and Keep It
by Will Block
In a recent issue of FEBS Letters (Federation of European Biochemical
Societies), researchers at Israel's respected Weizmann Institute published an
elucidation of the mechanism by which galantamine
- a compound extracted from the common snowdrop (Galanthus nivalis) -
blocks the action of a key brain enzyme involved in Alzheimer's disease.1
The researchers studied galantamine in detail and found that it seems to achieve
the same effect as drugs such as Aricept®
or tacrine, but that it may go well beyond them.
Alzheimer's disease is a severe degenerative disorder that causes memory loss
and other cognitive deficits in as many as 10 percent of the elderly. A hallmark
of this ominous and pervasive age-related decline is the deterioration of nerve
cells that release acetylcholine, a neurotransmitter that is needed to
shuttle messages in the form of electrochemical impulses within the brain. In
the absence of adequate messaging, severe, age-related cognitive decline such as
Alzheimer's eventually results in the reduced synthesis of proteins related to
the growth of neuronal structures.2
THE AGING CHOLINERGIC SYSTEM
Adding insult to injury, all the while that the release of acetylcholine (ACh)
is being compromised by degenerating nerve cells, the enzyme acetylcholinesterase
(AChE) is cleaving acetylcholine molecules in two at the rate of about 20,000
molecules per AChE molecule per second. Even if AChE activity declines with age,
as seems to be the case, the real issue is the balance between acetylcholine
production, release, and breakdown. For example, if ACh breaks down faster
than it's produced and released, or if its production and release are
substantially diminished, even if the rate of breakdown is not, then in these
cases (and others), the result is a cholinergic dysfunction (cholinergic
means pertaining to actions mediated by acetylcholine), and one's memory
The decline of acetylcholine production and release is relevant not only to
Alzheimer's disease but also to dementia and other age-related memory
impairments (ARMIs). Because Alzheimer's and other cognitive impairments steal
away the "light" of memory, they may be thought of as "ARMIs of
Using x-ray crystallography, the Weizmann Institute researchers found that
galantamine binds to AChE in such a way as to destroy its ability to cleave ACh,
thus putting the brakes on the depletion of these vital, memory-enhancing
messenger molecules. By preserving more ACh molecules, galantamine permits the
better maintenance of memory function.
Moreover, as the researchers found, galantamine does something else that none
of the drugs or other herbs used to treat cholinergic decline do: it binds to
acetylcholine receptors (proteins on the surface of the nerve cell that are
activated by acetylcholine), thus directly stimulating neuronal function. More
recent research indicates that this involves nicotinic receptors, in
particular. This is a class of specialized ACh receptors that are activated by
nicotine (which is known to enhance cerebral blood flow and cognitive and
psychomotor functions),* but 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 their
progressive loss is one of the distinctive neuroanatomical symptoms of
Alzheimer's. Another symptom is the buildup of a deleterious substance called amyloid.
It is significant that the stimulation of nicotinic receptors may be associated
with an inhibition of amyloid, thus perhaps helping to preserve or recover
GALANTAMINE IS A MIND-BODY
In terms of biological evolution, acetylcholine is an ancient compound, having
occurred very early in the lower species of life, both plant and animal.5
It is thought that non-neuronal (vegetative) acetylcholine first appeared in the
Precambrian era, as far back as 3 billion years ago. Its appearance in animals
is dated to approximately 500-400 million years ago, in the Paleozoic era.
Clearly, acetylcholine has played an important role in the evolution of
living things, including us. This role is not confined, however, to the realm of
the mind - nor, therefore, is that of galantamine, acetylcholine's
In lower animals as well as in humans, acetylcholine is the "universal
neurotransmitter" for the neuronal activation of muscle fibers. Small
wonder, then, that larger amounts of it can yield benefits for the body, as has
been reported in the scientific literature. Thus it is especially interesting to
note that when galantamine was rediscovered by European scientists in the 1950s,
it was found to be in folk-medicine use for neuromuscular relief, not for memory
In the 1960s, the snowdrop (a flowering plant) was discovered to be in use in
Italy for muscular soreness.6
Indeed, its earliest modern clinical use was for anesthesiology.7
Since then, it has been used for a variety of neurological, ophthalmological,
gastroenterological, cardiological, and physiotherapeutic purposes, as well as
for intensive care and resuscitation.
Galantamine crosses the blood-brain barrier freely8
and has not been found to accumulate in tissue.9
Side effects are rare, especially compared with drugs used for Alzheimer's
disease, such as tacrine.
SEXUAL ENHANCEMENT TOO
Although there is little evidence for the continuous use of galantamine as a
restorative of lost or declining cognitive functions in European systems of folk
medicine, other phytonutrients do have a long history, such as Melissa
officinalis, Salvia elegans, and Artemisia absinthium.10
These have also been known to activate nicotinic receptors. Nevertheless,
studies of galantamine in clinical usage indicate that it is one of the most
extraordinary of these phytonutrients in terms of its scope. Studies have shown
it to be valuable for psychogenic impotence, or psychologically caused sexual
dysfunction. One study found that 30 days of treatment with 10 mg of galantamine
taken three times daily resulted in stabilizing erectile function and
eliminating premature ejaculation in 108 of 170 men, a 64% success rate.11
- Gift from the Gods
The modern rediscovery of galantamine alluded to in the accompanying article led
eventually to a startling hypothesis regarding the Odyssey, Homer's epic
celebration of heroic memory. Our current knowledge of pharmacology and
ethnobotany suggests that the "drug" delivered by Hermes, the
messenger of the gods, to Odysseus to enable him to rescue his crew of sailors
from the mind-numbing spell that the sorceress Circe had put them under was
probably galantamine! The spell, in Homer's description, bore the earmarks of
atropine (from jimsonweed).
Atropine is an anticholinergic, a substance that disrupts the brain's
acetylcholine-mediated messaging system, resulting in cognitive dysfunction and
memory impairment. The ideal antidote to such a drug would be an
acetylcholinesterase inhibitor, and Homer's description of Hermes' gift from the
gods points to galantamine, which was well suited to the purpose.
How uplifting it is to think that Homer's imperishable words could convey to
us, over the millennia since he composed them, the hidden messages that have
allowed modern scientists to deduce some of the pharmacological knowledge of the
ancients. Looking back on them, we think, "They still had so much to
learn." But then, so do we.
* These benefits of nicotine are
near enough to compensate for the harm it causes from smoking. Nicotine is a
food for mind and
rescues brain cells
the old become young
- Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL. Structure of
acetylcholinesterase complexed with (-)-galanthamine at 3-Å resolution. FEBS
Lett 1999 Dec 17;463(3):321-6.
- Callahan LM, Chow N, Cheetham JE, Cox C, Coleman PD. Analysis of message
expression in single neurons of Alzheimer's disease brain. Neurobiol
Aging 1998 Jan-Feb;19(1 Suppl):S99-105.
- Beeri R, Andres C, Lev-Lehman E, Timberg R, Huberman T, Shani M, Soreq H.
Transgenic expression of human acetylcholinesterase induces progressive
cognitive deterioration in mice. Curr Biol 1995 Sep 1;5(9):1063-71.
- Galantamine improves memory and learning ability in Alzheimer's patients.
July 20, 1998. http://www.pslgroup.com/dg/8F5D6.htm
- Wessler I, Kirkpatrick CJ, Racke K. The cholinergic "pitfall":
acetylcholine, a universal cell molecule in biological systems, including
humans. Clin Exp Pharmacol Physiol 1999 Mar;26(3):198-205.
- Venturi VM, Piccinin GL, Taddei I. Pharmacognostic study of self-sown Galanthus
nivalis (var. gracilis) in Italy. Boll Soc Ital Biol Sper
1965 Jun 15;41(11):593-7.
- Paskov DS, Stoyanov KA, Saev SK, Tenev KA, Mincheva ML. Clinical
experience with Nivalin as anticholinesterase drug in anaesthesiological
practice. Proc First Eur Congr Anesthesiol, Vienna, Sep 3-9, 1962.
- Cozanitis DA. Galanthamine hydrobromide, a longer acting
anticholinesterase drug, in the treatment of the central effects of
scopolamine (Hyoscine). Anaesthesist 1977 Dec;26(12):649-50.
- Thomsen T, Kewitz H. Selective inhibition of human acetylcholinesterase by
galanthamine in vitro and in vivo. Life Sci 1990;46(21):1553-8.
- Wake G, Court J, Pickering A, Lewis R, Wilkins R, Perry E. CNS
acetylcholine receptor activity in European medicinal plants traditionally
used to improve failing memory. J Ethnopharmacol 2000
- Ludianskii EA. On the use of anticholinesterase agents in the treatment of
neurological diseases. Sov Med 1964 Mar;27:84-7.