The Old Become the Young
and the Young Become Younger
  by Will Block
The young become the old,
And mysteries do unfold,
Cause that's the way of time:
Nothing and no one goes unchanged.

              - "Everything Must Change,"
              lyrics by P. Young & I. Kewley

When we are young, we remember the past easily. Yet as we age, it becomes harder to learn new things and commit them to memory. One explanation for age-related memory decline is the deterioration of the brain's binding mechanisms that are needed to activate neural storage.1 Memory binding takes place when two or more things are associated in memory and stored for retrieval at a later time. Short-term memory is consolidated into longer-term memory for storage and retrieval. In the elderly, the stimulus of new information does not engage binding mechanisms anywhere nearly as much as it does in the young.2 But is it inevitable that the young become the old with regard to memory?

Perhaps not. In a very recent report published in the Proceedings of the National Academy of Sciences, it is shown that the acetylcholinesterase inhibitor galantamine appears to counteract the slowdown of memory-binding mechanisms.3 Acetylcholine (ACh) is a fundamental neurotransmitter, a memory molecule that transmits information between nerve cells. Acetylcholinesterase (AChE) is an enzyme that breaks down ACh in the body; thus anything, such as galantamine, that inhibits the action of AChE has the effect of enhancing ACh. The authors of the PNAS paper observed that galantamine improved the efficiency of learning and memory-storage mechanisms in rabbits independently of whether they were old or young. In a sense, the old rabbits became younger, and the young rabbits became younger still, memory-enhanced by galantamine. We will describe this study later in the article.

It has long been known that acetylcholine's ability to enable the transmission of neural (nerve) messages is essential for learning and memory, and it is now clear that a decline in acetylcholine function is connected to memory impairment in Alzheimer's disease and other cognitive impairments.

Enter galantamine, a phytonutrient (plant-based nutrient) with a history of use that goes back at least 3200 years. Some scholars believe that in the Greek epic the Odyssey, it was galantamine (in the form of an extract from the snowdrop) that was presented by Hermes, the messenger of the Gods, to the hero, Odysseus, who used it as an antidote to protect himself from the goddess Circe's mind-altering drugs.4 Circe had used her potion - believed to have been made from jimsonweed, which contains atropine, a centrally acting anticholinergic agent (a substance that inhibits or blocks the actions of acetylcholine at a receptor site) to induce amnesia and a delusional state in Odysseus' crew. With the help of galantamine, Odysseus was able to retrieve the lost memories of his crew, and protect his own memory, thus enabling them to return, eventually, to their beloved homeland of Ithaca. Galantamine may represent the oldest recorded use of an acetylcholinesterase inhibitor for reversing central anticholinergic intoxication.

In today's world, galantamine offers the possibility that we may be able to restore and maintain proper memory function, thus preserving the part of us that is often lost to time - those aspects of our being that become less accessible with age and that we may forget altogether.

Scientists have found that galantamine has at least two principal mechanisms of action:

  1. It enhances the availability of ACh by inhibiting the action of AChE.
  2. It enhances the function of nicotinic receptors in the cholinergic system (a system activated by or capable of liberating acetylcholine).

In the second mechanism, galantamine operates indirectly on nicotinic receptors. This class of specialized ACh receptors is activated by nicotine (which is known to enhance cerebral blood flow and cognitive and psychomotor functions) and also by various other substances, among which galantamine is one of the most potent. Nicotinic receptors play an important role in memory and learning, and the progressive loss of these receptors leads to the distinctive symptoms of Alzheimer's disease.

Because of its indirect route, galantamine does not usually induce the negative consequences provoked by drugs that directly affect nicotinic receptors. Unlike other AChE inhibitors, such as the drug physostigmine and the neurotransmitter serotonin, galantamine does not desensitize nicotinic receptors or overwhelm them with too much activity. Tolerance to it does not develop, because of its indirect activity on nicotinic receptors.

Galantamine creates more powerful memory and induces a type of cognitive activity indistinguishable from that induced by ACh. While galantamine does not increase the availability of ACh at the synapse - the junction across which a nerve impulse passes - as much as other AChE inhibitors, it increases the efficacy of ACh.

One of the most reliable ways to measure certain aspects of memory is through what is known as eyeblink conditioning, a type of associative learning known to engage the cholinergic system. In normal aging, this form of conditioned learning is impaired. Like Pavlov's famous dog experiment, eyeblink conditioning is a conditioned response to a specific stimulus. In this case, the conditioning is achieved with a tone and a harmless puff of air directed at the subject's eye, causing it to blink. When these two stimuli are simultaneously presented often enough, the subject forms a mental association so strong that eventually the tone alone will cause the blink - the puff of air is no longer necessary. In Alzheimer's disease, eyeblink conditioning is severely disrupted, as is the function of nicotinic cholinergic receptors. By enhancing cholinergic function - which galantamine does - eyeblink conditioning is improved, as are associative learning and memory function in general

In a study that preceded the PNAS study mentioned at the beginning of this article, researchers used the eyeblink conditioning procedure over a period of a decade to test hundreds of rabbits treated with nicotinic agonists (compounds that can combine with a receptor on a cell to produce a physiological reaction typical of naturally occurring substances) and AChE inhibitors, including galantamine.5 They used galantamine because of its well-known ability to enhance nicotinic cholinergic receptor activity, and to increase acetylcholine. Young adult rabbits (with a mean age of 5 months) measured without galantamine acquired the conditioned response of eyeblinking in about 400 trials, whereas older rabbits (with a mean age of 29 months) took about 1000 trials. With galantamine, however, the older rabbits acquired the conditioned response in just 233 trials, on average. With galantamine, the older rabbits required 42% fewer trials than the young rabbits to learn the same conditioned response!

In other words, the old became younger than the young. The "tortoise" generation of rabbits ended up defeating (with the help of galantamine) the "hare" generation.

In the Proceedings of the National Academy of Sciences study, 53 older rabbits were divided into four groups and tested over a 15-week period. One group received no galantamine; one group received a small daily dose for the entirety of the study; one group received a large daily dose for the entirety; and the fourth group received galantamine at the large dose for only 15 days rather than 15 weeks, after which they received none for the remainder of the experiment.

When the rabbits were tested for acquisition, learning, and retention through eyeblink conditioning, those receiving the large continuous dose of galantamine had significantly fewer learning deficits than the controls.The group receiving the large dose for 15 days was found to have significantly higher nicotinic receptor binding than the controls, and all the galantamine-treated rabbits had lower levels of brain AChE. The ability of galantamine to help improve one type of learning that is severely impaired in Alzheimer's disease is consistent with the findings of clinical studies.

As another part of the experiment, 16 young and 16 older rabbits received galantamine for 15 days during eyeblink conditioning. Galantamine was found to facilitate learning in both groups. Of the compounds tested that facilitated learning and memory in older rabbits, galantamine was the only one that did the same in young rabbits, which were found to increase their conditioned-response learning time by 26%!

That's impressive! The young rabbits, unimpaired by cognitive decline, became younger in their ability to learn and remember. It was as if they had lined up to receive their undergraduate college diplomas but were rewarded instead with graduate degrees because they had done so much better than expected.

With most nicotinic cholinergic agonists that are used for the treatment of age-related dementias, such as Alzheimer's disease, it is difficult to establish the appropriate dose, because higher levels often cause desensitization rather than increased activation of the nicotinic receptors.6 Moreover, there are additional problems, including poor transport of the agonists to the receptors (meaning low bioavailability). Galantamine represents an alternative approach, with its ability to enhance memory by modulating nicotinic receptors through alternative binding sites used by ACh and other nicotinic agonists.

At the Memory and Aging Laboratories at the University of Arizona, researchers have shown that old rats treated with galantamine undergo important behavioral changes.7 In effect, this has been the finding of the large-scale randomized double-blind, placebo-controlled galantamine studies. When galantamine is administered to older humans diagnosed with Alzheimer's disease or other forms of dementia, the results have been significant inprovement in behavioral symptoms and the activities of daily living.

Distinct from other AChE inhibitors, galantamine helps restore proper neurochemistry in the brain by elevating the number of the brain's nicotinic receptors. The behavioral study was the first significant demonstration of cholinergic enhancement, over the course of just a few days, of synaptic plasticity - a measure of the ability of neural cells to accommodate new data.

Galantamine brought about a profound change in long-term memory function, one that was significantly correlated with enhanced nicotinic receptor binding. The greater the binding, the longer the memory. These facts suggest not only that galantamine may be useful for those with age-related dementia but also that it may have neurophysiological effects that are near the threshold of positive behavioral changes. When combined with the suggestion - substantiated by strong anecdotal evidence - that galantamine may be able to do for you what it does to make old rabbits younger and young rabbits younger yet, you have to stand and whistle a tune. How about "Everything Must Change?"

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  1. Schreursa BG, Bahro M, Molchan SE, Sunderland T, McIntosh AR. Interactions of prefrontal cortex during eyeblink conditioning as a function of age. Neurobiol Aging 2001 Mar;22(2):237-46.
  2. Nadel L, Moscovitch M. Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol 1997 Apr;7(2):217-27.
  3. Woodruff-Pak DS, Vogel RW, Wenk GL. Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning. Proc Natl Acad Sci USA 2001 Feb 13;98(4):2089-94.
  4. Plaitakis A, Duvoisin RC. Homer's moly identified as Galanthus nivalis L.: physiologic antidote to stramonium poisoning. Clin Neuropharmacol 1983 Mar;6(1):1-5.
  5. Woodruff-Pak DS, Santos IS. Nicotinic modulation in an animal model of a form of associative learning impaired in Alzheimer's disease. Behav Brain Res 2000 Aug;113(1-2):11-9.
  6. 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.
  7. Barnes CA, Meltzer J, Houston F, Orr G, McGann K, Wenk G. Chronic treatment of old rats with donepezil or galantamine: effects on memory, hippocampal plasticity and nicotinic receptors. Neuroscience 2000;99(1):17-23.

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