Uridine and Phosphatidylcholine, Perfect Together

article4-cellsWhether the human body contains ten trillion or a hundred trillion cells makes little difference. It would take several lifetimes to count them. What does matter is how those cells communicate with each other, how they share messages about function, repair and reproduction. The basic unit of structure and function of living things, the cell is the building block of life. The word “cell” means “small room,” a fitting term for a structure that houses an assembly of bodies that direct life processes. Environment, genetics and lifestyle exert a greater influence on a cell’s viability than many people can imagine. To remain healthy, the cell must overcome insults every day. Air and water degradation, tobacco and alcohol use and abuse, and wretched eating habits are major participants in the unremitting assault on cellular equilibrium.

Of the several compounds vital to the cell’s structure and function, phosphatidylcholine, at 50% or more the major constituent of the cell membrane, is deemed paramount. As a circus would be useless without a tent, so would be the cell without its membrane. Phosphatidylcholine, abbreviated as PC, is a ubiquitous, naturally occurring phospholipid composed of a phosphate group, two fatty acids, and choline. Often confused with lecithin, PC verifiably stands alone, while lecithin is a mix of several second-team players that make a perfect emulsifier for mayonnaise but an inferior contributor to cellular integrity and health. PC is responsible for the surfactants critical to lung function and gastrointestinal stability, and is the precursor to the neurotransmitter, acetylcholine, responsible for arousal, learning, memory and motor activity.

PC is one of four phospholipids that comprise the membrane. The others are phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylinositol (PI). Without its membrane, the cell would cease to function altogether—the Krebs cycle would be interrupted and there would be no energy and thus no life. It has been postulated that almost one third of all the genetic output of the human DNA cache is rooted in the membrane (Mouritsen, 2005).

The fluid character of the membrane is provided by essential fatty acids (EFA), both the omega-6 and omega-3 that the body must get from dietary sources. It’s not enough that we supply the proper amount of EFA’s; the ratio is perhaps more important. The proportion of n-6 to n-3 fats has been established as 4:1, as discovered in studies that have examined improvement in quality of life for both the well and the infirm (Yehuda, 1993, 1996) (Simopoulos, 2002, 2004, 2008).

All biological processes—every single one— rely on PC for their unimpeded activity. Information flowing from DNA to RNA to proteins needs PC; the manufacture of cellular energy and intracellular communication or signal transduction demands it. EFA-rich PC fluidizes the cell membrane to allow the smooth passage of vital substances into the cytoplasm and the movement of detritus out. It is well-accepted that some diseases, such as certain cancers, liver disease, neurological disorders and cell death, are related to a decrease in cell membrane fluidization resulting from a deficit of PC (PDR, 2001).

article4-bluegraphicThe shape of the PC molecule is ideal to serve as the basic structural unit of the biological membrane. The kink in the polyunsaturated fatty acid (PUFA) chain affords fluidity that acts to balance the lipids—and cholesterol—that are not members of the bilayer family. Lined up, shoulder-to-shoulder, PC molecules organize themselves into a protective phalanx that guards every cell and every organelle within. PC’s two tails are hydrophobic, face the inside of the cell and directly oppose others of their kind, thus forming an inner and an outer leaf. The hydrophilic head group faces the watery environs of which the body is largely made. The channels, gates and receptors that occupy the membrane help to run the machinery of life. Having both hydrophobic and hydrophilic properties, PC is an amphiphilic molecule. Its arrangement in the cell membrane parallels the structure, activity and function of a liposome.

A liposome is a tiny bubble (a vesicle) made from the same material as the cell membrane. But a liposome can be filled with medications and be used to deliver drugs in the treatment of some diseases, such as cancers. The core of a liposome is almost always aqueous and the circumference always a hydrophobic bilayer.

article4-liposomeHydrophobic substances, including pharmacologically active non-drugs, may be encapsulated by a liposome to increase their water solubility, thereby improving bioavailability and absorption. Liposomal delivery protects the contents from degradation in blood, thus increasing efficacy and reducing the possibility of a toxic event. By manipulating the lipid bilayer, scientists can create a time-released product that targets delivery of the material. A liposome can be made when a legitimate phospholipid, such as phosphatidylcholine (not lecithin) is placed in water and agitated or sonicated to form a bilayer. Low shear rates will form multilamellar liposomes, which resemble the layers of an onion. Sonication is the application of ultra sound to disrupt the stable condition of matter, allowing the lipid perimeter to re-amalgamate around the chosen material. (It works especially well to deactivate bacteria and to clean things, like jewelry, by breaking intermolecular interactions.) Vitamins, antigens, and even monoclonal antibodies may constitute a liposomal core.

One bioactive candidate substance that has garnered attention recently is uridine, a nucleoside component of RNA made from one molecule of uracil and one molecule of D-ribose. Uracil is a pyrimidine that replaces the thymine in DNA to make RNA. Together, pyrimidines and purines make both DNA and RNA. Ribose, or rather D-ribose as found naturally, is a simple sugar (monosaccharide) that forms the backbone of RNA. It’s related to the deoxyribose found in DNA.

article4-dna-strandsWhat’s the difference between DNA and RNA? That’s a good question. Both are nucleic acids, but they differ in that RNA is single-stranded while DNA is double-stranded. In RNA, uracil is an unmethylated form of thymine. It might be easier to view RNA as a carrier of messages and DNA as the owner’s manual for cell replication. There’s more, but that can be saved for another time.

Uridine is the active ingredient of its compounds, some of which may be phosphorylated or acetylated. It’s made by the liver from some foods, notably tomatoes, sugarcane, brewer’s yeast, broccoli and organ meats. Eating foods that are rich in RNA, however, may lead to health concerns because RNA also contains purines, the elements (adenosine and guanosine) responsible for conditions such as gout. But on the bright side—the very bright side—uridine as a supplement, combined with the essential n-3 fatty acids EPA and DHA, has been found to be as effective an antidepressant as commonly prescribed medications, such as Prozac® and other SSRI’s (Carlezon, 2005). Not only is uridine associated with positive mental health outcomes, but also with the resolution of mitochondrial disorders, some of which may be induced by certain medications, particularly those related to treatment of HIV and orotic aciduria, the latter a genetic disorder characterized by retarded growth, macrocytic anemia, and leukopenia, accompanied by urinary excretion of large amounts of orotic acid. (Weinberg, 2011).

In its monophosphate form, uridine is synthesized de novo from glycine, the smallest of the twenty amino acids found in proteins. Glycine is non-essential and can be manufactured by the body from another amino acid, serine. In the central nervous system, glycine acts as an inhibitory neurotransmitter, with primary activity in the brainstem, spinal cord, and retina. Alone, it’s been used to enhance sleep quality (Yamadera, 2007). Uridine monophosphate is successfully converted to its di- and triphosphate forms, eventuating to a factor crucial in the formation of dendritic spines, which are bodies that protrude from the dendrites of a neuron in order to receive messages across the synapse. They act as a storage unit, a kind of capacitor, to assist the transmission of electrical signals to the neuron’s cell body.

article4-blue-orange-strandsDendritic spines are essential for intellectual ability, where their plasticity is associated with motivation, learning and memory. Long-term memory is mediated by the growth of new spines or the enlargement of existing ones. This helps to reinforce specific neural pathways. Because their lifespan is heavily influenced by (sensory) input activity, spine dynamics play a role in the maintenance of memory over a lifetime. In youngsters, the rate of spine turnover is relatively high, producing a net loss because the rate of elimination surpasses the rate of formation. Spines remain persistent in adulthood (Alvarez, 2007) (Zuo, 2005).

A form of uridine known as triacetyluridine is classified as a pro-drug because it serves as a precursor to an endogenous compound—cytidine triphosphate (CTP)—that has the capability to address the progressive degeneration of dopaminergic neurons that characterize Parkinson’s disease (Cansev, 2008). In its several forms, uridine promotes neurite outgrowth and stimulates downstream messengers that modulate neurotransmitter release (Krügel, 2001) (Shoji-Kasai, 2002) and helps to increase the number of dendritic spines in the brain (Sakamoto, 2007).

Living in an impoverished sensory environment retards memory development and impairs its function in adulthood. Brain phosphatidylcholine synthesis uses uridine as an element of its totality and, in combination with polyunsaturated fatty acids, has been found to improve cognitions in young and aged laboratory animals and humans, much the same as would be expected from living in an enriched sensory environment from birth (Holguin, Aug. 2008). In later study by Holguin, phosphatidylcholine constituents, PUFA omega-3’s, and uridine combined to make a cocktail shown to increase total brain phospholipids and to enhance cognitive function by increasing synaptic membrane content (Holguin, Nov., 2008).

When cerebral function is disrupted and presents with periodic convulsive seizures, a diagnosis of epilepsy may be anticipated. Here, a sudden discharge of excess electrical activity may affect many areas of the brain or focus on only a few, resulting in either grand mal or petite mal episodes, the former being characterized by loss of consciousness and the latter by clouded consciousness. More than one condition may elicit seizures, making etiology difficult to pinpoint, although genes, head trauma, dementia, or developmental disorders, among others, may be implicated. Anti-epileptic drugs, because of their limited efficacy and unwelcome side effects, have spurred an interest in new, perhaps even alternative, treatments. The Neuroscience Center at Dartmouth investigated uridine as a possible endogenous anti-epileptic modulator in specific patterns of epilepsy. It was learned that administration of uridine effected a reduction in EEG spike frequency and improved visual spatial memory in laboratory animals exposed to lithium-pilocarpine-induced status epilepticus, which may entail hippocampus damage (Müller, 2009) (Zhao, 2006).

Of greater concern to the general public is Alzheimer’s disease (AD), whether addressing prevention or the presence of inchoate dementia. Often beginning with slight memory loss and culminating with the inability to exercise judgment and to communicate effectively, Alzheimer’s has been the target of a number of pharmaceutical approaches. Decades-old research from the U. of California identified synapse degradation as a major factor in the onset of cognitive impairment (Terry, 1991). Years later, a medical food containing phosphatide precursors (PC) and associated cofactors, including uridine and PUFA’s, was found to improve memory in mild AD patients (Scheltens, 2010). Subjects suffering mild cognitive decline in the absence of dementia also found significant benefit from this medical food. In both mild AD and incipient cognitive impairment, total phospholipid and fatty acid levels were deficient (Conquer, 2000). Herein lies but one rationale for marrying uridine to PC. Because the typical American diet lacks the nutritive wholeness of the past, based on the shared rogueries of perfunctory agricultural practices and food handling, and on the dubious ways of too many home and commercial kitchens, supplementation of uridine and PC might a prudent habit to cultivate.


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