The Old Become
and the Young
by Will Block
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
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?
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.
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
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.
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
enhances the availability of ACh by inhibiting the action of AChE.
enhances the function of nicotinic receptors in the cholinergic system (a
system activated by or capable of liberating acetylcholine).
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
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.
IN THE BLINK OF AN EYE
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
OLD BECOME YOUNGER
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,
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!
other words, the old became younger than the young. The "tortoise"
generation of rabbits ended up defeating (with the help of galantamine) the
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
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.
YOUNG BECOME YOUNGER
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%!
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.
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
ONE GOES UNCHANGED
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.
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.
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?"
food for mind and
rescues brain cells
the old become young
- 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
- Nadel L, Moscovitch M. Memory consolidation,
retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol
- Woodruff-Pak DS, Vogel RW, Wenk GL. Galantamine: effect on nicotinic receptor binding, acetylcholinesterase
inhibition, and learning. Proc Natl Acad Sci USA 2001 Feb
- 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.
- 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.
- 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.
- Barnes CA, Meltzer J, Houston F, Orr G, McGann
K, Wenk G. Chronic treatment of old rats with donepezil or
effects on memory, hippocampal plasticity and nicotinic receptors. Neuroscience
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