Two benefits for rundown legs …

Galantamine Preserves Muscles
And May Benefit Arteries

By Will Block

P eripheral vascular disease (PVD) is a common circulatory problem in which narrowed arteries reduce blood flow to our limbs. It occurs when the large arteries in the legs are obstructed to a greater or lesser degree by atherosclerosis and inflammatory processes. PVD may result in either acute or chronic ischemia (lack of blood supply). PVD is a very common condition in Americans age 65 and older, affecting an estimated 8–10 million Americans.

PVD signs and symptoms include:

  • Claudication—pain, weakness, numbness, or cramping in muscles caused by walking or exercise

  • Sores, wounds, or ulcers that heal slowly or not at all

  • Noticeable change in color (blueness or paleness) or temperature (coolness)

  • Diminished hair and nail growth on affected limb and digits

PVD can be a debilitating and agonizing problem.


Fig 1. Angiogenesis occurs when triggers such as VEGF cause increased blood vessel growth. These new vessels can reduce the stress caused by PVD.
Galantamine Enhances Angiogenesis

Fortunately, it has recently been found that acetylcholinesterase inhibitors—such as galantamine—accelerate angiogenesis, the physiological process through which new blood vessels form from pre-existing vessels.1 This can alleviate the pressure, pain, and damage of PVD. Galantamine enhances angiogenesis by up-regulating the expression of vascular endothelial cell growth factor (VEGF).1 See Figure 1.

A new study conducted in Tokyo and Kochi, Japan by the same researchers,2 reported that:

  1. A nicotinic receptor, partly through an a7 nicotinic receptor (a type of nicotinic acetylcholine receptor), is responsible for the effect of nicotine to sustain skeletal muscle mass in a hindlimb ischemia (HLI) mouse model*

  2. Myoblast cells (aka satellite cells) respond to nicotine and express angiogenic factors through the nicotinic receptor

  3. Nicotine represses gene expression of muscle atrophic markers and up-regulates the gene expression of the myosin heavy chain, comprised of motor proteins that are best known for their role in muscle contraction
  4. Nicotine inhibits progression of muscle atrophy induced by HLI in certain mice, but not in α7 knock-out mice (lacking the α7 receptor), and galantamine, which possesses the effect of an allosteric potentiating ligand, comparably prevents skeletal muscle from being affected by HLI.


* HLI entails (no pun intended) the surgical ligation of the femoral artery near the hindlimb of a mouse. This triggers the arteriogenesis of small, pre-existing collateral arteries into functional conduit vessels proximally and ischemic angiogenesis at a distance.



PVD is a very common condition in
Americans age 65 and older, affecting
an estimated 8–10 million Americans.


These results indicate that nicotine plays an angiogenic role in an HLI model partly through satellite cells, which produce angiogenic factors. Consequently, the researchers suggest that the cholinergic system in skeletal muscle is involved in anti-atrophy of muscle. In other words, a healthy cholinergic system helps maintain muscle mass and functionality.

Nicotinic Activity Accelerates Angiogenesis

Other studies have reported that nicotine helps accelerate angiogenesis in several models using a mechanism in which nicotine directly stimulates the proliferation of endothelial cells through nicotinic receptors.


Cholinergic system in
skeletal muscle is involved in
anti-atrophy of muscle.


Despite the disadvantageous effect of enhancing the growth of already existing tumors in some instances, nicotine has some advantages in a model of ischemic disease because it is identified to be a powerful angiogenic substance. However, the angiogenic effect of nicotine appears to be beneficial in a short-term application, but not in a long-term application. Thus, the researchers also used galantamine, a nicotine-like substance, on skeletal muscle.

Satellite Cells Help with Muscle Regeneration

To the best of the researcher’s knowledge, there are few studies showing that nicotine or an acetylcholinesterase inhibitor can suppress muscle atrophy induced by muscle disuse or inactivity.

Fig. 2. Satellite cells produce angiogenic factors, which can help with muscle regeneration.
LEM1407satellitecells260.jpg
(click on thumbnail for full sized image)

Nonetheless, the new study definitely demonstrates that the extravasculature effect of nicotine is attributed to the anti-atrophy effect on satellite cells. Satellite cells are well known to play a specific role of stem cell-like cells in skeletal muscle. When skeletal muscle is subjected to injury, the skeletal satellite cells respond by proliferating to help with regeneration of the muscle. The anatomic characteristic of satellite cells in skeletal muscle is that they are located between muscle fibers. Therefore, it is speculated that satellite and endothelial cells establish interactions by releasing factors from each other. (See Figure 2.)

Angiogenic Factors May Activate Survival Signals

In the recent Japanese study, VEGF-positive cells were detected not only in endothelial cells but also in satellite cells in vivo. Taken together, this suggests that satellite and microvascular endothelial cells both have the potential to synthesize VEGF and promote cell-cell interactions through angiogenic factors. These factors are known to be survival factors for not only vascular endothelial cells, but also non-vascular cells.

As the researchers show, nicotine activates several survival signals through phosphorylation of Akt and CREB. Akt is a protein kinase that plays a key role in multiple cellular processes such as cell proliferation, transcription, and cell migration. CREB is a cellular transcription factor. It has been speculated that nicotine-induced expression of angiogenic factors may be responsible for this activation of survival signals. Thus, nicotine is supposed to exert an anti-ischemic effect through the activation of survival signals in satellite cells.

Nicotine Helps Inhibit Muscle Atrophy Caused by Ischemia

These in vitro results were strongly supported by in vivo studies using HLI mice treated with nicotine. As already shown, nicotine-treated mice remarkably sustained skeletal muscle mass in the subjected left hindlimb compared with non-treated mice, suggesting that nicotine helps inhibit muscle atrophy caused by ischemia.

Furthermore, the beneficial anti-atrophy effect of nicotine in wild type mice was canceled by α7 KO mice. Alternatively, an α7 nicotinic receptor agonist also suppressed HLI-induced muscle atrophy and nicotine. These in vivo data strongly support the fact that nicotine plays a role in suppressing ischemia-induced muscle atrophy to sustain muscle mass.


Satellite cells are well known to
play a specific role of stem cell-like
cells in skeletal muscle.


However, in α7 KO mice the ability of nicotine to prevent its anti-atrophy effect on muscle was blunted, and other types of nicotinic receptors did not alter the impairment. This failed compensation was also observed in the impaired effects of nicotine on accelerating angiogenesis in α7 KO mice.

Galantamine Bypasses the Negative Effects of Nicotine

When considering the clinical application of nicotine, particularly through systemic administration, the serious side effects of nicotine—including excitation, seizure, addiction, and death—should be recognized. Moreover, chronic application of nicotine may result in signaling down-regulation. These facts pose significant difficulties in the practical application of nicotine in clinical situations. Therefore, instead of nicotine, the scientists selected the acetylcholinesterase inhibitor galantamine bromide.

Galantamine Efficiently Conserves Muscle Mass

Galantamine has already been prescribed worldwide to patients with Alzheimer’s disease, and is also known to exert a pharmacologic action through nicotinic receptors because it can act as an allosteric potentiating ligand. In the present study, galantamine was applied to the mouse HLI model. As expected, galantamine could efficiently conserve muscle mass in the subjected left hindlimb in comparison with nontreatment. This beneficial effect of galantamine was associated with increased VEGF signals in both satellite and vascular endothelial cells.


Satellite and microvascular
endothelial cells both have
the potential to synthesize VEGF
and promote cell-cell interactions
through angiogenic factors.


PVD Increasing in Western Countries

The number of patients with PVDs has recently increased, particularly in western countries because of a higher incidence of diseases such as metabolic syndrome, diabetes mellitus, hypertension, and atherosclerosis. Despite the development of several orthodox therapeutic strategies against PVD, including stents, bypasses, and regenerative therapies (these will come) using endothelial progenitor cells, the disease is far from fully cured. In serious cases, it finally progresses to gangrene, and amputation is required. The unfortunate outcome of current therapeutic tactics highlights the need for alternative strategies, such as highly effective oral and intravenous chelation therapy, to which we can now advocate the use of galantamine.

The Japanese study presents a novel strategy in PVD therapy. Galantamine targets not only vasculature but also skeletal satellite cells. It activates the satellite cells to accelerate myogenesis (muscle growth) using nicotinic receptors, and enhances the expression of angiogenic factors. This new research indicates that galantamine can be used as a substitute for nicotine to sustain skeletal muscle mass subjected to ischemia.

The Therapeutic Target is Satellite Cells

In the researchers’ previous study,1 they reported that another acetylcholinesterase inhibitor, donepezil, accelerated angiogenesis through activation of endothelial cell tube formation. Their current study progressed to identify a novel therapeutic target in PVD—that is, satellite cells.

This concept of myogenic cell-derived angiogenic factors driven by a nicotinic signal will eventually result in a clinical study to test whether galantamine may be effective in patients with PVD.

If you are already taking galantamine for memory support, you have nothing to lose and possibly a big gain ahead for your muscles and gait.

Galantamine Helps Maintain Muscles and Better Contraction

Activating nicotinic receptors (including an α7 nicotinic receptor) may lead to prevention of muscle atrophy, upregulation of myosin heavy chain gene expression, and better muscle contraction. For the present, at least, the use of galantamine for PVD may be a wise strategy.

References

  1. Kakinuma Y, Furihata M, Akiyama T, Arikawa M, Handa T, Katare RG, Sato T. Donepezil, an acetylcholinesterase inhibitor against Alzheimer’s dementia, promotes angiogenesis in an ischemic hindlimb model. J Mol Cell Cardiol. 2010 Apr;48(4):680-93.
  2. Kakinuma Y, Noguchi T, Okazaki K, Oikawa S, Iketani M, Kurabayashi M, Furihata M, Sato T. Antimuscle atrophy effect of nicotine targets muscle satellite cells partly through an α7 nicotinic receptor in a murine hindlimb ischemia model. Transl Res. 2014 Apr 24. pii: S1931-5244(14)00140-6. doi: 10.1016/j.trsl.2014.02.005. [Epub ahead of print].


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

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