565-574: The more specific term is ex vivo . Once cells are disrupted and individual parts are tested or analyzed, this is known as in vitro . According to Christopher Lipinski and Andrew Hopkins, "Whether the aim is to discover drugs or to gain knowledge of biological systems, the nature and properties of a chemical tool cannot be considered independently of the system it is to be tested in. Compounds that bind to isolated recombinant proteins are one thing; chemical tools that can perturb cell function another; and pharmacological agents that can be tolerated by

2622-503: The nervous system. Choline is involved in early development of the brain, gene expression , cell membrane signaling , and brain metabolism. Although humans synthesize choline in the liver , the amount produced naturally is insufficient to meet cellular functions, requiring that some choline be obtained from foods or dietary supplements . Foods rich in choline include meats, poultry, eggs, and other animal-based products, cruciferous vegetables , beans, nuts, and whole grains . Choline

2679-408: The new Daily Value and the new Nutrition Facts and Supplement Facts Labels. It reflects data from the U.S. Department of Agriculture, Agricultural Research Service. FoodData Central, 2019. DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for choline

2736-562: The nutrient content of many foods and provides a comprehensive list of foods containing choline arranged by nutrient content. Insufficient data is available to establish an estimated average requirement (EAR) for choline, so the Food and Nutrition Board established adequate intakes (AIs). For adults, the AI for choline was set at 550 mg/day for men and 425 mg/day for women. These values have been shown to prevent hepatic alteration in men. However,

2793-523: The portal vein. Due to their water solubility, some of them escape unchanged to the portal vein. Fat-soluble choline-containing compounds (phosphatidylcholines and sphingomyelins ) are either hydrolyzed by phospholipases or enter the lymph incorporated into chylomicrons . In humans, choline is transported as a free ion in blood. Choline–containing phospholipids and other substances, like glycerophosphocholines, are transported in blood lipoproteins . Blood plasma choline levels in healthy fasting adults

2850-430: The pulmonary and other muscles in humans via acetylcholine deficiency. In knockout mice , their dysfunction results easily in death with cyanosis and paralysis . CTL1s have moderate affinity for choline and transport it in almost all tissues, including the intestines, liver, kidneys, placenta and mitochondria . CTL1s supply choline for phosphatidylcholine and trimethylglycine production. CTL2s occur especially in

2907-554: The reduction of phospholipase A2 activity. Citicoline increases phosphatidylcholine synthesis. The mechanism for this may be: The brain preferentially uses choline to synthesize acetylcholine . This limits the amount of choline available to synthesize phosphatidylcholine. When the availability of choline is low or the need for acetylcholine increases, phospholipids containing choline can be catabolized from neuronal membranes. These phospholipids include sphingomyelin and phosphatidylcholine . Supplementation with citicoline can increase

SECTION 50

#1733092274302

2964-596: The relation between folate and NTDs. This may also apply to choline. Certain mutations that disturb choline metabolism increase the prevalence of NTDs in newborns, but the role of dietary choline deficiency remains unclear, as of 2015. In vivo Studies that are in vivo ( Latin for "within the living"; often not italicized in English ) are those in which the effects of various biological entities are tested on whole, living organisms or cells , usually animals , including humans , and plants, as opposed to

3021-458: The study used to derive these values did not evaluate whether less choline would be effective, as researchers only compared a choline-free diet to a diet containing 550 mg of choline per day. From this, the AIs for children and adolescents were extrapolated. Recommendations are in milligrams per day (mg/day). The European Food Safety Authority (EFSA) recommendations are general recommendations for

3078-457: The study's meta-analysis of the relevant literature did not support this hypothesis. At most, citicoline may exacerbate psychotic episodes or interact with antipsychotic medication. Phosphatidylcholine is a major phospholipid in eukaryotic cell membranes. Close regulation of its biosynthesis, degradation, and distribution is essential to proper cell function. Phosphatidylcholine is synthesized in vivo by two pathways Choline Choline

3135-591: The synthesis of VLDLs : 70–95% of their phospholipids are phosphatidylcholines in humans. Choline is also needed for the synthesis of pulmonary surfactant , which is a mixture consisting mostly of phosphatidylcholines. The surfactant is responsible for lung elasticity, that is for lung tissue's ability to contract and expand. For example, deficiency of phosphatidylcholines in the lung tissues has been linked to acute respiratory distress syndrome . Phosphatidylcholines are excreted into bile and work together with bile acid salts as surfactants in it, thus helping with

3192-480: Was 269–444 mg/day in adult women and 332–468 mg/day in adult men. Intake was 75–127 mg/day in infants, 151–210 mg/day in 1- to 3-year-olds, 177–304 mg/day in 3- to 10-year-olds and 244–373 mg/day in 10- to 18-year-olds. The total choline intake mean estimate was 336 mg/day in pregnant adolescents and 356 mg/day in pregnant women. A study based on the NHANES 2009–2012 survey estimated

3249-403: Was not exceeded in any subpopulations. A 2013–2014 NHANES study of the US population found the choline intake of 2- to 19-year-olds to be 256 ± 3.8  mg/day and 339 ± 3.9  mg/day in adults 20 and over. Intake was 402 ± 6.1  mg/d in men 20 and over and 278 mg/d in women 20 and over. Symptomatic choline deficiency is rare in humans. Most obtain sufficient amounts of it from

#301698