In the hippocampus, where information is consolidated, …

Galantamine Births Neurons
Enabling enhanced memory,
spatial navigation, and pattern separation

By Will Block

G alantamine is generally considered to be an acetylcholinesterase inhibitor that helps prevent the breakdown of the important memory molecule acetylcholine. However, less well known is the fact that galantamine also promotes hippocampal neurogenesis—i.e., the creation of new neurons!

Alzheimer’s disease—for which galantamine is frequently used—is associated with some increased production of neurogenesis, which may help repair the brain.1 But the amounts are not sufficient. Emerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer’s disease.2 Consequently, galantamine-induced neurogenesis may help reverse the retreating tide of new neuron generation. Yet the exact mechanism for this “birthing action” of galantamine is not known.

Galantamine Enhances Activity of Nicotinic Receptors

In a new study, researchers examined the mechanisms underlying the effects of acute galantamine on neurogenesis in the mouse hippocampus.3 They found that galantamine at 3 mg/kg,* i.p. (injected into the peritoneum, the membrane that lines the abdominal cavity) increased the number of proliferating cells in the dentate gyrus (DG), within which neurogenesis occurs.


* The equivalent of about 20 mg per day in a 176 lb. human, half way between a standard 16 mg and 24 mg daily dose.


The Importance of Neurogenesis for Pattern Separation

According to a very recent study in Science,4 most animal brains cease production of new neurons (neurogenesis) soon after birth. But there are exceptions, such as in humans, mice, and some other species, where neurogenesis continues throughout life in the DG. It is in the DG that memories about space and events are encoded. In adult humans, the DG produces roughly 700 new brain cells each day.5 These new brain cells may help erase old memories and establish new ones.


Galantamine also promotes
hippocampal neurogenesis
i.e., the creation of new neurons.


That’s not all. The DG is important—perhaps critical—for what is known as pattern separation. Technically, pattern separation is the formation of distinct and orthogonal (i.e., statistically independent) representations of mnemonic information. In other words, pattern separation is the process of memory distinction, where similar patterns of neural activity are separated when perhaps only one element is different. This is of great value for learning and memory (particularly episodic memory) because while many of our experiences are similar to each other, they must be remembered as distinct from one another.

Moreover, in a recent article in the journal Hippocampus,6 researchers propose, “… a continuum that reflects underlying hippocampal neuropathology whereby patients with aMCI [amnestic mild cognitive impairment] are able to properly encode information into memory but rapidly lose these memory representations, and patients with AD [Alzheimer’s disease], who have extensive hippocampal and parahippocampal damage, cannot properly encode information in distinct, orthogonal representations.” (Emphasis added.)


These new brain cells may help erase
old memories and establish new ones.


The Science study’s results indicate that adult neurogenesis appears to be important for the ability of the DG to perform the pattern separation function optimally. What is not known is whether immature neurons contribute to pattern separation directly or whether their contribution represents a greater complexity for normal DG function. Is the function of immature neurons distinct from that of mature neurons?

An Intriguing Finding

Returning to the Japanese study, the researchers note that galantamine interacts with the nicotinic receptor at binding sites, in addition to those for acetylcholine, and acts specifically to sensitize (and thereby enhance) the activity of nicotinic receptors in the presence of acetylcholine (the same way that Metformin is a hormone receptor sensitizer).

An intriguing finding of the study shows that ­galantamine promotes the survival of newly-divided cells in mice in the DG through neurogenesis via activation of the M1 muscarinic and α7 nicotinic acetylcholine receptors. Muscarinic receptors are widely distributed throughout the body where they mediate many vital functions in both the brain and autonomic nervous system. Inside the brain, muscarinic receptors play an important role in learning, memory, and the control of posture.

The Role of IGF2

The study also suggests that insulin-like growth factor 2 (IGF2) is involved in the effects of galantamine on the survival of 2-week-old immature cells in the DG. In an earlier study, researchers found that galantamine increases hippocampal IGF2 levels.7 This suggests that IGF2 signaling plays a key role in galantamine-induced survival of immature cells in the granule cell layer of the DG.


Pattern separation is the process of
memory distinction, where
similar patterns of neural activity
are separated when perhaps only
one element is different.


See “Galantamine protects, stimulates, and improves memory … through elevation of insulin-like growth factor 2” in the November 2012 issue. In that article, “IGF2 is known to be important in body growth and development, but its role in the adult brain has not been established. While highly expressed in the hippocampus, Alberini and colleagues [ ] showed that in this region IGF2 has a crucial role in memory consolidation and can make memories last longer.” Also, “The systemic administration of galantamine at doses of 0.3–3 mg/kg (for 3/mg/kg, the human equivalent is 21 mg for a 187 lb person) caused a significant increase in IGF2 mRNA levels in the hippocampus … .”

Galantamine-induced increases in cell survival were blocked by the α7 nicotinic receptor antagonist methyllycaconitine, but not by the muscarinic receptor antagonist scopolamine. This helped the researchers to form their conclusions about the role of the M1 muscarinic receptor. Also, bilateral injection of recombinant IGF2 into the DG of the hippocampus mimicked the effects of galantamine.

Mechanistically, these findings suggest that galantamine promotes neurogenesis via activation of the α7 nicotinic acetylcholine and the M1 muscarinic receptors. And also that IGF2 is involved in the effects of galantamine on the survival of 2-week-old immature cells in the granule cell layer.

Alzheimer’s and Neurogenesis

Adult hippocampal neurogenesis is impaired in Alzheimer’s disease,8–10 and may be a target for the treatment of mental decline including Alzheimer’s disease patients.

The authors speculate that the increases in hippocampal IGF2 levels and neurogenesis may be involved in the clinical effect of galantamine.

LEM1407hippocampal274.jpg
(click on thumbnail for full sized image)

Other Neurogenesis Enhancers

Hesperidin enhances neurogenesis. Durk Pearson & Sandy Shaw write, “Neurogenesis is the creation of new neurons that takes place in adult mammals in particular areas of the brain. This process enables adults to maintain the ability to learn throughout life. But the mechanisms that make neurogenesis possible become less effective with age, thus rendering older people less able to produce new neurons and, consequently, less able to deal with complex cognitive activities necessary for rewarding adaptation to ever-changing conditions. As people age, they tend to use compensatory mechanisms to help deal with their less effective cognitive functions. For example, when faced with complex problems, older people generally use more areas of the brain than do younger people. [References removed.]” (See their article “Would You Like To Enjoy Life More?” in the March 2014 issue.)

The Neurogenesis of a Young Person

Continuing, “There is quite a bit known now about how neurogenesis works. It has been found possible to improve the process so that it functions more like that in young individuals by using specific nutrients, food components, herbs, or certain drugs. We have added hesperidin [to our galantamine formulation], a flavonoid widely found in fruits and vegetables, for its ability to promote the survival of neural progenitors that are developing into mature neurons. The effect of hesperidin on neural progenitors in cell culture was due to increased survival rather than increasing proliferation. An earlier paper by the same authors found hesperidin to reduce neuronal death by 50% after 48 hours of 10 μM hesperidin treatment in culture. Hesperidin-primed astrocytes were protected against neural progenitor death. A significant advantage of having a larger population of young newly developed neurons is that they tend to be more youthful (have more energy, are more active and more responsive to stimuli, and learn more easily) than mature adult neurons, thus helping maintain that youthful zest for life. [References removed.]”

“Is the world moving too fast for you? Do something about it by nurturing your newborn neurons!”

Then there is curcumin, the turmeric-derived component, “to reverse impaired hippocampal neurogenesis and to increase brain-derived neurotrophic factor in chronically stressed rats.” (See the source of the quote, with references in the article, “Announcing Durk & Sandy’s … New Lithium Formulation” in the June 2014 issue of Life Enhancement.)

Another neurogenesis enhancer is lithium. See “Lithium Restores Neurogenesis in Mouse Model of Down’s Syndrome, Correcting Cognitive Defects” in the August 2013 issue of Life Extension News, where Durk & Sandy write, “… researchers publishing a new paper found that treatment with the mood stabilizer lithium markedly increased adult neurogenesis in the subventricular zone (SVZ) of the brain as well as restoring brain volume in several areas where it is smaller than in normal mice. [Reference removed.]”

In another new study,11 lithium was found to be helpful for traumatic brain injury because, “Lithium exerts neuroprotective effects and stimulates neurogenesis via multiple signaling pathways… [Emphasis added].” And another new study12 found that, “the combination of enriched environment and lithium has both synergistic and additive effects on the generation of new cells [neurogenesis] in the healthy adult DG …”

So here you have some valuable information about how to keep your brain more youthful: galantamine, turmeric, ­hesperidin, and lithium. Do not be left behind!

References

  1. Jin K, Xie L, Mao XO, Greenberg DA. Alzheimer’s disease drugs promote neurogenesis. Brain Res. 2006 Apr 26;1085(1):183-8.
  2. Wesnes KA, Annas P, Basun H, Edgar C, Blennow K. Performance on a pattern separation task by Alzheimer’s patients shows possible links between disrupted dentate gyrus activity and apolipoprotein [element of]4 status and cerebrospinal fluid amyloid-03B242 levels. Alzheimers Res Ther. 2014 Apr 15;6(2):20.
  3. Kita Y, Ago Y, Higashino K, Asada K, Takano E, Takuma K, Matsuda T. Galantamine promotes adult hippocampal neurogenesis via M1 muscarinic and α7 nicotinic receptors in mice. Int J Neuropsychopharmacol. 2014 May 12:1-12.
  4. Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey TJ. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 2009 Jul 10;325(5937):210-3.
  5. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Boström E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, Frisén J. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013 Jun 6;153(6):1219-27.
  6. Ally BA, Hussey EP, Ko PC, Molitor RJ. Pattern separation and pattern completion in Alzheimer’s disease: evidence of rapid forgetting in amnestic mild cognitive impairment. Hippocampus. 2013 Dec;23(12):1246-58.
  7. Kita Y, Ago Y, Takano E, Fukada A, Takuma K, Matsuda T. Galantamine increases hippocampal insulin-like growth factor 2 expression via α7 nicotinic acetylcholine receptors in mice. Psychopharmacology (Berl). 2013 Feb;225(3):543-51.
  8. Crews L, Masliah E. Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum Mol Genet. 2010 Apr 15;19(R1):R12-20.
  9. Lazarov O, Marr RA. Neurogenesis and Alzheimer’s disease: at the crossroads. Exp Neurol. 2010 Jun;223(2):267-81.
  10. Curtis MA, Low VF, Faull RL. Neurogenesis and progenitor cells in the adult human brain: a comparison between hippocampal and subventricular progenitor proliferation. Dev Neurobiol. 2012 Jul;72(7):990-1005.
  11. Leeds PR, Yu F, Wang Z, Chiu CT, Zhang Y, Leng Y, Linares GR, Chuang DM. A NewAvenue for Lithium: Intervention in Traumatic Brain Injury. ACS Chem Neurosci. 2014 Apr 11. [Epub ahead of print]
  12. Schaeffer EL, Cerulli FG, Souza HO, Catanozi S, Gattaz WF. Synergistic and additive effects of enriched environment and lithium on the generation of new cells in adult mouse hippocampus. J Neural Transm. 2014 Feb 20. [Epub ahead of print]


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

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