It may have saved the Greek hero Odysseus, and now it might save you …

Galantamine Dismantles
Brain Plaque

This natural neuronutrient may also
enhance microglial Aβ phagocytosis
By Will Block

I

So that Santa can remember where he is, and not forget the presents he has promised to bring.
n the history of western literature, there are few books that continue to captivate us as does the Odyssey. Aristotle, in his Poetics, praises Homer’s composition of the Odyssey for its construction, in which unity is fused to a magnitude sufficient enough so that its length can be easily embraced by memory.1 The Odyssey is the tale of the travels and ordeals of the hero Odysseus returning home from the vicissitudes of the Trojan Wars. Odysseus is driven by foresight and “memory of an insistently enduring sort that constitutes the core of personal identity.”2 [Emphasis added] As strong a virtue as the hero’s foresight is his memory, not merely a capacity, but what makes Odysseus the man that he is. At every turn of the story, his memory is challenged, and almost confiscated at one point by the enchantress Circe, who tries to control him by altering his mind. She fails because he employs moly, which according to research done in 1983 is the galantamine-containing plant Galanthus nivalis.3 As a cholinergic enhancer it is an antidote to thorn apple, the anticholinergic poison with which Circe suppresses the memories of his crewmen. However, after Circe feeds the poison to Odysseus who is protected by the galantamine consumed, he feigns to be drugged only to leap to his feet with his sword to her neck. Her plan to control his mind is thus dismantled.


Galantamine dramatically
sensitized microglial
nAChRs to choline.


In actuality, galantamine is a neuronutrient that has been reported to have multiple actions on neurons. First, it causes acetylcholinesterase inhibition, an effect that results in enhanced cholinergic neurotransmission due to an increase in acetylcholine levels. Second, galantamine offers neuroprotection brought about through its allosteric* modulation of nicotinic acetylcholine receptors (nAChRs) on cholinergic neurons to increase acetylcholine release. And it is these two features that have made it unique. However, it has been suspected that there are other benefits not accounted for by its established duality of mechanisms.


* Allosteric refers to the alteration of an enzyme’s activity as a result of its combination with a regulator molecule. For example, allosteric inhibition by an end product represents negative feedback control of an enzyme’s activity.


A Third Mechanism That Dismantles Amyloid

This suspicion has motivated a group of Japanese researchers at Kyoto Pharmaceutical University in Japan to discover a third mechanism. In a new paper, they have shown for the first time that galantamine allosterically modulates microglial nAChRs and enhances microglial amyloid-beta (amyloid-β or Aβ) phagocytosis, a process by which Aβ is dismantled.4 Phagocytosis (from Greek “phago,” meaning eating, “cyte,” meaning vessel, and “osis” meaning process) is the cellular process by which the white blood cells called phagocytes engulf and digest microorganisms and cellular debris. Because their target “foods”—Aβ peptides—are neurotoxic, this newly identified effect of galantamine may contribute to its neuroprotective properties. It might also reduce the Aβ-dependent formation and/or maturation of neurofibrillary tangles. This finding is a great discovery, and one which involves an activity which may rescue those moving toward the cliff’s edge of Alzheimer’s disease (AD). At the same time, it may help to explain galantamine’s effect on microglia and how it relates to the long-term cognitive benefits of galantamine, as reported in AD patients. Unquestionably, this added and third advantage of galantamine may establish it as a more powerful agent for the prevention and the treatment of AD.


The data support greater benefits for
those who consume choline
along with galantamine.


Galantamine Employs Choline to Enhance Aβ Phagocytosis

The researchers found that at least 2 sites on nAChRs contribute to galantamine-enhanced microglial Aβ phagocytosis. These are the acetylcholine-binding site and the allosterically potentiating ligand (APL)-binding site. Furthermore, they found that galantamine may require some natural or acetylcholine competitive agonists to enhance microglial Aβ phagocytosis and bring it to third mechanism sufficiency. In fact, galantamine utilized the nutrient choline to enhance Aβ phagocytosis. Choline is an acetylcholine competitive and (relatively selective) full agonist for alpha-7 (α7) nAChRs. An examination of the researcher’s concentration-dependent curves of galantamine and the tobacco alkaloid nicotine on microglial Aβ phagocytosis revealed that galantamine enhanced phagocytosis at 1 micromole (μM), and nicotine at concentrations of approximately 1000 μM significantly enhanced Aβ phagocytosis. Although nicotine is toxic with many side effects, and addictive even at low concentrations, choline is an established nutrient with a daily value, although that amount is far too low (see “Are You Getting Enough Choline?” in the August 2007 issue).


Chronic treatment with galantamine
improved impaired
spatial learning and memory in
aged mice and significantly
reduced the amounts of
Ab in their brains.


In the Presence of Galantamine …

When the researchers gave as little as 1 μM of galantamine, it dramatically increased choline (and nicotine*) sensitivity of microglial nAChRs, while 1 μM choline or 0.03 μM nicotine was enough to enhance microglial Aβ phagocytosis. While further studies are needed to clarify why nicotine was more sensitive than choline, the researchers found that galantamine dramatically sensitized microglial nAChRs to choline and nicotine. The findings of a previous study suggest that choline alone, at physiological concentration, is unlikely to activate nAChRs’ effects on microglia in the brain. But, in the presence of galantamine, even such a low concentration of choline may suffice to activate nAChRs’ effects on microglia and consequently increase microglial Aβ phagocytosis in the brain. The data support greater benefits for those who consume choline along with galantamine. Other research has shown that adding vitamin B5, a cofactor to choline for the production of acetylcholine in the body, is also of significant value.5


* Smokers, who receive a heavy dose of nicotine, have been reported to have far lower amounts of Alzheimer’s disease. However, a new paper has challenged that notion, finding huge correlations between smoking and AD. (See Rusanen M, Kivipelto M, Quesenberry CP Jr, Zhou J, Whitmer RA. Heavy Smoking in Midlife and Long-term Risk of Alzheimer Disease and Vascular Dementia. Arch Intern Med 2010 Oct 25. [Epub ahead of print] PubMed PMID: 20975015.)


Is an Extended Period of Treatment Required?

The researchers were able to clearly demonstrate an increased clearance of Aβ in the brains of Aβ-injected rats administered galantamine interperitoneally (1 mg/kg and 5 mg/kg), subchronically for 14 days. Other recent studies with an animal AD model that develops Aβ plaques in the brain have revealed that nicotine reduces brain Aβ levels. This supports the hypothesis of the Japanese researchers that modulation of α7 nAChRs by galantamine effectively increased Aβ clearance in Aβ-injected rat brain.

Galantamine Benefits Sensory
Information-Processing

Clinical studies show that the phytonutrient galantamine improves negative and cognitive symptoms in schizophrenia, while the drug donepezil, a more potent acetylcholinesterase inhibitor, does not. It has recently been found that galantamine, but not donepezil, reversed isolation rearing-induced deficits of prepulse inhibition (PPI),* sensory information-processing deficits, in mice.1 Japanese researchers at Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan unexpectedly found that the galantamine-induced improvements in PPI deficits were prevented by the muscarinic acetylcholine receptor (mAChR) antagonists scopolamine and telenzepine (preferential for M1 subtype of mAChR), but not by nicotinic acetylcholine receptor (nAChR) antagonists.2


* Prepulse Inhibition (PPI) is a neurological phenomenon in which a weaker prestimulus (prepulse) inhibits the reaction of an organism to a subsequent strong startling stimulus (pulse). Deficits of prepulse inhibition manifest in the inability to filter out unnecessary information; they have been linked to abnormalities of sensorimotor gating, the state-dependent regulation of transmission of sensory information to a motor system. Such deficits are noted in patients suffering from illnesses like schizophrenia and Alzheimer’s disease.


Galantamine, like donepezil, increased extracellular ACh levels in the prefrontal cortex. However, donepezil, unlike galantamine, inhibited the M1-mAChR that mediates a specific signal transduction pathway in a human neuroblastoma cancer cell line. These results suggest that galantamine improves isolation rearing-induced PPI deficits via an activation of mAChRs and the difference in the effect on the PPI deficits between galantamine and donepezil is due to that in their action on M1-mAChRs. The possible mechanisms for the beneficial effect of galantamine amplify the prospects of its use for schizophrenia, as well as Alzheimer’s disease.


† Rats reared in social isolation from weaning show prepulse inhibition (PPI) deficits which are thought to model the sensorimotor gating deficits seen in schizophrenia and other psychiatric disorders.


  1. Koda K, Ago Y, Kawasaki T, Hashimoto H, Baba A, Matsuda T. Galantamine and donepezil differently affect isolation rearing-induced deficits of prepulse inhibition in mice. Psychopharmacology (Berl) 2008 Feb;196(2):293-301.
  2. Ago Y. Beneficial effect of galantamine on sensory information-processing deficits. Yakugaku Zasshi 2010 Oct;130(10):1305-10.

Contrary to these findings, another paper reported that subchronic subcutaneous treatment with galantamine (2 mg/kg) in animal AD model mice had no effect on brain Aβ levels when administered for 10 days.6 Could it be that galantamine treatment requires a period of longer than 10 days in order to detect a difference in brain Aβ levels? This is considered plausible because of the massive amount of Aβ continuously produced in the brains of the aged mice.

Improved Spatial Learning and Memory

Returning to the Kyoto paper, when the Japanese researchers investigated whether a chronic 56-day administration of galantamine to a mouse model of AD is effective on the Aβ clearance in the brain, they found that indeed it was. Moreover, chronic treatment with galantamine improved impaired spatial learning and memory in aged mice and significantly reduced amounts of Aβ, judging from analysis of extracted fractions from their brains. Altogether, these data make a strong case that the promotion of Aβ clearance in the brains of Aβ-injected rats and AD model mice may be induced by galantamine treatment through the enhancement of microglial Aβ phagocytosis as shown in the study of primary-cultured rat microglia.

As with Rats, So with Humans

Significantly, the researchers speculated that long-term clinical treatment with galantamine for patients with AD may show the same effect on the Aβ clearance through the microglial Aβ phagocytosis. If this is shown to be true, the effect of galantamine on microglia may, at least partially, contribute to its long-lasting cognitive benefits revealed in the latest long-time clinical trial. It would also herald an expanded view of galantamine’s power.


Galantamine requires
extracellular choline to
significantly enhance microglial
Aβ phagocytosis.


Of added interest, a recent long-term follow-up study of patients with AD who were immunized with Aβ42 peptide* suggests that the immunization is associated with a reduction in fibrillar Aβ plaques.7 Unfortunately, this study could not detect the inhibitory effect on the time to severe dementia in the peptide group compared to the placebo group. What is also suggested from this study is that immunization should occur as early as possible. And further, that anti-Aβ antibodies produced by immunization induced not only microglial Aβ phagocytosis and drainage of brain Aβ into systemic circulation, but also caused disaggregation of fibrillar Aβ.


* Aβ42 is the most susceptible amyloid peptide to conformational changes leading to amyloid fibrillogenesis.


Another possible explanation for the follow-up study results is that immunization failed to reduce the concentration of oligomeric Aβ, a synaptotoxic form of Aβ,8 and might even have increased it during the active phase of disaggregation of fibrillar Aβ plaques.9 On the other hand, microglia act to phagocytose and degrade oligomeric Aβ.10

In the present study, although the Japanese researchers could not detect a significant reduction of Aβ in the extracted fractions of AD model mouse brain tissue, the amounts of Aβ were not increased by the use of galantamine. This led to the thought that enhanced microglial Aβ phagocytosis by galantamine may exert Aβ clearance from brains barring diffusion of toxic oligomeric Aβ.

Galantamine and Choline Enhance Aβ Phagocytosis

In conclusion, the Kyoto paper provides new evidence that modulation of microglial nAChRs by galantamine or stimulation of nAChRs by choline and galantamine together enhance Aβ phagocytosis in primary-cultured rat microglia. Also, galantamine sensitizes microglial nAChRs to choline by binding to the APL-binding site on nAChRs.


Amyloid-β transmembrane structure
Image by Boku wa Kage. http://creativecommons.org/licenses/by-sa/2.0/deed.en
Consequently, galantamine requires extracellular choline (or possibly other acetylcholine competitive agonists) to significantly enhance microglial Aβ phagocytosis. While nicotine alone directly induces enhanced microglial Aβ phagocytosis, it is a substance better not taken. Altogether, these results strongly suggest a further advantage of galantamine as a therapeutic nutrient for AD and the significant therapeutic potential of microglial nAChRs, when properly sensitized by choline, in the treatment of AD.

The Odyssean Diet

If Odysseus had only known better, he would have eaten lots of fish (a good source of choline) along with whole-grain cereals, legumes, eggs, meat, and royal jelly (all of which contain vitamin B5), to amplify the benefits he derived from galantamine-containing moly, or in another timescape, he would have taken choline and vitamin B5 supplements. But Homer didn’t know, and now you do.

References

  1. Butcher HS, ed. The poetics of Aristotle. London: MacMillan and Company; 1898.
  2. Barnouw J. Odysseus, hero of practical intelligence: deliberation and signs in Homer’s Odyssey. Lanham, Maryland: University Press of America; 2004.
  3. 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.
  4. Takata K, Kitamura Y, Saeki M, Terada M, Kagitani S, Kitamura R, Fujikawa Y, Maelicke A, Tomimoto H, Taniguchi T, Shimohama S. Galantamine-induced amyloid-{beta} clearance mediated via stimulation of microglial nicotinic acetylcholine receptors. J Biol Chem 2010 Oct 14. [Epub ahead of print] PubMed PMID: 20947502.
  5. Rivera-Calimlim L, Hartley D, Osterhout D. Effects of ethanol and pantothenic acid on brain acetylcholine synthesis. Br J Pharmacol 1988 Sep;95(1):77-82.
  6. Unger C, Svedberg MM, Yu WF, Hedberg MM, Nordberg A. Effect of subchronic treatment of memantine, galantamine, and nicotine in the brain of Tg2576 (APPswe) transgenic mice. J Pharmacol Exp Ther 2006 Apr;317(1):30-6.
  7. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008 Jul 19;372(9634):216-23.
  8. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002 Apr 4;416(6880):535-9.
  9. Patton RL, Kalback WM, Esh CL, Kokjohn TA, Van Vickle GD, Luehrs DC, Kuo YM, Lopez J, Brune D, Ferrer I, Masliah E, Newel AJ, Beach TG, Castaño EM, Roher AE. Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer’s disease patients: a biochemical analysis. Am J Pathol 2006 Sep;169(3):1048-63.
  10. Shimizu E, Kawahara K, Kajizono M, Sawada M, Nakayama H. IL-4-induced selective clearance of oligomeric beta-amyloid peptide(1-42) by rat primary type 2 microglia. J Immunol 2008 Nov 1;181(9):6503-13.


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

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