Better for your neurons in 3 ways …

Galantamine protects, stimulates,
and improves memory

… through elevation of insulin-like growth factor 2

By Will Block

Intelligence is the wife, imagination is the mistress, memory is the servant.
— Victor Hugo, Post-scriptum de ma vie (1901)

I

nsulin-like growth factor 2 (IGF2) significantly enhances memory retention and prevents forgetting. That’s what researchers reporting in Nature found last year.1 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 (the authors of the Nature paper) showed that in this region IGF2 has a crucial role in memory consolidation and can make memories last longer.

Using what is known as inhibitory avoidance learning training—a hippocampus-depend­ent learning task that measures fear memory—the researchers placed rats in an environment where upon entering dark areas the rats received a shock to the feet. Their fear memory was enhanced as they learned to avoid the dark areas (into which they are naturally inclined to enter), and this in turn led to an increase in the hippocampal expression of IGF2.

The creation of this IGF2 requires the transcription factor CCAAT enhancer binding protein β,* which is also essential for memory consolidation. Furthermore, injections of recombinant IGF2 into the hippocampus, after either training or memory retrieval, significantly enhanced memory retention and prevented forgetting.


* CCAAT-enhancer-binding proteins are a family of transcription factors, composed of six members that promote the expression of certain genes through interaction with their promoter. Once bound to DNA, these transcription facts can recruit so-called co-activators that, in turn, can open up chromatin structure or recruit basal transcription factors. They are involved in different cellular responses, such as in the control of cellular proliferation, growth, and differentiation, metabolism, immunity, and memory enhancement.


The time factor for efficacy

To be effective, IGF2 needs to be administered within a sensitive period for memory consolidation. IGF2-dependent memory enhancement requires IGF2 receptors, new protein synthesis, the function of activity-regulated cytoskeletal-associated protein, and glycogen-synthase kinase 3 (GSK3). This is intriguing because GSK3 is a regulatory kinase that is implicated in a number of diseases, including type 2 diabetes, Alzheimer’s disease, inflammation, cancer, and bipolar disorder. In hippocampal slices, IGF2 promotes IGF2 receptor-dependent, persistent long-term potentiation after weak synaptic stimulation. Thus, IGF2 may represent a novel target for cognitive enhancement therapies.

Galantamine significantly increases IGF2

In a new study conducted in Japan, researchers examined the effects of acute galantamine treatment on the mRNA levels of neurotrophic growth factors in the mouse hippocampus and prefrontal cortex.2

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, but not in the prefrontal cortex. The effect of galantamine was also observed at the protein level. IGF2 promotes cell growth, survival, migration, and differentiation and plays an important role in normal fetal development.


IGF2 significantly enhances memory
retention and prevents forgetting.


IGF2 increases memory consolidation in rats

In the study cited above,1 it was shown that inhibitory avoidance learning led to an increase in hippocampal expression of IGF2, closely linking to memory consolidation in rats. The researchers showed that injection of recombinant IGF2 into the hippocampus after either training or memory retrieval enhanced memory retention and prevented forgetting. They also showed that IGF2 promoted IGF2 receptor-dependent persistent long-term potentiation after weak synaptic stimulation in the rat hippocampal slices.

Three-way neuronal help

Thus, IGF2 has been implicated in cognitive function associated with the hippocampus. In addition, another study recently demonstrated that IGF2 is an important regulator of adult hippocampal neurogenesis.3 As the authors of the Japanese galantamine/IGF2 study2 observed in a separate experiment, acute galantamine treatment (3 mg/kg) increased newly divided cell proliferation in the hippocampal dentate gyrus of mice 24 hours after the injection (unpublished).


IGF2 has a crucial role in memory
consolidation and can make
memories last longer.


When taken together, the present finding implies that galantamine: 1) protects neurons, 2) stimulates neurogenesis, and 3) improves cognitive dysfunction in Alzheimer’s disease via its action on IGF2 expression.

The researchers also observed that the higher dose of galantamine (3 mg/kg) caused a transient increase in fibroblast growth factor 2 (FGF2) mRNA level and a decrease in brain-derived neurotrophic factor (BDNF) mRNA level in the hippocampus of mice. The exact reason for these effects is not known, but previous studies show that nicotine or nicotine acetylcholine receptor (nAChR) agonists increase the expression of FGF2 and decrease the expression of BDNF in the hippocampus.

What is suggested, however, is that the galantamine-induced changes in FGF2 and BDNF mRNA levels may be due to its action on nAChR, although galantamine even at low doses binds allosterically to nAChR and potentiates its function which is to make acetylcholine perform better. With regard to the effect of galantamine on BDNF levels, the Japanese researchers reported that galantamine increases phosphorylation of BDNF’s trkB receptor and transcription factor CREB in the mouse hippocampus. Thus, it is thought unlikely that galantamine-induced reduction in the BDNF mRNA levels per se is involved in the facilitation of hippocampal neurotrophin signaling.


† CREB (cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the downstream genes. cAMP (cyclic adenosine monophosphate) is a second messenger important in many biological processes.


Other signals that are not involved

Among the neurotrophic/growth factors examined in the study, galantamine did not affect NGF, VEGF, or IGF1 mRNA levels in the hippocampus and prefrontal cortex. Thus, these factors may not act as the downstream signals of galantamine in either brain region.


Galantamine 1) protects neurons,
2) stimulates neurogenesis, and
3) improves cognitive dysfunction
in Alzheimer’s disease
via its action on IGF2 expression.


Previous in vitro studies have shown that galantamine is an allosterically potentiating ligand of nAChR. In fact, the nAChR-modulating properties play a key role in the effects of galantamine, while muscarinic acetylcholine receptor (mAChR) activation contributes at least partly to the antipsychotic effect and improvement of cognitive dysfunction by galantamine in rodents.

Antagonists and agonists

The present study2 found that both a nonselective nAChR antagonist and a selective α7 nAChR antagonist block the galantamine-induced increase in hippocampal IGF2 mRNA levels. But, it is not blocked by a preferential M1 mAChR antagonist.


These findings suggest that α7 nAChR
is involved in the increasing effect of
galantamine on IGF2 expression.


Moreover, the injection of a selective α7 nAChR agonist, at doses of 0.3 and 1 mg/kg increased IGF2 mRNA levels in the hippocampus. These findings suggest that α7 nAChR is involved in the increasing effect of galantamine on IGF2 expression.


In contrast to galantamine, donepezil
did not affect IGF2 mRNA levels
in the hippocampus.


Getting the dose right

Concerning the effect of the selective α7 nAChR agonist, others have reported that its injection at doses of 1 mg/kg, but not 0.3 mg/kg, improved the performance of rats in the novel object recognition test and much higher doses (0.3 and 1 mg/kg, intravenously) reversed amphetamine-induced auditory gating deficits in rats. The apparent difference in the effect of this agonist at 0.3 mg/kg between the behavioral and biochemical studies may be due to the difference in pharmacokinetics of the drug between rats and mice. Rats have twice the surface area of mice, and this difference determines the right dose.

Donepezil, another inhibitor of acetylcholinesterase, fails

In another study,4 the effect of donepezil was also examined to study the role of galantamine as an allosterically potentiating ligand of nAChR. Donepezil, an inhibitor of acetylcholinesterase, increases extracellular levels of acetylcholine (ACh), which interacts with the α7 nAChR as well, but is not an allosterically potentiating ligand of nAChR.


Galantamine increases hippocampal
IGF2 mRNA levels in
a dose-dependent manner.


In contrast to galantamine, donepezil did not affect IGF2 mRNA levels in the hippocampus. This difference may be explained by the evidence that ACh has a lower affinity for the α7 nAChR compared to the α7 nAChR agonist references above, and that galantamine is an allosterically potentiating ligand of nAChR.


The present finding suggests that the
effect of galantamine on hippocampal
IGF2 levels may contribute to the
mechanism for its neuroprotective
and neurogenesis effects.


Recalling the music of memory

In conclusion, the Japanese researchers found that acute administration of galantamine increases hippocampal IGF2 mRNA levels in a dose-dependent manner. Their study suggests that the galantamine-induced increase in the hippocampal IGF2 mRNA and protein levels is mediated by the α7 nAChR. Recall that IGF2 has been implicated in cell growth and survival, and hippocampus-associated function. Consequently, the present finding suggests that the effect of galantamine on hippocampal IGF2 levels may contribute to the mechanism for its neuro­rotection or neurogenesis. This may be why people taking galantamine like the way that they feel, and that one musician who was forgetting certain music chords that he had known by heart for years, brought back those chords, instrumental to his music, with galantamine.

Abbreviations

ACh

Acetylcholine

BDNF

Brain-derived neurotrophic factor

CREB

cAMP response element-binding protein

FGF2

Fibroblast growth factor 2

GSK3

Glycogen-synthase kinase 3

IGF2

Insulin-like growth factor 2

mAChR

Muscarinic acetylcholine receptor

nAChR

Nicotinic acetylcholine receptor

NGF

Nerve growth factor

References

  1. Chen DY, Stern SA, Garcia-Osta A, Saunier-Rebori B, Pollonini G, Bambah-Mukku D, Blitzer RD, Alberini CM. A critical role for IGF-II in memory consolidation and enhancement. Nature 2011 Jan 27;469(7331):491-7.
  2. 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). 2012 Aug 30. [Epub ahead of print]
  3. Bracko O, Singer T, Aigner S, Knobloch M, Winner B, Ray J, Clemenson GD Jr, Suh H, Couillard-Despres S, Aigner L, Gage FH, Jessberger S. Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. J Neurosci 2012 Mar 7;32(10):3376-87.
  4. 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;196:293–301.


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

Featured Product

  • Learn more about Galantamine benefits and implementation strategies.

Ingredients in this Article

FREE Subscription

  • You're just getting started! We have published thousands of scientific health articles. Stay updated and maintain your health.

    It's free to your e-mail inbox and you can unsubscribe at any time.
    Loading Indicator