Memory Enhancement Therapy
   by Will Block

Twenty-five years ago, researchers discovered that people with Alzheimer's disease suffered sharp declines in their brain levels of the important messenger molecule acetylcholine (ACh).1 This finding was truly important, because life itself is dependent on acetylcholine.

So ancient is this neurotransmitter in evolutionary biology that the development of its neuronal receptors in primitive species preceded those of adrenaline and dopamine (which govern excitatory and motor-function mechanisms, respectively). This occurred before the divergence in the lineages of fish, amphibians, and reptiles (vertebrates), and insects and spiders (arthropods).2 In humans, at the top of the evolutionary tree, ACh has been found to be intimately involved in:

  • Every motion of our muscles
  • Every thought we have
  • Every feeling we experience
  • Everything that goes on at the foundation of memory and consciousness

ACETYLCHOLINE = NIMBLE MIND
Sadly, with advancing age, ACh levels drop - as does our ability to form memories and to recall them readily. We are unable to use our minds as nimbly as we once did. And as our nervous system degenerates and stumbles into dementia - and for some, devolves into Alzheimer's disease - ACh levels drop dramatically.3

In advanced Alzheimer's disease (AD), acetylcholine levels drop by an astonishing 90%, especially in the brain's hippocampus and cerebral cortex, which are devastated by AD. Personality is weakened and diluted, and ultimately disappears. Eventually, consciousness terminates, followed by life.

GALANTAMINE/ENHANCEMENT THERAPY
On a much happier note, it is now possible to enhance ACh function in normal individuals, as well as in those with mild and even advanced dementias. A class of compounds known as acetylcholinesterase inhibitors (AChEIs) has been found to help maintain and restore ACh levels, enabling proper memory function to prevail. (Acetylcholinesterase, or AChE, is the enzyme that breaks down ACh, so compounds such as galantamine, which inhibit AChE's function, serve to boost ACh levels.) These compounds, found mostly in so-called medicinal plants, have been used in traditional Chinese, Indian, and European folk medicines for the relief of cognitive impairment in the elderly.4 The long-term use of AChEI-containing plant extracts in these traditional medicines has demonstrated an impressive absence of toxicity.

Conceptually, hormone replacement therapy has created a new paradigm for our thinking about some of the problems of aging, the idea being that what we lose with age, we should replace by supplementation. With this model in mind, researchers have looked at brain aging and proposed an equivalent model: cholinergic replacement therapy.5 In more familiar terms, it could be called memory enhancement therapy.

MILD MEMORY IMPAIRMENT PRECEDES ALZHEIMER'S
In the last few decades, other studies have verified and expanded upon the earlier findings. They have shown that dramatic declines in ACh are tied to memory impairment and that such impairment often precedes Alzheimer's disease. According to a recent paper, mild cognitive impairment may be a marker (a warning signal) for imminent progression to dementia or AD.6 If that is so, then halting the impairment may be helpful in thwarting the development of more serious degradations, such as AD.

In the cholinergic nervous system, defined as that portion of our entire nervous system (central and peripheral) for which acetylcholine is the neurotransmitter, a number of important activities take place, including the:

  • Synthesis of ACh
  • Breakdown of ACh
  • Neuroregulation of ACh

As recent studies have also found, the process of cholinergic decline entails deterioration in the cells that use ACh and in the enzymes that take part in its creation and activity. According to the cholinergic theory of memory decline, cognitive deficits are related to the loss of central cholinergic activity, and restoration of this activity produces improvement in cognitive function and clinical well-being.

A MEMORY STREAM GONE DRY
At the beginning of life, ACh-mediated neurotransmission can be likened to a rushing, bubbling stream. In the aging process, however, ACh levels decline, and their receptors are degraded. As they degenerate, we lose the sharp edge of mental function, and ultimately our stream of consciousness becomes a dry creek.

To date, much of the research on Alzheimer's has been directed toward seeking compounds that could increase the levels of ACh, or replace the amount lost due to rapid breakdown, or slow its breakdown (which has the same effect) - all in the hope of finding an effective treatment. The two drugs that are currently approved for use in treating AD - donepezil and tacrine - are acetylcholinesterase inhibitors, which tend to maintain or increase ACh levels. However, each of these drugs has serious side effects.

ENZYMES ARE ONLY PART OF THE STORY
At the Mount Sinai Alzheimer's Disease Research Center in New York, scientists have been thinking "outside the box" about the role of the cholinergic system in the early stages of AD.7 In their study, the researchers asked: At what point does the loss of cholinergic function in specific areas of the brain occur? Is it before, after, or at the same time as the earliest signs of cognitive deterioration?

MECHANISMS OF ACETYLCHOLINESTERASE INHIBITION
(FOR THE TECHNICALLY MINDED)

There are several problems with the aging cholinergic system that become particularly rife in dementia and Alzheimer's:

  1. Decline of the cholinergic basal-cortical projection mechanism.11 When the cholinergic system is optimal, an excitation emanating from the basal forebrain and projecting through to the cortical neurons directs the release of ACh in the cortex of the brain.
  2. Cholinergic loss of neurons in the nucleus basalis, a structure of the basal forebrain associated with focused attention.12 The nucleus basalis contains cholinergic neurons that project to most regions of the neocortex.
  3. Reduced activity of the cholinergic synthesizing enzyme acetylcholinetransferase. Less acetylcholine gets produced.13
  4. Decreased endurance of activity of acetylcholine. The enzyme acetylcholinesterase is quicker to break it down to choline and acetate.
  5. Cortical plaque density increase. Including the deposition of amyloid and the formation of neurofibrillary tangles, higher plaque density is directly associated with cholinergic fiber loss.14

One of the distinctive symptoms (seen at autopsy) of cholinergic deficit is a reduced number of acetylcholine receptors in the brain, especially the very important ones that are called nicotinic receptors because of their sensitivity to nicotine. Galantamine stimulates nicotinic receptor function, thus mimicking the effects of ACh. Significantly, it does so in a manner that avoids long-term desensitization of the receptors, which could lead to tolerance and therefore reduced effectiveness.15 By binding to a site on the nicotinic receptor other than the one normally occupied by ACh, galantamine actually amplifies the actions of ACh.

It is also significant that the stimulation of nicotinic receptors may be associated with an inhibition of the formation of amyloid, a hard, waxy substance that results from tissue degeneration and is often found in the brains of Alzheimer's patients. Preventing amyloid formation may help to preserve or recover memory.16

What they found indicates that patients in the early stages of AD have relatively normal levels of the enzymes that regulate ACh levels - even when they first exhibit memory deficits and some of the classic brain-anatomical signs of deterioration, such as plaques and tangles (which can be detected only at autopsy). It is only in the later stages of the disease, when severe conditions begin to manifest, that the researchers saw significantly diminished levels of these enzymes.

Therefore, they concluded, overall deficits in these enzymes may not be an early sign of damage in the disease. Instead they conjectured that either the overall ACh levels (which cannot be directly measured) are lower for some reason other than an enzyme deficit, or there is an enzyme deficit elsewhere in the cholinergic system. As a third alternative, they speculated that there may be losses in specific neuron populations early in the course of the disease.

Given these findings and hypotheses, it is possible that the positive effects of AChEIs in mild to moderate Alzheimer's disease result from their ability to boost normal levels of ACh, rather than just prevent them from falling.

GALANTAMINE BOOSTS CHOLINERGIC FUNCTION
Of all the AChEIs, the natural plant extract galantamine is a standout. Not only has it been found (in studies dating back to the 1960s) to help maintain proper ACh levels,8 but it also improves the activity of cholinergic neurotransmission. With the use of galantamine, ACh levels can be higher - especially in the areas of the brain that malfunction with age - and the ACh can be more easily released and made bioavailable. Furthermore, galantamine can improve the responsiveness of certain receptors to ACh by making them more sensitive.9

GALANTAMINE AFFECTS OTHER NEUROTRANSMITTERS TOO
There is another bonus in galantamine's action: it modulates the release of other neurotransmitters, such as glutamate, serotonin, and GABA (gamma-aminobutyric acid), that have been shown to be helpful in ensuring proper memory function.10 Galantamine's mechanism of action on the brain's nicotinic receptors is thus believed to be responsible for significant therapeutic benefits in age-related memory loss.

As a measure of galantamine's effectiveness, those who have taken it continuously for at least one year have found that it holds the memory baseline, i.e., memory decline stops.10 And, unlike any other phytonutrient or drug, galantamine may improve cognitive function when it is used for at least one year. Such an outcome has not been reported for any other AChE inhibitor. One possible explanation for galantamine's sustained efficacy is that it may increase the synthesis of nicotinic receptors.10

CURRENT NUTRITIONAL THERAPIES
Among the current nutritional strategies for increasing cholinergic activity and reducing age-related memory decline are the following:10 AChEIs, such as galantamine and tacrine Cholinergic agonists,* such as DMAE (dimethylaminoethanol) Nicotinic agonists (which are a special class of cholinergic agonists, because nicotinic receptors are part of the cholinergic nervous system), such as galantamine ACh precursors, such as choline and CDP-choline ACh releasers, such as potassium-channel blockers, e.g., carbamates Acetylcholinetransferase restorers, such as vitamin E Stimulants of nerve growth factors, such as neurotrophin

Unfortunately, most of these cholinergic strategies have proved to be far from effective, or they are effective but too toxic, or they have not been fully developed. Conventional medical wisdom has tended toward a heavy reliance on drugs, which are typically laden with side effects.

*An agonist is a substance that can bind to a receptor on a cell in such a way as to produce a physiological reaction similar to that of the naturally occurring substance for which the receptor is specific. In other words, it is a kind of stimulant for the system in question.

GALANTAMINE MAKES A SIGNIFICANT DIFFERENCE
Only the AChEIs have demonstrated consistent symptomatic efficacy in trials lasting from 3 to 12 months. For the most part, these have been standardized, well-controlled, multicenter studies and have included agents such as tacrine, physostigmine, donepezil, rivastigmine, and galantamine. But even in the AChEI trials, dropouts have been common because of efficacy problems and especially because of the long-term toxicity of some of the agents.

Galantamine is very well tolerated.  Long-term studies have found cognitive benefits in a substantial proportion of the subjects taking it, with few ongoing side effects. The side effects that have been recorded seem to dissipate with continued use or never manifest if the dosage is built slowly.

As the quintessential AChEI, galantamine is now moving strongly into the forefront of nutritional therapies for age-related memory impairment.  It owes this in part to its multiple approach to the problem.  As a replacement therapy, it rectifies deficits and their consequences in the brains of those suffering memory decline.  As an enhancement therapy, it elevates receptor activity and increases the utility of other neurotransmitters.  If one day we look back and see the present as pivotal in our being able to remember, we may very well have galantamine to thank.

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ARTICLES
   Galantamine  boosts memory
  Galantamine  food for mind and body
  Galantamine  rescues brain cells  
  Galantamine  fights Alzheimer's
   Galantamine  the old become young 

References

  1. Davies P, Maloney AJ.  Selective loss of central cholinergic neurons in Alzheimer's disease [letter]. Lancet 1976 Dec 25;2(8000):1403.
  2. Fryxell KJ.  The evolutionary divergence of neurotransmitter receptors and second-messenger pathways. J Mol Evol 1995 Jul;41(1):85-97.
  3. Winblad B, Hardy J, Backman L, Nilsson LG.  Memory function and brain biochemistry in normal aging and in senile dementia. Ann NY Acad Sci 1985;444:255-68.
  4. Mantle D, Pickering AT, Perry EK.  Medicinal plant extracts for the treatment of dementia: a review of their pharmacology, efficacy and tolerability. CNS Drugs 2000;13(3):201-13.
  5. Schneider LS. The future of cholinergic replacement therapy in Alzheimer's disease. Curr Opin CPNS Invest Drugs 2000;2(4):427-37.
  6. Shah S, Tangalos EG, Petersen RC. Mild cognitive impairment. When is it a precursor to Alzheimer's disease? Geriatrics 2000 Sep;55(9):62,65-8. Review.
  7. Davis KL, Mohs RC, Marin DB, Purohit DP, Perl DP, Lantz M, Austin G, Haroutunian V. Neuropeptide abnormalities in patients with early Alzheimer disease. Arch Gen Psychiatry 1999 Nov;56(11):981-7.
  8. Ludianskii EA. On the use of anticholinesterase agents in the treatment of neurological diseases. Sov Med 1964 Mar;27:84-7.
  9. Maelicke A, Schrattenholz A, Samochocki M, Radina M, Albuquerque EX. Allosterically potentiating ligands of nicotinic receptors as a treatment strategy for Alzheimer's disease. Behav Brain Res 2000 Aug;113(1-2):199-206.
  10. Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 2000 Jun 27;54(12):2261-8.
  11. Gaykema RP, Gaal G, Traber J, Hersh LB, Luiten PG. The basal forebrain cholinergic system: efferent and afferent connectivity and long-term effects of lesions. Acta Psychiatr Scand Suppl 1991;366:14-26.
  12. Iraizoz I, Guijarro JL, Gonzalo LM, de Lacalle S. Neuropathological changes in the nucleus basalis correlate with clinical measures of dementia. Acta Neuropathol (Berl) 1999 Aug;98(2):186-96.
  13. Maneesub Y, Sanvarinda Y, Govitrapong P. Partial restoration of choline acetyltransferase activities in aging and AF64A-lesioned rat brains by vitamin E. Neurochem Int 1993 May;22(5):487-91.
  14. Geula C, Mesulam MM, Saroff DM, Wu CK.  Relationship between plaques, tangles, and loss of cortical cholinergic fibers in Alzheimer disease. J Neuropathol Exp Neurol 1998 Jan;57(1):63-75.
  15. Maelicke A.  Allosteric Modulation of nicotinic receptors as a treatment strategy for Alzheimer's disease. Dement Geriatr Cogn Disord 2000 Sep;11 Suppl 1:11-8.
  16. Galantamine improves memory and learning ability in Alzheimer's patients. July 20, 1998. http://www.pslgroup.com/dg/8F5D6.htm.

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