Citicoline ia a Memory-Function Enhancer

Memory De-Aging:
The City of Choline
By Will Block
    Are you a lucky little lady in The City of Light
    Or just another lost angel . . . City of Night
    City of Night, City of Night, City of Night, woo, c'mon
    -- L.A. Woman, The Doors

        eurons, the principal cells of our brain, along with glial cells, are the doorways to memory. These amazing elements of cerebral life are responsible for orchestrating all the functions of cognition. Out of these brain cells arise our diverse abilities to contemplate the sum total of the universe or investigate the very nature of how our neurons actually perform their incredible tasks. Yet without a lot of healthy neurons we would not be able to store, access, or recall the detailed and extensive information that our brains process into thoughts, ideas and even into wisdom. Neurons help make us what we are. They can wake us up or put us to sleep. They can bring us to full mental readiness or render us unconscious. They can bring us into the light or keep us in the dark.

        When our brains are working properly, it is like the spontaneous order of a great city, a city of light and energy. Imagine viewing a sped-up film of the taillights of automobiles moving rapidly through the streets of a city - in building after building, you see flickering light as the energy is exchanged from the human neurons that fuel creativity and growth. Like the city, our brains burn bright with energy.


        Neurons and glial cells of our brain
        require nutrition; otherwise they fail
        to live up to their potential
        and die premature deaths.

        RESPONSIBILITY TO OUR BRAIN
        There is no inevitability that the biochemical energy that electrically paints the cityscape of our brains will continue to flow. When our brains falter and the lights dim and start to go out, we can bemoan this fact or take matters into our own hands by preparing in advance. After all, it is our responsibility to take care of our own brain, to pamper it, and to feed its cells the choicest of raw materials. No one else will do that for us. Without adequate attention to brain nutrition, our neurons and glial cells will fail to live up to their potential and die premature deaths.

        Fortunately, neuroscience is progressively discovering the secrets of how the brain operates and what it requires to function optimally. One of the principal areas of scientific study has been the research on the membrane that surrounds the neuronal cell and the role that this membrane plays in ensuring proper function of the neuron. Above all, the function of this membrane is to protect the cell; but, it also entails the coordination of a high level of communication and much, much more.

        It has become increasingly clear that phospholipids - the various fatty-acid mineral molecules that comprise a significant portion of the membrane - play key roles in maintaining brain cell efficiency. Phospholipids are the attendants at the entry gates into our neural cells (and indeed into all the cells of our body) helping to transport substrates as fuel needed for healthy and efficient operation. Phospholipids help maintain and regulate cell membrane integrity, strength, permeability, elasticity, and resistance to stress, among other functions. Without sufficient nutrients to properly maintain phospholipids, we would not be able to think very well. Our lights would grow dim.


        Neuroscience is discovering the secrets
        of  what the brain requires to
        function optimally.

        THE MEMBRANE DONOR
        More than 30 years of brain research has resulted in a convergence of knowledge about citicoline (cytidine-5'-diphosphocholine; a.k.a. CDP-Choline), a naturally-occurring precursor to one of the most important phospholipids, phosphatidylcholine. In addition to its role in neuron membrane structural function, phosphatidylcholine is thought to play a major role in lipid turnover (utilization of fatty acids) and communication signaling. It also acts as a neuroprotector. Citicoline donates the components choline and cytidine (both of which are precursors to the synthesis of phosphatidylcholine), required to form, repair, and even restore function to nerve cell membranes. Cytidine is involved in the synthesis of other phospholipids. In addition, choline promotes the synthesis of acetylcholine, a neurotransmitter intimately associated with cognition. As an information-transmitting molecule, acetylcholine is necessary for proper memory function and is especially important for aging brains.

        To summarize, orally supplied citicoline has beneficial physiological actions on cellular function that have been extensively studied and characterized by mechanism. Citicoline has been found to support membrane integrity, enhance acetylcholine formation, and to contribute to such critical metabolic functions as nucleic acids (e.g., RNA and DNA) and protein synthesis. In the brain, in addition to promoting phospholipid synthesis, citicoline also inhibits phospholipid degradation.1


        Without sufficient nutrients to properly
        maintain phospholipids, we would not
        be able to think very well.
        Our lights would grow dim.

        TURN ON YOUR CITY'S LIGHTS WITH CITICOLINE
        As we age, our quality of life diminishes across the board with declining vision, hearing, and memory, for example. It is characteristic of our advancing years to find ourselves struggling to recall details, facts, and names that were once at our mind's fingertips. It is as if our mind's city lights are going out. This is where citicoline can be particularly valuable. Indeed, citicoline induces bioelectrical changes in the brain (that have been measured using a spectral electroencephalogram) showing increased alpha activity.2 Researchers who have studied the effects of citicoline on electrical activity, specifically regarding mapping and mental performance, have observed that it lights up certain maps of the brain. Areas of the brain found to be affected by citicoline include the cortex,3 hypothalamus,4 and the Purkinje's cells of the cerebellum.5
         

        A properly working brain is like the spontaneous order of a great city, a city of light and energy.

        Citicoline was found to significantly improve memory at the EuroEspes Biomedical Research Center in La Coruna, Spain. When citicoline was given to 24 elderly subjects with memory deficits and without dementia, the results were remarkable.6 Over a course of four weeks, subjects taking citicoline in oral doses of either 500 or 1,000 mg were found to have improved memory when compared to those taking placebo. Word recall, immediate object recall, and delayed object recall were all significantly improved after citicoline supplementation. When the 24 were divided into groups of eight and tested again, citicoline was found to possess impressive memory-enhancing activity at doses of 300-1000 mg/day.

        Additional benefits included reduction in blood pressure and positive changes in lymphocyte cell count, reflecting immune readiness. The researchers concluded that citicoline improves memory performance in elderly subjects, and that it is suitable to help prevent age-related memory deficits. Citicoline's mechanism of action is thought to entail cerebrovascular (blood circulation of the brain) regulation and neuroimmune (immune function of the nervous system) actions in the brain. Neuroimmune decline has been reported to occur with advancing Alzheimer's disease.7

        As we age, alterations in membrane function may occur because our ability to synthesize phosphatidylcholine decreases at the same time that catabolism (the breaking down) of choline and other related phospholipids increases. The result is impairment of our cognitive function. Experimental studies have shown that citicoline helps increase the total amounts of phosphatidylcholine and other related phospholipids in the brain.8 Moreover, in some instances citicoline may enhance nerve transmission.

        In a surveillance study that took place in Spain, citicoline was given to 2817 subjects of all ages, but predominantly in the age range of 60 to 80 years old.9 The subjects were suffering from various neurological problems, mainly insufficient blood circulation to the brain and volume shrinkage of the brain. When they were clinically assessed and neuropsychologically tested after citicoline use, the conclusions strongly suggested that as a choline and cytidine donor, citicoline may improve some of the deficits associated with aging, including dizziness, headaches, insomnia, depression, and memory shortage. The safety of the citicoline was excellent with side effects observed in only about 5% of the subjects, and among the most frequent were digestive complaints in 3.6% of the cases.


        Citicoline is a naturally occurring precursor
        to one of the most important
        phospholipids, phosphatidylcholine.

        RETARDING AND PREVENTING AGE-RELATED COGNITIVE DECLINE
        In a randomized, double-blind, placebo-controlled, parallel group study, 95 older volunteers identified to have relatively inefficient memories, were given citicoline at a level of 1000 mg/day for three months. The same subjects - consisting of 47 female and 48 male volunteers, 50 to 85 years old - were recruited for a second study that used a crossover design. In the crossover study, subjects took both placebo and citicoline, 2000 mg/day, each for two months. In the initial study, at 30, 60 and 90 days, the subjects were screened for dementia, memory disorders, and other neurological problems. The crossover subjects were tested at 90 days. While citicoline improved delayed recall on logical memory in both the initial and the crossover study, the lower dose (1000 mg/day) benefited only those with relatively inefficient memories. In the crossover study, the higher dose (2000 mg/day) was clearly associated with improved immediate and delayed logical memory. This was true even for those who weren't memory deficient. The conclusions found citicoline to be of benefit not only for those with pronounced memory problems but also for those older individuals with little-to-no perceivable decline. Thus citicoline may prove effective for helping to prevent age-related cognitive decline which may be the predecessor of dementia.10

        A three-month study examined the use of citicoline on 150 aging subjects with primary memory deficits.11 When administered in repeated cycles of four weeks, with an interval of one week between cycles, citicoline was found to improve cognitive and behavioral efficiency while stabilizing cognitive decline. The subjects were reported to have better memory recall and increased attention span. Citicoline demonstrated this as a long-lasting effect on cognition and behavior of these patients, with improved activation levels and attention responsiveness.


        Citicoline supports membrane integrity,
        enhances acetylcholine formation, and
        contributes to such critical metabolic
        functions as nucleic acids (e.g.,
        RNA and DNA) and protein synthesis.

        MORE INDEPENDENCE AND AUTONOMY OF LIFE
        The efficacy of citicoline (1000 mg/day) administered for two 21-day treatment cycles, with a one-week wash-out (after stopping the treatment) period between them, was evaluated for 237 subjects experiencing moderate brain aging. Using a geriatric measurement scale, the study demonstrated that the positive effects of citicoline persisted through the wash-out period with an even further decrease in measurable symptoms of cognitive decline. The most statistically significant improvement was in the area of the ability to achieve an independent and an autonomous life. Also positively affected were human relations and social life as measured by increased interest and attentive capacity with other people. The study concluded citicoline could thus be recommended for functional and social recovery of the elderly who socially withdraw due to age-related cognitive decline.12


        With age we find ourselves struggling to
        recall details, facts, and names that
        were once at our mind's fingertips. It is as
        if our mind's city lights are going out.

        CITICOLINE INCREASES VIGILANCE
        When rats were deprived of oxygen by reducing the quantity available over a period of 103 days, their behavior was observed at each increment of oxygen deficiency. Twenty-four of the animals were given citicoline by adding it to their food. Citicoline showed a protective effect, increasing vigilance under mild hypoxia (oxygen deficiency), while those not receiving the citicoline lost vigilance which indicated the possible use of citicoline for cerebral syndromes due to deficient oxygen supply.13


        Citicoline was found to possess impressive
        memory-enhancing activity at
        doses of 300-1000 mg/day.

        CITICOLINE HELPS LEVEL OF CONSCIOUSNESS
        A multicenter, double-blind, placebo-controlled study of citicoline was conducted to evaluate its effect in patients with acute, moderate-to-severe cerebral infarction (brain tissue that dies due to lack of blood supply, as in a stroke). The patients subsequently suffered moderate to mild disturbances of consciousness, and all were admitted to the hospital within 14 days of these cerebral incidents. One hundred-thirty-three subjects received 1000 mg/day i.v. of citicoline for 14 days while 139 received placebo. The group treated with choline showed significant improvements in level of consciousness compared with the placebo-treated group. And choline was an entirely safe treatment.14


        Citicoline helps prevent
        age-related cognitive decline.

        CITICOLINE ENHANCES MECHANISMS OF MEMORY
        Researchers have isolated several mechanisms by which citicoline might work to improve cognitive function, at least in dementia-type disease. Patients with Alzheimer's disease (AD) were given a 1000 mg daily dose of citicoline for a period of one month and were found to have slight improvements in mental performance.15 The scientists noted reduced brain theta activity and increased alpha activity in specific regions of the brain. Theta activity is associated with mental sluggishness while alpha activity is connected to mental acuteness. There were also indications of citicoline's favorable effects on the immune system. Malfunctioning immune response mechanisms are believed to be responsible for age-related dementia-type mental decline.

        In another study, researchers correlated citicoline's effects on cerebral blood flow to changes in cognitive function in demented subjects after daily administration for one week.16 The study group consisted of seven patients with dementia of vascular origin and three patients with dementia of non-vascular origin. The average age of the subjects was 65 years. Cognitive function increased significantly after one week but only for the vascular group, indicating that the mechanism of action involved cerebral blood flow enhancement. These influences were not found in the brains of the subjects with a non-vascular origin of dementia.

        Much of the work done with citicoline and age-related degenerative disease has been done by scientists working at the Basic/Clinical Neuroscience Research Center in La Coruna, Spain. In assessing the results of one study, the scientists detected a significant improvement in mental performance after one month of treatment with citicoline in patients with early-onset AD. In these patients, they correlated brain electrical activity data with cognitive decline. Citicoline produced positive bioelectrical changes indirectly as a result of its effect on immunogenic (immune function producing) and/or neurotrophic (growthful nervous system) activity which, in turn, resulted from improvement of the vascular microenvironment.17 What is remarkable about their conclusion is that it represents a kind of grand theory correlation suggesting: Citicoline enhances vascular function in the brain resulting in strengthened immune function which, in turn, improves bioelectrical activity - all of which translated into cognitive benefits. Schematically: Citicoline: vascular enhancement: immune enhancement: bioelectrical enhancement: cognitive enhancement.


        Citicoline demonstrated a long-lasting effect
        on cognition and behavior with improved
        activation levels and attention responsiveness.

        STAYING OUT OF HARM'S WAY
        A passive avoidance procedure was used to measure the ability "to remember to avoid" a noxious and therefore potentially harmful stimulus. The test used 13-month-old mice in order to test the effects that citicoline had on these processes. Half of the mice received 500 mg/kg per day of citicoline orally for four months. The two groups were compared with a third group of younger animals (four-month-old mice). The older mice showed marked impairment in avoiding harm's way; however, the older mice (treated with citicoline) had significant improvement in their performance 24 hours after learning the task.18 This study did not examine the effects of citicoline on younger mice.

        Young rats, however, were shown to benefit from citicoline in an active avoidance test.19 Using a maze method of memory measurement, old and young rats with existing memory deficits were given both positive feedback (rewards) and negative feedback (punishment) reinforcement. The old rats (22 months), which were administered 10 mg/kg of citicoline, were tested for retention at 24 hours and seven days after training. They were found to be able to retain more of what they learned and able to increase the number of correct responses to the adverse condition.

        When the same test given to older rats was given to younger ones (five-months old) the results were similar. Other studies, as well, have borne out that citicoline's memory-enhancing effects are particularly pronounced in animals with memory deficits whether they are old or young, especially when they have pre-existing memory deficits.20


        Citicoline's memory-enhancing effects are
        particularly pronounced in young
        and old animals with memory deficits.

        CITICOLINE BEATS PIRACETAM
        Water maze experiments were carried out on 104 male white rats measuring the effects of four nootropic (affecting cognitive function) drugs and citicoline. All investigated substances were administered immediately after morning training with an oral 100 mg/kg dose for a period of five days. The length of time in the water maze and the number of mistakes (entering blind canals) were measured. Only one of the four nootropics, pyracetamat (a form of piracetam), had any measurable effect, as did citicoline. Pyracetamat and citicoline both improved rat memory while the other three nootropics showed no effect. In this study, citicoline improved spatial memory as well as the best nootropic.21

        In one other study, the memory effects of citicoline surpassed that of the premier nootropic drug, piracetam.22 Mice given citicoline in single doses of 25, 50, 100 and 500 mg/kg, one hour prior to training, were found to have significantly enhanced memory retention both at 24 hours and seven days after the memory session. At a dose of 500 mg/kg, piracetam improved the retention in memory tests 24 hours after training, but had no significant effect during the tests performed seven days after the training. In amnesia induced by the drug scopolamine, 100 mg/kg of citicoline not only prevented memory loss but increased memory as well. In preventing loss of memory from induced amnesia, the amount of citicoline found to be effective was only 20% that of piracetam (500 mg/kg). Yet even five times the level of piracetam did not increase memory retention at the same time as citicoline was able to do.


        In amnesia-induction protection, citicoline
        was found to increase memory
        retention but piracetam did not.

        CITICOLINE ENHANCES COGNITION AND COORDINATION IN ANIMALS AND HUMANS
        Another interesting benefit of citicoline is its apparent ability to help with cognitive and motor deficits. When injected at a dose of 10 or 20 mg/kg/day for 20 days, 24-month-old male rats showed enhanced learning memory capacity. Only one injection was needed to protect against behavioral alterations caused by an amnesia-producing drug. An improvement in motor performance and coordination were also observed in aged rats.23

        A double-blind random block trial was carried out on 58 patients suffering from chronic cerebrovascular diseases in order to evaluate the effects of citicoline. The researchers found that citicoline treatment brought about an improvement in awareness and coordination faculties. This effect can be attributed to overall drug action on neural energy metabolism.24


        Citicoline enhances membrane maintenance,
        membrane repair, and neuronal function in
        traumatic conditions that injure the brain.

        HEAD INJURY
        Not surprisingly, citicoline has found a role in treating postconcussional symptoms after mild-to-moderate closed-head injury. In one study, 14 young men (admitted to the neurosurgery service with such injuries) were randomized and given 1000 mg citicoline or placebo. Control groups were matched for age, education, and severity of impaired consciousness. Citicoline produced a greater reduction of postconcussional symptoms than placebo and further analysis revealed a significantly greater improvement in recognition memory for designs. Other areas tested found no differences between placebo and citicoline.25

        In another study, also blind and randomized, 216 patients with severe or moderate head injury were treated with citicoline. Results found improved general outcome including a trend toward better motor (coordination), cognitive and psychic function for those treated with citicoline. Patients also had shorter hospital stays than those not receiving citicoline.26


        Citicoline helps prevent age-associated
        cognitive impairment, something we
        all naturally suffer . . . or soon will.

        Free of Side Effects

        Interestingly, citicoline is absorbed almost completely, and its bioavailability is approximately the same as when administered intravenously. Once absorbed, citicoline breaks down into cytidine and choline which are dispersed widely throughout the body. They 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. No serious side effects have been found in any of the groups of patients treated with citicoline, which demonstrates the safety of the treatment.

        Curiously, citicoline acts to enhance levels of various neurotransmitters including noradrenaline and dopamine levels in the CNS.28 The heightened activities of these brain molecules have a neuroprotective effect in situations of hypoxia and ischemia, as well as improved learning and memory performance in animal models of brain aging. 

        Citicoline appears to improve functional outcome and reduce neurologic deficit with 500 mg of citicoline appearing to be the optimal dose.29 In rat studies no essential differences in the effects of citicoline were established upon oral and intraperitoneal administration.30

        CITICOLINE SUMMARY
        Many studies have shown that citicoline prevents, reduces, or reverses the negative effects of a deficient blood supply in most human, animal and cellular models studied. Citicoline acts in head trauma models to decrease and limit nerve cell membrane damage, restore intracellular regulatory enzyme sensitivity and function, and limit edema. Considerable accumulated evidence supports the use of citicoline to enhance membrane maintenance, membrane repair, and neuronal function in traumatic conditions that injure the brain.

        In rats with posttraumatic motor and spatial memory-performance deficits caused by traumatic brain injury, citicoline increased acetylcholine release in the dorsal hippocampus and neocortex. Eighteen days of citicoline administration resulted in significantly less cognitive deficits than injured saline-treated rats. Citicoline also lessened the memory-disrupting effects of scopolamine. Amazingly, a single-injected administration of citicoline increased extracellular levels of acetylcholine in dorsal hippocampus and neocortex in normal, awake, freely moving rats. It was concluded that spatial memory performance deficits are, at least partially, associated with deficits in central cholinergic neurotransmission and that treatments which enhance acetylcholine release (following traumatic brain injury) may lessen cholinergic-dependent neurobehavioral deficits.27

        Beneficial effects of exogenous citicoline also have been postulated and/or reported in experimental models for dyskinesia, Parkinson's disease, cardiovascular disease, aging, Alzheimer's disease, learning and memory, and cholinergic stimulation.

        By activating the synthesis of critical components in cell membranes, citicoline boosts levels of neurotransmitters such as acetylcholine, and enhances cerebral energy metabolism. Citicoline can help preserve and protect proper memory structure and function. Thus, citicoline can be of significant value in helping to prevent age-associated cognitive impairment - something we all naturally suffer . . . or soon will. It even boosts mitochondrial energy production, causing the re-absorption of cerebral edema which can be caused by trauma or even stroke. With all of this going for it, citicoline is a new supplement choice I plan to make part of my regular program and maybe you should too. Who knows? Together, especially combined with some of our other cognitive selections, we can turn on our brain's city lights and perhaps keep them burning bright a lot longer.

        References

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        2. Franco-Maside A, Caamano J, Gomez MJ, Cacabelos R. Brain mapping activity and mental performance after chronic treatment with CDP-choline in Alzheimer's disease. Methods Find Exp Clin Pharmacol 1994;16(8):597-607.
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