Review at The Medical Dictionary Abstract 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 Alzheimers 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.Altern Med Rev 2.Introduction Citicoline is a complex organic molecule Figure 1 that functions as an intermediate in the biosynthesis of cell membrane phospholipids.Citicoline is also known as CDP choline and cytidine diphosphate choline cytidine 5 diphosphocholine.CDP choline belongs to the group of biomolecules in living systems known as nucleotides that play important roles in cellular metabolism.Optic Nerve Treatment Trial Results Oregon' title='Optic Nerve Treatment Trial Results Oregon' />Nabil Altememi, M.D.Dr. Nabil Altememi received his M.D.Virginia Commonwealth University School of Medicine in Richmond, VA in 2009.The basic structure of a nucleotide contains ribose with a nitrogenous base and a phosphate group.CDP choline is composed of ribose, pyrophosphate, cytosine a nitrogenous base, and choline.Grouped with the B vitamins, choline is a trimethylated nitrogenous base that enters three major metabolic pathways 1 phospholipid synthesis via phosphorylcholine 2 acetylcholine synthesis and 3 oxidation to betaine, which serves as a methyl donor.Endogenously, formation of citicoline is the rate limiting step in the synthesis of phosphatidylcholine, a key membrane phospholipid, from choline.Exogenous citicoline, which is hydrolyzed in the small intestine and readily absorbed as choline and cytidine, enters the various biosynthetic pathways that utilize citicoline as an intermediate.Citicoline thus has a sparing effect on systemic choline reserves, as well as inhibiting the breakdown of membrane phospholipids.Citicoline is produced from choline chloride and orotic acid by an enzymatic process.Freebase citicoline is the form marketed as a dietary supplement in the United States and as a drug in Japan.The sodium salt of citicoline, the form used in clinical trials, is sold as a drug in Europe.Pharmacokinetics and Metabolism Citicoline is a water soluble compound with greater than 9.Pharmacokinetic studies on healthy adults have shown oral doses of citicoline are rapidly absorbed, with less than one percent excreted in feces.Plasma levels peak in a biphasic manner, at one hour after ingestion followed by a second larger peak at 2.Citicoline is metabolized in the gut wall and liver.The byproducts of exogenous citicoline formed by hydrolysis in the intestinal wall are choline and cytidine.Following absorption, choline and cytidine are dispersed throughout the body, enter systemic circulation for utilization in various biosynthetic pathways, and cross the blood brain barrier for re synthesis into citicoline in the brain.Pharmacokinetic studies using sup.C citicoline show citicoline elimination occurs mainly via respiratory CO.The initial peak in plasma concentration is followed by a sharp decline, which then slows over the next 4 1.In the second phase, an initially rapid decline after the 2.The elimination half life is 5.CO.Endogenous citicoline serves as an intermediate in the biosynthesis of phospholipids, including phosphatidylcholine, the pmnary phospholipid in cell membranes.Cytidine a major component of RNA, undergoes cytoplasmic conversion to cytidine triphosphate CTP.In the citicoline metabolic pathway, choline is phosphorylated by the enzyme choline kinase the resulting phosphorylcholine combines with CTP to form citicoline.Citicoline then combines with diacylglycerol DAG, forming phosphatidylcholine, with choline phosphotransferase serving as the enzyme catalyst in this reaction.Oral administration of citicoline raises plasma levels of cytidine and choline in rats within six to eight hours.Prolonged administration for 4.Evidence for the role of these metabolites as substrates for phosphatidylcholine synthesis was found in a study giving rats daily oral doses of citicoline for 9.At a dose of 5. Deep Well Pump Installation Guide . Administration of citicoline to aged rats activates CTP phosphocholine cytidylyl transferase, the rate limiting enzyme in the citicoline pathway of phosphatidylcholine synthesis in the brain cell membrane.Choline and cytidine are the major metabolites released via hydrolysis of citicoline during absorption.A single oral dose of citicoline raises plasma choline levels in both younger and older subjects.Using protein magnetic resonance spectroscopy, it was found that brain choline levels in older subjects decreased after citicoline administration, but increased in younger subjects.The postulated explanation is that the cytidine moiety of citicoline may be taken up by brain cells in older adults more rapidly than choline.Based on this finding, it is suggested that cytidine is the citicoline component primarily responsible for stimulating phosphatidylcholine synthesis in older subjects.Using protein decoupled phosphorus magnetic resonance spectroscopy, it has been shown that citicoline administration to older subjects for six weeks increases brain levels of phosphodiesters, byproducts of phospholipid metabolism.This is seen as evidence that citicoline increases phospholipid synthesis and turnover, which may help reverse cognitive functional deficits associated with aging.In clinical trials, citicoline has been administered orally and by intramuscular injection.Mechanisms of Action Phospholipid Precursor The pharmacological action of citicoline appears to involve mechanisms that extend beyond phospholipid metabolism.Citicoline metabolites choline, methionine, betaine, and cytidine derived nucleotides enter a number of metabolic pathways.Evidence of citicolines role as a phosphatidylcholine precursor has been found in animal studies.Biochemical markers of cholinergic nerve transmission are known to be deficient in conditions characterized by degeneration of cholinergic neurons, such as Alzheimers disease AD.Citicoline modestly improves cognitive function in AD by serving as an acetylcholine precursor.The brain uses choline preferentially for acetylcholine synthesis, which can limit the amount of choline available for phosphatidylcholine production.When the demand for acetylcholine increases or choline stores in the brain are low, phospholipids in the neuronal membrane may be catabolized to supply the needed choline.Exogenous citicoline may thus help preserve the structural and functional integrity of the neuronal membrane.Defense Devil Vol 3 Cap 23 Es Numero .In an in vitro study, citicoline at high concentrations stimulated brain acetylcholinesterase ACh.E, along with NaK ATPase.The postulated mechanism involves bioconversion of citicoline to phosphatidylcholine in the external leaflet of the neuronal membrane, the site of ACh.E activity.
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