More findings on memory enhancement and spatial navigation . . .

Galantamine Improves
Hippocampal Cognition

Targeting an essential part of the limbic system,
crucial for longterm memory and movement
By Will Block

Sapere Vedere (Know How to See)
— Leonardo da Vinci’s motto for
anatomical research


n the blink of an eye, the Renaissance anatomist Giulio Cesare Aranzio (1529–1589) made his first discovery at the age of nineteen when he grasped (and then described) the elevator muscle of the upper eyelid. During his tenure at the University of Bologna—where he received a doctorate in medicine and held the chair in the newly created department of anatomy—Aranzio discovered many mechanisms, structures, and functions of the body. He continued to explore the human body at Bologna until his death.

Although famed for his correct depictions of the anatomical peculiarities of the fetus, the muscles of the eye, and the anatomical relations of the cavities of the heart, its valves, and great vessels—enabling a deep understanding of how the blood follows in passing from the right to the left side of the heart—Aranzio was the first anatomist to distinctly describe the inferior cornua of the ventricles of the cerebrum. At the same time, Aranzio gave the nearby paired structure the name by which it is still known, hippocampus, from the Greek word for seahorse (hippos = horse, kampos = sea creature), of which it reminded the early anatomist. The hippocampus is a major component of the human brain, along with the brains of other mammals. It is an essential part of the limbic system, where it plays crucial roles in long-term memory and spatial navigation (see sidebar, “Cognitive Enhancers and the Risk of Falling”). The limbic system is embryologically older than other parts of the brain, dating back several hundred million years. It developed to manage “fight or flight” chemicals and is an evolutionary necessity for reptiles as well as humans.

Aranzio gave the paired structure the
name by which it is still known,
hippocampus, from
the Greek word for seahorse.

Cognitive Enhancers and the Risk of Falling

As we get older, we are at increased risk for falling, and at the same time we tend to lose aspects of our memory and suffer cognitive problems. But did you know that older adults with memory problems suffer twice the risk of falls? In these populations, the consequences of falls can be very serious, and often put one on a slippery slope for maintaining health. That’s because age-related cognition-associated falls in the elderly result in more injuries, including the high risk of major fall-related injuries such as fractures and head injuries, leading to increased mortality. Furthermore, such multiple fallers are approximately five times more likely to end up in institutional care.

Loss of attentional resource
allocation while walking can result
from impaired cognitive abilities.

Although we can not say for certain what causes the increased fall risk in cognitively impaired people, research has shown that loss of attentional resource allocation while walking can result from impaired cognitive abilities.1 The good news, however, is that cognitive enhancers, including cholinesterase inhibitors (AChEIs), can improve attention and executive function, as a recent study has shown.2 Moreover, a case series found that individuals with dementia taking galantamine (a natural AChEI) for 24 weeks had less decline in gait performance compared with age matched controls.3

A Trail to Test the Hypothesis

In a new paper, researchers report the design of a study to test the hypothesis that cognitive enhancers may reduce fall risk in elderly people, specifically in the early stages of cognitive decline by improving their gait and balance performance due to an enhancement in attention and executive function.4 This randomized double-blind placebo-controlled trial will be fielding 140 older individuals (aged 65 years and older) with mild cognitive impairment (MCI). The subjects will be randomly divided in two, half of whom will be given the AChEI drug donepezil, initially at 5 mg for one month, which will then be raised to 10 mg/day for 5 months. The other half, the control group, will receive a placebo.

Individuals with dementia taking
galantamine (a natural AChEI) had
less decline in gait performance
compared with controls.

Baseline and follow-up testing at 1 and 6 months will include gait analysis, balance sway, and balance confidence along with the cognitive measurement of attention and executive function. Galantamine has already proved its efficacy for gait and balance enhancement. It will be important to determine if another AChEI can do the same and keep the elderly away from institutional care.


  1. Woollacott M, Shumway-Cook A. Attention and the control of posture and gait: a review of an emerging area of research. Gait Posture 2002;16:1-14.
  2. Seltzer B, Zolnouni P, Nunez M, Goldman R, Kumar D, Ieni J, Richardson S. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol 2004;61:1852-6.
  3. Assal F, Allali G, Kressig RW, Herrmann FR, Beauchet O. Galantamine improves gait performance in patients with Alzheimer’s disease. J Am Geriatr Soc 2008;56:946-7.
  4. Montero-Odasso M, Wells JL, Borrie MJ, Speechley M. Can cognitive enhancers reduce the risk of falls in older people with mild cognitive impairment? A protocol for a randomised controlled double blind trial. BMC Neurol 2009 Aug 12;9:42.

Damage to the hippocampus can be caused by epilepsy, oxygen starvation (hypoxia), encephalitis, and the antecedents of Alzheimer’s disease (AD), one of the great travesties of our time. In AD, the hippocampus is often one of the first regions of the brain to suffer damage, concomitant with memory problems and disorientation. Those with extensive hippocampal damage are likely to experience amnesia—the inability to form or retain new memories—as is commonly the case with AD.

Can Cognitive Enhancers Affect the Hippocampus?

In a recent study,1 researchers asked the question: can galantamine result in detectable hippocampal metabolite changes that correlate with benefits in cognition? As you ought to know by now (Life Enhancement has published more articles on this natural compound than any other publication in the world), galantamine has two principal mechanisms: it is an acetylcholinesterase inhibitor (AChEI) and also an allosteric potentiating ligand that modulates presynaptic nicotinic acetylcholine receptors. This means that galantamine inhibits the breakdown of acetylcholine molecules and improves the receptivity of neurons to acetylcholine molecules that are trying to transmit nerve impulses across a synaptic junction.

In Alzheimer’s, the hippocampus is
often one of the first regions of
the brain to suffer damage,
concomitant with memory problems
and disorientation.

Remember that acetylcholinesterase (remember or face the consequences!) is the enzyme whose function is to destroy excess acetylcholine molecules in the neural synapses; when it is inhibited there is more acetylcholine. It can’t be emphasized enough that a well-functioning cholinergic system is critical for preserving and protecting memory and other aspects of cognitive function. Given these facts, it is no surprise that galantamine is beneficial for the treatment of AD.

Scanning Hippocampal Tissue

Using magnetic resonance imaging (MRI) data gathered from 10 subjects—who met the criteria for probable early AD—taking galantamine, researchers scanned their right hippocampus to qualify absolute metabolite levels for N-acetylaspartate, glutamate, choline, creatine, and myo-inositol. The MRI scans, along with two standard cognitive tests (MMSE and ADAS), were performed at baseline and 4 months after beginning galantamine treatment, starting with an 8 mg daily dose for the first month, followed by a 16 mg daily dose for the remaining three months.

Glutamate to Creatine Ratio Association

The levels of all metabolites increased after four months of treatment, although none could be related to changes in the cognitive scores. However, the changes in glutamate metabolites over the time of the study correlated with the change in N-acetylaspartate metabolites, and the change in the ratio of glutamate to creatine did in fact correlate with one of the two cognitive test scores. This ratio change was associated with increased cognitive performance. The increase in glutamate may be related to the action of galantamine as an allosteric potentiating ligand for presynaptic nicotinic acetylcholine receptors, which increases glutamatergic neurotransmission.

Donepezil No Show

Although a few other studies have noted metabolite changes in AD, fewer studies have examined treatment response. Of the several studies examining treatment effects, using donepezil and rivastigmine (two other AChEIs, albeit drugs), the results have been uncertain, or have shown no benefit on the relationship between improved cognition and metabolites, although only non-hippocampal brain regions were considered. In fact, a study by the same authors of the hippocampal study employing the same methodology, but using donepezil instead of galantamine, showed continued neuronal impairment after treatment!2 These inconsistencies may be due to the differences of effects on other brain regions.

Indeed, the current study is the first to report metabolite changes associated with the use of galantamine. However, the current study did not show any of the changes in the levels or ratios found in the above mentioned studies using other AChEIs. Yet the increase in glutamate following galantamine treatment suggests that measured glutamate levels may be related to neurotransmission and cognitive function.

The Chain of Events

Previously, galantamine has been reported to improve cognitive functions in subjects with AD by increasing the activity of the cholinergic system.3 AChEIs diminish acetylcholine breakdown, thereby increasing cholinergic neurotransmission. Among AChEIs, galantamine is unique because it is a weak cholinesterase inhibitor, but able to allosterically stimulate nicotinic acetylcholine receptors, which are found in high concentration in the hippocampus. Accordingly, galantamine binds to nicotinic receptors acting as a potentiating ligand, the result of which is enhancing receptivity to activation by acetylcholine. This in turn stimulates glutamatergic release. Neurotransmission within the hippocampus depends on cholinergic and glutamatergic mechanisms.

The ratio of glutamate to creatine
change was associated with increased
cognitive performance.

Furthermore, the increase in glutamate was found to help stimulate post-synaptic N-methyl-D-aspartic acid (NMDA) receptors and this produced positive effects on learning and memory. The authors thus concluded that the increase in glutamate in the hippocampus may be related to the second action of galantamine, i.e, as an allosteric potentiating ligand for nicotinic receptors. Finally, this action by galantamine may also prevent glutamate neurotoxicity, the ensuing death (apoptosis) of neurons containing glutamate.

Using donepezil
instead of galantamine, showed
continued neuronal impairment
after treatment!

Nevertheless, the noteworthy increase in total glutamate may identify glutamate as an important metabolite marker to determine AD progression as well as the response to treatment. Further studies are required to determine if the increase in glutamate continues with galantamine for more advanced stages of AD.

Seahorse as Medicine

Back to the seahorse, a species of fish belonging to the genus Hippocampus (which came first, the chicken or the egg?), of which there are over 47 species, mainly found in shallow tropical and temperate waters throughout the world. Strange as it may seem, the seahorse is used in Traditional Chinese Medicine (TCM), and perhaps as many as 20 million seahorses are caught each year and sold for this purpose. This is because seahorses bred in captivity are susceptible to disease and presumably don’t have the right “energetics” for TCM. The Chinese are not alone in their pursuit of sea harvest of Hippocampus; they are joined by Indonesians, Central Filipinos, and a number of other racial and ethnic groups around the world.

Seahorse is found
in some Chinese
cognitive enhancement

Among these cultures, seahorses are used to treat arteriosclerosis, asthma, incontinence, impotence, thyroid disorders, and skin ailments, as well as for broken bones and heart disease. Not to mention their use for childbirth in certain regions. In Taiwan, seahorse is used as an aphrodisiac or to enhance sexual function. In Hong Kong, top uses include asthma and impotence. Lastly—and here’s where the snake bites its tail—seahorse is found in some Chinese cognitive enhancement formulations. Imagine that! But if you’re looking for a way to treat yourself and your hippocampus to better cognition, you might try galantamine.


  1. Penner J, et al, Increased glutamate in the hippocampus after galantamine treatment for Alzheimer disease, Prog Neuro-psychopharmacol Biol Psychiatry (2009), doi:10.1016/j.pnpbp.2009.10.007.
  2. Bartha R, Smith M, Rupsingh R, Rylett J, Wells JL, Borrie MJ. High field (1)H MRS of the hippocampus after donepezil treatment in Alzheimer disease. Prog Neuro-psychopharmacol Biol Psychiatry 2008;32:786-93.
  3. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 432 2006:CD005593.

Will Block is the publisher and editorial director of Life Enhancement magazine.

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