Through a non-neural pathway …

Galantamine Benefits
Heart as Well as Mind

… by delivering more oxygen and
nutrients for your heart and brain

By Will Block

The damage that the human body can survive these days is as awesome as it is horrible: crushing, burning, bombing, a burst blood vessel in the brain, a ruptured colon, a massive heart attack, rampaging infection. These conditions had once been uniformly fatal.

— Atul Gawande, M.D.

T he ability to grow new blood vessels from existing ones is called angiogenesis. This process occurs though an interlocking chain of molecular actions. Indeed, it is a marvel of biochemical and biomechanical splendor. Angiogenesis facilitates the delivery of more blood—hence more oxygen, nutrients, and essential growth factors—to areas of the body that request it. Normally, angiogenesis is good.

In adults, angiogenesis is not a frequent occurrence, except during wound healing, when new blood vessels are needed to nourish new tissue. Wound healing depends on a well-balanced regulation of inflammation and angiogenesis. Also, it happens during the menstrual cycle in women, when new blood vessels are needed in the uterine lining.

Angiogenesis: The Difference Between Life and Death

However, angiogenesis can also occur in the body’s organs—such as the heart and brain—when some partial area is denied blood due to an obstruction in the normal blood supply. A prior study has demonstrated that the amino acid arginine can come to the rescue and be of great assistance in promoting angiogenesis.1 Its use can spell the difference between life and death for the tissue in question. Unquestionably, angiogenesis holds great promise when adversity takes over (see “Arginine Promotes Angiogenesis” in the July 2011 issue).


Angiogenesis facilitates the delivery
of more blood—hence more oxygen,
nutrients, and essential growth
factors—to areas of the body that
request it.


Angiogenesis Is a Double-Edged Sword

Regrettably, angiogenesis may be a bad thing as well as a good thing, depending on the physiological context.

Bad Angiogenesis—Cancer, along with a host of other diseases, may use the angiogenic process to create the growth of new and excessive new blood vessels to feed diseased tissues or destroy normal tissues (this is true in the “wet” form of age-related macular degeneration). In cancer, angiogenesis also facilitates metastasis, the process whereby tumor cells escape into the general circulation and lodge elsewhere in the body, starting new tumors.

Good Angiogenesis—As already partly explained, angiogenesis helps speed up wound healing (this is true in diabetes). In two notorious killers, coronary artery disease and stroke, it can help restore proper blood flow, and the rate of growth of new blood vessels. For these dilemmas, angiogenesis can be of vital importance.


Angiogenesis can also occur in the
body’s organs—such as the heart and
brain—when some partial area is
denied blood due to an obstruction in
the normal blood supply.


When to Promote or Inhibit Angiogenesis?

What determines whether angiogenesis is invoked? The unhappy truth is that people don’t conveniently have only one medical condition at a time, so if angiogenesis is such an important phenomenon in health and disease, then how do we know when to inhibit it and when to promote it? And with what agents, in what amounts, according to what protocols, and so forth? These are complex questions.

The Answer Involves Balancing Angiogenesis Switches

The human body controls angiogenesis through a series of “on” switches (angiogenesis factors, of which at least 20 are found in the body) and “off” switches (anti-angiogenesis factors, aka angiogenesis inhibitors, of which at least 30 are found in the body). When people are healthy, there is a perfect balance between these two opposing groups of agents, with the off switches dominating until a problem arises.

Nonetheless, in many disease states, the balance is disordered by overproduction or underproduction of various agents in one group or the other (or both), resulting in either excessive or insufficient angiogenesis.

Altogether, these problems are a common denominator shared by diseases—including cancer, cardiovascular disease, blindness, arthritis, diabetes, Alzheimer’s disease, complications of AIDS, and more than 70 other health conditions—that afflict well over 1 billion people worldwide.


Angiogenesis helps speed up
wound healing.


Angiogenesis Switches Are Research Targets

Enormous effort has been devoted to anti-angiogenesis research for the treatment of cancer (hundreds of agents have been discovered, but only a few have become prescription drugs). And of these, there are many significant adverse effects. Then there is the escalating field of pro-angiogenesis research, called therapeutic angiogenesis, for cardiovascular and cerebrovascular disease treatment. So far, only a few drugs have been FDA-approved for such therapy, and most of the research is focused on finding ways to activate the body’s own pro-angiogenic agents. The only drug approved is the recombinant protein drug becaplermin (a gel), which is indicated for diabetic neuropathic lower extremity ulcers. Currently, there are no FDA-approved angiogenic drugs for the treatment of ischemic cardiovascular disease.

Galantamine Joins Arginine for Pro-Angiogenesis

Because of their general benevolence, nutrient agents, such as arginine, have entered the realm of pro-angiogenesis research. And now, a very new paper has just been ePublished (it has not yet occurred in print) suggesting that galantamine may yet be another nutrient able to act as pro-angiogenesis agent.2

Galantamine has not been associated with bad angiogenesis in the scientific literature. In fact, a recent study3 demonstrated that acetylcholinesterase inhibitors (AChEIs), including galantamine, “promoted angiogenesis and also protected endothelial cells against oxidative stress-induced cytotoxicity. Therefore, these effects of AChEIs may be involved in their beneficial effects on Alzheimer’s disease.”


Fig. 1. Angiogenesis occurs when triggers such as vascular endothilial growth factor cause increased blood vessel growth. These new vessels can reduce the stress caused by pulmonary vascular disease.
In the new study,2 galantamine was found for the first time to enhance angiogenic factor expression through nicotinic receptors or AChEI. This study, conducted at Nippon Medical School Graduate school of Medicine, in Tokyo is the first to show—to the best of the researchers’ knowledge—that skeletal muscle-derived stem cells expressing non-neuronal acetylcholine (ACh) can be modulated by nutrients (i.e., galantamine). See Fig. 1.

It now seems clear that certain satellite cells—i.e. muscle stem cells—possess the ability to produce angiogenic factors, including fibroblast growth factor (FGF)-2 and vascular endothelial growth factor (VEGF) in vivo.4,5 Both of these factors are needed for angiogenesis. These muscle stem cells also synthesize ACh and this synthesis is augmented by the AChEI galantamine. In other words, in addition to muscle stem cells synthesizing ACh, galantamine inhibits the enzymatic breakdown of ACh. Thus making for more active ACh.

Cholinergic Neurons Sustain Life

Human life is controlled by neurons and, of these, cholinergic neurons play a crucial role. Cholinergic neurons release ACh, which, via nicotinic and muscarinic receptors, mediate chemical neurotransmission, a highly integrative process.6

Consequently, owing to cholinergic neurons, humans respond to external and internal stimuli to maintain and optimize survival and mood. When cholinergic neurotransmission is blocked, immediate death follows! It is well known that cholinergic communication has been established from the beginning of life in primitive organisms such as bacteria, algae, protozoa, sponge and primitive plants and fungi, irrespective of neurons.

All Cholinergic Components Found in Non-Neuronal Cells

All the components of the cholinergic system (ChAT, ACh, nicotinic and muscarinic acetylcholine receptors, high-affinity choline uptake, esterase) have been demonstrated in mammalian non-neuronal cells, including those of humans. ChAT stands for choline acetyltransferase, a transferase enzyme responsible for the synthesis of the neurotransmitter ACh. Embryonic stem cells (mice), epithelial, endothelial, and immune cells synthesize ACh, which via differently expressed patterns of nicotinic and muscarinic acetylcholine receptors modulates cell activities to respond to internal or external stimuli.

This process helps to maintain and optimize cell function, such as proliferation, differentiation, formation of a physical barrier, migration, and ion and water movements. Blockade of nicotinic and muscarinic acetylcholine receptors on non-innervated cells causes cellular dysfunction and/or cell death.

Thus, cholinergic signalling in non-neuronal cells is comparable to cholinergic neurotransmission. Dysfunction of the non-neuronal cholinergic system is involved in the pathogenesis of diseases. Alterations have been detected in inflammatory processes and a pathobiologic role of non-neuronal ACh in different diseases. These results provide a novel concept that muscle stem cells express non-neuronal ACh and thus can be a therapeutic target for regulating angiogenic factor synthesis. Galantamine hits that target.


Thus, cholinergic signalling in non-
neuronal cells is comparable to
cholinergic neurotransmission.


Stem Cells Synthesize ACh

In the present study, the Japanese researchers presented data demonstrating that mouse skeletal muscle stem cells synthesize ACh. To date, it has been reported that several cells possess the ability to synthesize ACh, including immune and epithelial cells. This novel concept of non-neuronal cholinergic system or non-neuronal ACh has been extensively discussed. However, there are only a few reports showing the existence of a non-neuronal cholinergic system or non-neuronal ACh by muscular type cells, excluding heart muscle cells This is because a previous study done by the same Japanese researchers, along with other reports, has confirmed that heart muscle cells synthesize ACh through their intrinsic machinery.


Muscle-derived cells are equipped
with this non-neuronal cholinergic
system, making them a therapeutic
target for some cardiovascular
disease, as suggested by the previous
studies of the Japanese scientists.


Adding to this, a few prior studies have disclosed the existence of a non-neuronal cholinergic system (or non-neuronal ACh) in skeletal muscle, which reported that myoblasts and satellite cells synthesized ACh. Yet, this research may have involved pharmacological upregulation. However, the current study uncovered the important finding that muscle-derived cells are equipped with this non-neuronal cholinergic system, making them a therapeutic target for some cardiovascular disease, as suggested by the previous studies of the Japanese scientists.

Skeletal myoblasts or muscle stem cells, which were used as an alternative to satellite cells in this study, are further differentiated compared with satellite cells, and they are not developmentally identical to satellite cells. However, satellite cells play a crucial role in muscle tissue generation, because they are considered to be muscle stem cells.


These studies suggest a close link
between the cholinergic system, i.e.
acetylcholine (ACh), and angiogenesis.


ACh increased VEGF, a Major Angiogenic Factor

In two prior studies, the researchers revealed that satellite cells as well as vascular endothelial cells were involved in accelerating angiogenesis in a mouse hindlimb ischemia model.4,5 In those studies, satellite cells were confirmed to be responsible for angiogenic factor expression. Moreover, their previous studies clarified that ACh increased VEGF, a major angiogenic factor. Taken together, these studies suggest a close link between the cholinergic system, i.e. ACh, and angiogenesis.

Since the first report of non-neuronal ACh or a non-neuronal cholinergic system, the biological significance of these systems has been investigated in many cells. Yet, studies addressing non-neuronal ACh with utilizing skeletal muscle-derived cells are few.

Non-Neuronal ACh Was Upregulated by Galantamine

Intriguingly, the current study confirmed that muscle stem cells synthesized ACh at levels comparable with those previously reported in heart muscle cells. Also confirmed, non-neuronal ACh was upregulated by galantamine, which was already known to function as an allosteric potentiating ligand through nicotinic receptors. Compatibly, nicotine itself also increased intracellular ACh levels; supporting a possibility that galantamine induces ACh synthesis in muscle stem cells through its allosteric potentiating ligand effect (modulating nicotinic receptors).

Thus, it is suggested that galantamine possesses three effects: 1) As an acetylcholinesterase inhibitor, thereby boosting brain levels of acetylcholine; 2) As a modulator of the brain’s nicotinic receptors, so as to maintain their function; and 3) As a non-neuronal ACh inducer. In contrast, donepezil, an AChEI drug, also is similar to galantamine in many ways, but without an allosteric potentiating ligand effect. As already reported by the researchers, donepezil plays a role in stimulating non-neuronal ACh in heart muscle cells, even without the allosteric potentiating ligand effect of galantamine. However, galantamine-treated muscle stem cells upregulated ChAT promoter activity and cellular ACh levels. These results suggest that, independently of the allosteric potentiating ligand effect, both AChEIs may share a common feature as a non-neuronal ACh inducer.


Galantamine possesses three effects:
1) As an acetylcholinesterase
inhibitor, 2) As a modulator of the
brain’s nicotinic receptors, and 3) As
a non-neuronal ACh inducer.


As previously reported, non-neuronal ACh was partly regulated via muscarinic receptors in a positive feedback fashion, i.e., ACh-induced ACh synthesis. To elucidate the mechanisms by which galantamine upregulated non-neuronal ACh in muscle stem cells and whether nicotinic receptors are involved in the upregulation, a ChAT promoter assay was performed.

Galantamine Augments ACh in Muscle Stem Cells


Figure 2. Schematic drawing of human tendon tissue showing the occurrence of a non-neuronal cholinergic system in tendinosis. Violet dots represent acetylcholine (ACh) that is locally produced in tenocytes of pathological appearance (unfilled arrow). Normal looking tenocytes (filled arrow) do not produce ACh. ACh can influence 1) nerves, 2) cells of blood vessel walls, and 3) the tenocytes themselves. These structures have been shown to be supplied with muscarinic ACh receptors of subtype M2 (M2R). Image by Gustav Andersson.

The reporter activity levels upregulated by galantamine were smaller than the Japanese researchers expected. Dependence on a selected promoter region may alter a transactivating potency, and therefore galantamine probably requires other specific ChAT promoter regions. However, what the researchers found was that galantamine actually augments ACh contents in muscle stem cells. Therefore, the increment in ChAT promoter activity is considered to be physiologically significant.


These results strongly suggest that
galantamine plays an additional role
in enhancing non-neuronal
acetylcholine through a non-nicotinic
receptor mechanism.


The reporter assay demonstrated that the effect of galantamine occurred through nicotinic and non-nicotinic receptors. In contrast, nicotine-induced ChAT upregulation was completely dependent on nicotinic receptors, because mecamylamine—a non-specific nicotinic receptor antagonist—completely abolished the nicotine-mediated upregulation. These results strongly suggest that galantamine plays an additional role in enhancing non-neuronal ACh through a non-nicotinic receptor mechanism.

More VEGF Secretion with Galantamine

The current study presents further evidence that muscle stem cells secrete VEGF, and, in response to nicotine or galantamine, they were stimulated to further secrete VEGF. The accumulated evidence in several other reports strongly supports their findings. Compatible with the ChAT reporter assay results, galantamine-induced VEGF secretion was blunted by neither mecamylamine (an antagonist of nicotinic acetylcholine receptors) nor atropine (a competitive antagonist of the muscarinic acetylcholine receptors).


Galantamine may help both the brain
and the heart when some partial area
is denied blood due to an obstruction
in the normal blood supply.


Emphatically, nicotine-induced VEGF secretion was completely suppressed by mecamylamine. This result definitely indicates that muscle stem cells serve as another source for angiogenic factors, and nicotine and galantamine stimulate angiogenic factor secretion, although the ability of galantamine to produce VEGF is not mediated by nicotinic receptors alone.

To the best of the Japanese researchers’ knowledge, the current study is the first to demonstrate that skeletal muscle-derived cells expressing non-neuronal ACh can be modulated by nicotinic receptor dependent and non-dependent mechanisms and can be a therapeutic target to enhance angiogenic factor expression through nicotinic receptors or ACh esterase inhibition. Once again, galantamine hits that target and accordingly—through the enhancement of angiogenic factor expression—may help both the brain and the heart when some partial area is denied blood due to an obstruction in the normal blood supply.

References

  1. Ruel M, Beanlands RS, Lortie M, et al. Concomitant treatment with oral L-arginine improves the efficacy of surgical angiogenesis in patients with severe diffuse coronary artery disease: The Endothelial Modulation in Angiogenic Therapy randomized controlled trial. J Thorac Cardiovasc Surg. 2008;135:762–70.
  2. Oikawa S, Mano A, Iketani M, Kakinuma Y. Nicotinic receptor-dependent and -independent effects of galantamine, an acetylcholinesterase inhibitor, on the non-neuronal acetylcholine system in C2C12 cells. Int Immunopharmacol. 2015 May 12. pii: S1567–5769(15)00221–0. doi: 10.1016/j.intimp.2015.04.057. [Epub ahead of print]
  3. Mortazavian SM, Parsaee H, Mousavi SH, et al. Acetylcholinesterase inhibitors promote angiogenesis in chick chorioallantoic membrane and inhibit apoptosis of endothelial cells. Int J Alzheimers Dis. 2013;2013:121068. doi: 10.1155/2013/121068. Epub 2013 Sep 16.
  4. Noguchi T, Kakinuma Y, Arikawa M, et al. Donepezil can improve ischemic muscle atrophy byactivating angiomyogenic properties of satellite cells. Circ J. 2014;78(9):2317–24.
  5. Kakinuma Y, Noguchi T, Okazaki K, Oikawa S, Iketani M, Kurabayashi A, 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 Jul;164(1):32–45. doi: 10.1016/j.trsl.2014.02.005. Epub 2014 Apr 24. Erratum in: Transl Res. 2014 Dec;164(6):515.
  6. Wessler I, Kirkpatrick CJ. Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol. 2008 Aug;154(8):1558–71.


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

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