http://drzarkov.com/delanoblog/?tag=alpha-gpc CDP-Choline and alpha-GPC By now it’s not exactly news that choline is good for your brain. It’s been known for a long while that choline is probably the most basic nutrient necessary for optimal cognitive function. That’s because choline is a precursor for acetylcholine, a key neurotransmitter (signaling molecule) without which we couldn’t move, think, remember, or sleep. The body also uses choline for synthesizing phosphatidylcholine (PC), a component of the fatty membrane of every cell, brain cells included. In addition to its role as a structural element in cell membranes, PC can act as a choline reservoir for synthesizing more acetylcholine when needed. Aging humans and animals tend to suffer from impaired short-term memory. This loss of working memory is largely the result of deficient functioning of the “cholinergic” neurons in a part of the brain known as the basal forebrain. (Cholinergic neurons are the brain cells involved in acetylcholine synthesis, signaling, and metabolism.) The age-related deficits in this part of the brain include decreased synthesis and release of acetylcholine, as well as decreases in the number of cholinergic brain cells and in the number and function of acetylcholine receptors on such cells. The same neurons that are vulnerable in aging are especially vulnerable in Alzheimer’s disease (AD). In AD the cholinergic cells of the basal forebrain shrivel and die in manner resembling normal aging but at an accelerated pace. This abnormal behavior is partly the result of defective cell membranes caused by decreased availability of choline and increased breakdown of phosphatidylcholine. When choline is in short supply and cholinergic cells are active, any available choline goes to make more acetylcholine at the expense of building membranes. Eventually enough choline is withdrawn from the membrane so that the amount of PC in a cell actually decreases, a process known as “autocannibalism”. In other words, the cell takes itself apart in an attempt to maintain normal acetylcholine signaling. You might reasonably conclude from this that all we need to do to slow down brain aging or Alzheimer’s disease is supply more choline to the brain, but you’d be only partly right. The problem is that choline transport into the brain is not especially efficient and tends to decline with age. Attempts have been made to treat dementia and cognitive impairment with choline supplements such as lecithin (dietary PC, typically derived from eggs or soy), but a review of all unconfounded, randomized trials comparing lecithin with placebo revealed no particular benefit. Alternatives to choline or lecithin are clearly needed in order to reverse age-related cognitive decline. Fortunately, there are two choline-based supplements that can do the trick—CDP-choline (cytidine 5’-diphosphocholine) and alpha GPC (alpha glycerophosphorylcholine). Both are natural, water-soluble compounds that achieve similar results in very different ways. CDP-choline is an essential intermediate in the biosynthesis of phosphatidylcholine and the better studied of the two compounds. Cells make CDP-choline out of choline and some other precursors before further processing it into PC. (If you’re eager for the biochemical details, an enzyme catalyzes PC synthesis by transferring the phosphocholine part of CDP-choline to diacylglycerol. Diacylglycerols are glycerine molecules with two fatty acids attached.) In contrast alpha GPC works at the opposite end of PC metabolism. Unlike CDP-choline, alpha GPC is a metabolic breakdown product of PC rather than a PC precursor. You might say that whereas CDP-choline is an “anabolic” product, alpha GPC is a “catabolic” one. When phosphatidylcholine is metabolized and stripped of its fatty acids, what’s left behind is alpha GPC-a glycerine molecule bound to phosphocholine. As such it’s a source of choline in the same form that a cell would obtain from scavenging its own membranes, and therefore a form of choline that neurons prefer to use for synthesizing acetylcholine during times of choline scarcity. Despite the fact that CDP-choline and alpha GPC are chemically distinct from each other and operate at opposite ends of the metabolic spectrum, both of them do pretty much the same thing. For example, both alpha GPC and CDP-choline have been shown to improve performance on behavioral and psychological tests among patients with mild to moderate Alzheimer’s disease. Both can also counteract the amnesia induced by scopolamine, a compound which blocks acetylcholine receptors, thus confirming the role of the cholinergic system in the cognitive enhancing effects of alpha GPC and CDP-choline. And both can promote cognitive recovery from a recent stroke. More generally, a review of all relevant, controlled clinical trials concluded that CDP-choline is beneficial for treating cognitive and behavioral deficits caused by chronic brain disease in the elderly. This is in striking contrast to a similar review cited earlier that found no benefit for treating cognitive decline with choline in the form of lecithin. The superiority of CDP-choline over lecithin as a choline source should be evident. Unfortunately, however, there’s no comparable large-scale overview of the effects of alpha GPC as a cognition enhancer because alpha GPC is a newer product than CDP-choline and fewer studies have been done with it. Nevertheless, as the following selected examples show, the effects of alpha GPC and CDP-choline are remarkably similar on the molecular and cellular levels and are therefore likely to be similar on the cognitive and behavioral levels as well: •When incubated with brain tissue from rats, CDP-choline stimulates the activity of acetylcholinesterase (AChE), an enzyme involved in choline metabolism. Similarly, high-dose oral alpha GPC restores decreased AChE activity to more youthful levels in the brains of aged rats. •Chronic administration of high-dose oral CDP-choline also restores the numbers of acetylcholine receptors in rat brain which otherwise decrease with normal aging. High-dose oral alpha GPC does the same. •Both CDP-choline and alpha GPC decrease the viscosity (stiffness) of cell membranes, an effect almost certainly due to increased phosphatidylcholine synthesis. Another useful property shared by alpha GPC and CDP-choline is that oral administration of either one increases the release of the neurotransmitter dopamine in the brain. It’s worth recalling that defective dopamine signaling is associated with Parkinson’s disease in much the same way that defective acetylcholine signaling is associated with Alzheimer’s disease. There is evidence of enhanced PC metabolism in Parkinson’s, perhaps as a result of brain cells trying to compensate for the neurodegenerative process. In this sense there may be an increased demand for CDP-choline or alpha GPC in Parkinson’s disease, where they may be needed to rebuild damaged cell membranes and to facilitate dopamine release as well. L-DOPA is an amino acid precursor to dopamine that is widely used in treating Parkinson’s. Animal studies have shown that oral CDP-choline treatment enhances the effects of L-DOPA by increasing the release of dopamine newly synthesized from it. In human trials, a combination of CDP-choline with L-DOPA was able to improve neurological symptoms with a smaller effective dose of L-DOPA than patients had previously received without CDP-choline. This result is important because chronic use of L-DOPA eventually results in neurotoxicity and loss of clinical effectiveness. The hope is that by combining CDP-choline with smaller doses of L-DOPA, it may be possible to prolong the period during which L-DOPA remains effective. In view of the known ability of alpha GPC to enhance dopamine release as well, a similar therapeutic enhancement of L-DOPA activity is also likely to occur with alpha GPC, but there aren’t any clinical data available yet to confirm this suggestion.