Galantamine/Choline synergy amps mind function and represents an …

Alzheimer’s Breakthrough
Galantamine, when taken with an acetylcholine precursor, improves the cholinergic
reuptake and release balance so necessary for optimum memory function
By Will Block


While snow is still on the ground, the snowdrop breaks through as if to remind us that it bears a memory of life.

A pril is approaching (or, when you read this, is already here) and winter’s snow is mostly gone (or soon will be), except in the mountains, along with Canada’s most northerly territories. In the USA, the winter of 2011–2012 has been moderate, except for Alaska where it has been severe. However, there has been no moderation in Europe. Quite the contrary, where the continuous icy cold fronts have taken many lives. In Bulgaria, as of late February (when this was written), seventeen regions were still under code orange (near disastrous) over extremely low temperatures, characterized as a “Polar Winter” according to the National Institute for Meteorology and Hydrology at the Bulgarian Academy of Sciences.

What does Bulgaria have to do with anything? That’s simple … if you are mindful. Bulgaria is the principal home of the commercial snowdrop and snowflake, the early spring flowers that break through the snow and are the principal sources of galantamine, the acetylcholinesterase inhibitor. This plant extract has been found beneficial for slowing the degeneration of the minds of countless victims of impaired memory, dementia, and the disease of Alzheimer’s (DA). Because galantamine helps to preserve acetylcholine (ACh)—an important memory molecule—it has prevented many minds from speeding off the cliff of consciousness.

And, according to recent research, it may also serve to prevent hypertension from precipitating vascular dementia (VaD), which in many instances is the forerunner of DA. The cerebrovascular injury caused by hypertension has been associated with compromised cognitive function, mainly memory dysfunction and decreased speed of information processing. What’s more, when galantamine is taken with an ACh precursor, galantamine works even better, not only to reduce the deleterious effects of hypertension on brain degeneration, but to improve upon the balance of cholinergic reuptake and release mechanisms so necessary for optimum memory function. Thus, the combination supplementation therapy can potentiate deficient cholinergic neurotransmission. Let us hope that the severity of this winter has not prevented a large crop of snowdrops and snowflakes.

Galantamine and a Cholinergic Precursor Protect Against Hypertension

In a study published in 2009, researchers at the University of Camerino, Italy set out to determine if treatment with the acetylcholinesterase inhibitor (AChEI) galantamine and the cholinergic precursor choline alphoscerate (CA), alone or together, had any protective effect on brain microanatomy in spontaneously hypertensive rats (SHR) used as an animal model of VaD.1 Microanatomy is the branch of anatomy dealing with microscopic structures, in this particular instance, of the brain.

Hypertension (aka high blood pressure) is a condition in which the blood pressure in the arteries is elevated. When this is chronic, the heart is required to work harder than it normally would to pump and circulate blood through the blood vessels of the body. There are two aspects of blood pressure, systolic and diastolic, which are determined by whether the heart muscle is contracting (systole) or relaxed (diastole) between beats. For most people, normal blood pressure is at or below 120/80 mmHg. On the other hand, high blood pressure is thought to exist if it is persistently at or above 140/90 mmHg. Unfortunately, this medical disorder, in addition to being the main risk factor for the development of cerebrovascular disease, has also been associated with the establishment of brain damage.

Diseases of the Brain May Intensify Cognitive Loss

LEM1204brain176.gif
(click on thumbnail
for full sized image)
Cerebrovascular diseases—including secondary ischemic brain injury induced by cardiovascular disorders—are common causes of adult onset cognitive impairment. Furthermore, the presence of cerebrovascular damage in DA may intensify cognitive loss. In the United States and Europe, VaD is the second most common form of adult onset dementia after DA. Bear in mind, VaD is not a single disease, but instead a group of syndromes relating to different vascular mechanisms. In terms of its symptoms, VaD is characterized by progressive cognition decline, functional ability impairment, and behavioral problems. It results mainly from ischemic injury or oligemia (blood deficiency) to brain areas involved in cognition, memory, and behavior.

The basal forebrain cholinergic system plays an important role in cognitive function, principally when it comes to attention, memory and emotion. It is also involved in the control of cerebral blood flow. Cholinergic specific brain areas such as the hippocampus are particularly sensitive to ischemic damage, which is why impaired cholinergic neurotransmission is part of the pathophysiology of VaD.

Together with the drug memantine, AChEIs are indicated for relieving the symptoms of DA. Stemming from those applications, they have also been proposed for the relief of VaD symptoms. Having been found to confer neuroprotective properties, along with other preclinical findings suggesting that they lessen neuronal damage and death from cytotoxic offenses, it is thought that AChEIs therefore might alter DA’s course.

The Problem with Straight Cholinergic Loading

Neurons cannot synthesize choline, which is ultimately derived from the diet and delivered through the blood stream. Recognizing the need for choline supplementation, loading up on cholinergic precursors was the first approach for treating cholinergic dysfunction and cognitive decline in adult-onset dementia disorders. However, this therapeutic option was largely dropt due to the lack of efficacy of several precursors investigated in clinical trials. Free choline administration increases brain choline availability, but it does not necessarily increase ACh synthesis or release. However, the failure to find this may be due to poorly designed studies. In no instances that we know of were choline cofactors, such as vitamin B5, employed. That’s too bad!

Nonetheless, among the choline precursors studied were lecithin (which contains very low levels of choline), choline chloride (plasma baseline choline doubled in one study), phosphatidylcholine (ACh was synthesized but there was concern that the process might lead to a depletion in membrane phospholipids adversely affect cellular viability), CDP-choline, and CA. Aside from being very expensive, the last two have been found to increase ACh synthesis and release. CA is derived from lecithin.

Anyway, CA was used in the Italian study. It has been demonstrated to increase ACh release in the rat hippocampus, while improving memory and attention, as well as dissipating affective and somatic symptoms (fatigue, vertigo) in VaD patients. Other studies, conducted by members of the Italian researchers’ group have reported that when CA is combined with the AChEI drug rigvastigmine, cholinergic enhancement is more effective than with each of the single compounds.

Consequently, the 2009 study was designed to determine if treatment with the AChEI galantamine and the CA alone or in combination has any protective effect on brain microscopic structures in SHR. Galantamine was chosen because of its more pronounced cerebrovascular profile versus other compounds of the same class. Thirty-two week old SHR and age matched normotensive rats were left untreated or treated for 4 weeks with an oral dose of 3 mg/kg/day of galantamine, of 100 mg/kg/day of CA or their association.*


* The human equivalent would be 36 mg/day of galantamine and 1215 mg/day of choline alphoscerate.


AChEIs Offer Neuronal Protection

Protection of neurons from damage and death is a challenge for neuroscience research and may offer new perspectives in the treatment of neurodegenerative disorders such as DA and VaD. The four AChEIs (tacrine, donepezil, rivastigmine and galantamine) and memantine have been found to be effective for symptomatic relief of DA. In vitro studies on models of neurodegenerative diseases have suggested that these may protect neurons from apoptosis and death. But the idea that AChEIs, by slowing down ACh degradation, increase deficient brain levels of the neurotransmitter turns out not to be true. Nor do AChEIs correct cholinergic imbalances in adult onset dementia, although some data suggest that they may play a disease modifying role.

As with DA, a cholinergic involvement is hypothesized in the pathophysiology of VaD. Yet different from DA, no drugs are indicated for relief of the cognitive symptoms of VaD, and as a recent review has concluded, few patients affected by mild to moderate VaD have shown benefit from AChEIs or memantine. There is simply no substantial support for widespread use of these drugs in VaD.

Prior Association between AChEIs and CA

Previous studies of the Italian researcher’s group have suggested that an AChEI along with CA increased dose-dependent ACh levels more effectively than CA alone.2 Thus, the 2009 study was conceived to evaluate whether the two compounds alone or in association countered to some extent microanatomical changes occurring in the brain of SHR.

SHR share several similarities with human essential hypertension. Moreover, this rat strain is also characterized by brain injury resonant with VaD. Nerve cell loss, astrogliosis (inflammation of astrocytes, a type of glial brain cell), cytoskeletal break down, and cortex and hippocampus atrophy are all common to middle-age SHR. Furthermore, young- and aged-SHR exhibit reduced nicotinic ACh receptors (nAChRs) in a number of important brain regions for cognitive functions such as cerebral cortex, hippocampus, and thalamus. These findings are relevant given that nAChRs play a significant role in memory and attention and are reduced in DA, dementia with Lewy bodies, autism, schizophrenia, and Parkinson’s disease, compared to age matched controls. Several lines of evidence suggest that deficits of nAChRs correlate well with the level of cognitive dysfunction occurring in adult onset dementia disorders.


The combination of the AChEI
galantamine and the cholinergic
precursor CA produces
neuroprotective effects greater than
the sum of those observed with
single compounds.


Administration of galantamine or CA alone countered to some extent microanatomical changes occurring in the frontal cortex and hippocampus of SHR. Since the two compounds did not affect blood pressure values, neuroprotective effects observed are not related with control of elevated blood pressure. Both galantamine and CA countered nerve cell loss in selected portions of cerebrocortical areas investigated. Galantamine was more active against cytoskeletal breakdown, whereas CA was effective in reversing astroglial reaction and in eliciting a protective effect on blood brain barrier. This suggests that the two drugs tested have different neuroprotection targets in the brains of SHR and, therefore, probably act via different mechanisms. Remarkably, the two compounds together induced a wider neuroprotective effect influencing the majority of microanatomical parameters affected in SHR.

Galantamine Enhances nAChRs.

Galantamine is an allosteric† modulator of nAChRs, in addition to being an inhibitor of AchE. Indeed, the researchers found a neuroprotective effect elicited by galantamine on brain damage in SHR. This is consistent with other findings in DA-related models, demonstrating an activity of galantamine on glutamate and beta amyloid toxicity in vitro and on cholinergic stress in vivo. As in these models, the neuro­protective activity of galantamine in the 2009 study may be related to up regulation of the protective protein Bcl 2 (a cell-suicide regulator protein) and may be mediated via a specific nAChR, alpha-7.


† Allosteric pertains to an effect produced on the biological function of a protein by a compound (galantamine in this instance) not directly involved in that function, or the regulation of an enzyme involving the increase or decrease in the rate of interaction between a reactant and a protein between multiple binding sites (allosteric sites).


Is CA the Most Effective ACh Releaser?

The other compound investigated, CA, is probably the most effective among choline containing phospholipids in enhancing in vivo ACh release, although it is much more expensive than non-phospholipid ACh releasers, such as choline dihydrogen citrate, which dollar per gram is 25 magnitudes less expensive than CA (both forms are about 35% choline). CA has also been investigated with positive results on cognitive domain in patients affected by cerebrovascular disorders and VaD. Choline citrate has never been tested for this, as far as we know.

Also, in an earlier study by the same Italian researchers, CA was shown to counter hypertension-related nerve cell loss in the hippocampus and to counter glial reaction in this key area for learning and memory.3 And the 2009 paper confirms and extends the results of this study, giving support to the hypothesis that CA may act as a neuroprotectant in an animal model of VaD.


Neurons cannot synthesize choline,
which is ultimately derived
from the diet and is delivered
through the blood stream.


Whereas the molecular mechanisms of neuroprotection elicited by AChEIs, including galantamine, were investigated using several approaches, no information is available on the mechanism of action of CA. The significant increase of ACh levels and release prompted by CA may promote nutritional and/or receptor stimulating mechanisms linked to cholinergic activation, but a comprehensive understanding of the effects is still lacking.

The message to take home: The combination of the AChEI galantamine and the cholinergic precursor CA produces neuroprotective effects greater than the sum of those observed with single compounds. They may be either additive or synergistic, but further studies are needed. Accordingly, the association between an ACh breakdown inhibitor (such as galantamine) and a choline precursor (such as CA) not only increases brain ACh levels more effectively, it may also produce a stronger neuroprotective effect by countering relevant aspects of brain injury in SHR.

The Goal of Reversing Cholinergic Underfunction

A new paper by the same Italian researchers, just published in 2012, begins with a worthy goal: Cholinergic hypofunction is a trait of DA as well as VaD and reversing it is one of the main therapeutic strategies available for these itating illnesses.4 Noting that cholinergic transporters control the cellular mechanisms of ACh synthesis and the release of this neurotransmitter—which is instrumental for memory properties, including concentration and focus—at presynaptic terminals, the new study examined the same two cholinergic enhancing nutrients used in the 2009 study: the AChEI galantamine and the cholinergic precursor CA. As they had done in their previous paper,1 the scientists measured the effects of the two nutrients separately and together, but in their new paper, they also looked at high affinity choline uptake transporter (CHT) and vesicular ACh transporter (VAChT) expression in the brain of SHR.

The rats (SHR) chosen for the study, among other properties, represent an animal model of cerebrovascular injury characterized by cholinergic hypofunction. Analysis found that both nutrients, galantamine and CA, increased expression of the rat’s ability to uptake choline and to transport it within their brains. CA increased choline uptake and to a greater extent VAChT expression while galantamine buffered the increase of CHT and VAChT.

Synthesis and Release Requires Uptake and Storage

CA increased ACh synthesis and release, as other studies have shown. This required an increase of systems that regulate neurotransmitter uptake and storage. The effect of CA on CHT and VAChT observed suggests an improved synaptic efficiency elicited by the compound. The AChE inhibitor slowed down ACh degradation in the synaptic cleft.

The greater availability of ACh elicited by galantamine counters the enhanced activity of cholinergic transporters compensating cholinergic deficits. Differences in the activity of the cholinergic precursor and AChE inhibitor investigated on CHT and VAChT suggests that association between CA and galantamine may represent a strategy for potentiating deficient cholinergic neurotransmission worthwhile of being investigated in clinical trials.

Studies show that cerebrovascular pathology is an important cause of dementia and vascular injury as a damaged brain worsens the course of DA. Cognitive impairment that is caused by malfunctioning or damaged cerebrovascular system characterizes VaD. Since arterial hypertension is a leading cause of brain vascular injury, it may also result in cognitive impairment.1

Hypoperfusion and Ischemia Related to DA

It is especially interesting to note that in addition to the role of cholinergic neuronal processes for cognitive functioning, cholinergic mechanisms also control cerebral blood flow. Thus, the pathogenesis of vascular disease—in which cognitive impairment results from decreased brain blood flow (hypoperfusion) and complete or incomplete restriction of blood flow (ischemia)—can also be related to DA, its course, and its complications.

Cholinergic structures and certain brain areas are particularly vulnerable to ischemic damage and may suffer progressive cognition decline. When this occurs, the results may include functional ability impairment, as well as behavioral problems, which can account for a central role of impaired cholinergic neurotransmission in dementia and DA.

The Value of Cholinergic Precursors

Considering ACh’s involvement in cognition, the Italian researchers were interested to retouch upon what is considered to be an old approach to treat cholinergic dysfunction and cognitive decline in adult-onset dementia disorders: the use of cholinergic precursors. Most of the precursors were early leaved (abandoned) because their efficacy was not clearly demonstrated. (See the subhead “The Problem with Straight Cholinergic Loading Strategies.”) The researchers settled on CA, which interferes with brain phospholipid metabolism, but also increases brain choline and ACh levels, along with improved release. CA also produces neuroprotective effects, alone or in association with AChEIs. This was demonstrated in SHR, used as an animal model of VaD in another study.

The Role of Transporters

The process of synthesis, storage and release of ACh requires the expression of specialized systems, including CHT and VAChT. CHT recollects choline deriving from ACh hydrolysis by AChE and makes it available for the neurotransmitter re-synthesis by choline acetyltransferase. ACh is then loaded into synaptic vesicles by VAChT, and ACh released from cholinergic synapses is hydrolyzed by AChE into choline and acetate. In terms of efficiency, almost 50% of choline derived from ACh hydrolysis is recovered by a high-affinity CHT.

The 2012 Italian study was designed to assess if prolonged treatment with the cholinergic precursor CA or with the AChE inhibitor galantamine interferes with cholinergic transport mechanisms in SHR. Using a model of cerebrovascular injury and of cholinergic hypofunction, their analysis included three brain areas in which cholinergic neurotransmission is widely represented, as well as peripheral blood lymphocytes. Lymphocytes are expressed in a cholinergic activity and may represent a marker of changes in brain cholinergic neurotransmission.

Hypertension Contributes to Alzheimer’s Pathogenesis

As already emphasized, arterial hypertension is one of the main factors promoting cerebrovascular injury. It is the main modifiable risk factor for stroke and has been associated with compromised cognitive function, mainly memory dysfunction and decreased speed of information processing. Recent studies highlight hypertension’s role in the pathogenesis of DA and what may be a forerunner, mild cognitive impairment (MCI). Hypertensive brain damage is accompanied by cerebrovascular changes affecting both large and small vessels.

Galantamine and Choline Precursor Improve Cholinergic Transporters

In the 2012 study, 32-week-old SHR (n=16) and age-matched normotensive rats were left untreated or treated for 4 weeks with an oral dose of 2 mg/kg/day of galantamine, of 150 mg/kg/day of CA or a combination.* The effects were measured on CHT and VAChT expression in the rats’ brains with the researchers examining frontal cortex, striatum and hippocampus, and also peripheral blood lymphocytes, used as a reference of changes of brain cholinergic markers.

Increased expression of the cholinergic transporters, VAChT and CHT, was observed in brain areas investigated in the SHR. At the same time, there was a similar trend for lymphocytes, suggesting that the latter might represent a marker of brain cholinergic transporters.

Treatment with CA increased CHT and to a greater extent VAChT expression. Treatment with galantamine countered the increase of CHT and VAChT. The different activity of the cholinergic precursor and of the AChE inhibitor on parameters investigated is likely related to their mechanism of action. CA increases ACh synthesis and release. This requires an augmentation of systems regulating neurotransmitter uptake and storage.

The effect of CA on CHT and VAChT in this study indicates an improved synaptic efficiency produced by the compound. The AChEI slowed down ACh degradation in the synaptic cleft. Thus, the greater availability of ACh elicited by galantamine counters the enhanced activity of cholinergic transporters compensating cholinergic deficits.

Synergy between Galantamine and Choline Precursor

The differences in the activity of the cholinergic precursor and AChEI investigated on CHT and VAChT indicate that the combination of CA and galantamine may represent a synergistic strategy for potentiating deficient cholinergic neurotransmission and one worthwhile of further investigation.

It is likely that the abnormal regulation of cholinergic neurotransmission might contribute to cognitive impairment associated with adult-onset dementia disorders including DA and VaD. Cholinergic transporters control cellular mechanisms of ACh synthesis and release at presynaptic terminals. CHT recaptures choline deriving from ACh hydrolysis by AChE. Choline is resynthesized into ACh by choline acetyltransferase. The neurotransmitter is loaded into synaptic vesicles by VAChT. Abnormal regulation of cholinergic transporters might contribute to the cognitive impairments associated with neurodegenerative disorders.

Notably, the cholinergic system of SHR changed in muscarinic ACh receptor density, nicotinic receptors and VAChT expression. The cholinergic system is involved in learning and memory and when cognitive deficits appear, they can be correlated with the measure of its impairment. While in the past, the main marker was the ACh biosynthetic enzyme, choline acetyltransferase, in recent years cholinergic transporters have received the lion’s share of attention. These include VAChT, known to package ACh into synaptic vesicles, and CHT, which imports choline from the extracellular space to presynaptic terminals.

Balancing Vesticular ACh Release and Choline Uptake

Relationships between mechanisms porting VAChT and choline uptake are crucial in maintaining efficiency of cholinergic synaptic activity. As previously stated, the different activity of CA or galantamine on cholinergic transporters probably depends on the different mechanism of action of the two compounds. CA increases ACh synthesis and release. This requires an augmentation of systems regulating neurotransmitter uptake and storage. The effect of CA on VAChT and CHT observed in this study suggests an improved synaptic efficiency elicited by the compound. The AChE inhibitor slows-down ACh degradation in the synaptic cleft. A greater availability of neurotransmitter elicited by galantamine counters the enhanced activity of cholinergic transporters aimed compensating cholinergic deficits.


The relationships between choline
synthesis, release, uptake, and storage
may be likened to the multiple
volume controls on your computer
when playing music from, for
example, YouTube, which also has its
own volume control.


The relationships between choline synthesis, release, uptake, and storage may be likened to the multiple volume controls on your computer when playing music from, for example, YouTube, which also has its own volume control. As does your computer, and your headset or your external speakers. If you turn one control too high, the sound tends to be distorted. The idea is to balance all three controls to optimize the quality of sound. So it is with ACh release and choline uptake. The cholinergic system needs to be balanced.

The findings confirm the presence of VAChT in some cerebral areas involved in the cognitive function such as cerebral cortex and hippocampus. In these structures immune reaction was located in swollen varicose veins along nerve fibers supplying cerebrocortical and hippocampal neurons. These vein swellings likely correspond to synaptic terminals. In the striatum, VAChT were expressed in nerve cell bodies, nerve fibers as well as in vein swellings around nerve cell bodies. A similar pattern was observed for CHT.

What Is Synergy?

Specialization’s preoccupation with parts deliberately forfeits the opportunity to apprehend and comprehend what is provided exclusively by synergy.
— R. Buckminster Fuller

In nutritional supplementation, synergy occurs when two or more nutrients function together to produce a result that cannot otherwise be independently obtainable. In the natural world, synergistic phenomena are ubiquitous. In physics, chemistry, genomics, or in division of labor in bacterial colonies and on up the tree of life, synergy is omnipresent. Life needs to be cohesive and more than the sum of its parts for it to survive. In fact, synergistic effects have played a major causal role in the evolutionary process, without which the evolution of complex systems—in nature and human societies alike—would not have developed. Synergy may be thought of as profit for living systems. If there is no profit, there is no business … of life!

Some synergies may have such a high degree of complexity involving many components, explaining why plants always possess multiple proactive materials, which act together to achieve a superior result—that all serve to enhance the life of the plant by working together.

An increased expression of VAChT and CHT was found in different brain areas of SHR. The higher levels of cholinergic transporters in the brain of SHR compared to normotensive rats was consistent with data reporting an increase of VAChT in early stages of DA and an increased cholinergic network in the hippocampus of individuals with MCI.

Countering Cholinergic Hypofunction

The enhanced cholinergic neurotransmission in early phases of dementia probably represents an upregulation mechanism to counter cholinergic hypofunction which is probable in MCI and obvious in DA. Speculatively the increased expression of vesicular ACh transporter observed in SHR represents a tentative to compensate cholinergic impairment in the first stages of hypertensive brain damage. With worsening of brain injury cholinergic dysfunction probably becomes no longer compensable through an up regulation of VAChT and CHT. This makes obvious the occurrence of signs of cholinergic deficits like those reported in SHR older than those used in this work.

Dynamics of cholinergic transporter expression was also investigated after challenge with two cholinergic neuro­transmission enhancing drugs, the cholinergic precursor CA and the AChEI galantamine. The different activities of the cholinergic precursor CA and of the AChEI galantamine on VAChT and CHT suggests that association between CA and AChEIs recently proposed may represent a strategy for potentiating deficient cholinergic neurotransmission worthwhile of further investigation.

The similar pattern of VAChT and CT expression in peripheral blood lymphocytes and in cerebral tissue suggests that these circulating cells may represent a mean to investigate the cholinergic system status using a simply available peripheral tissue. Speculatively, VAChT and CT analysis in peripheral blood lymphocytes could represent an early marker to reverse brain cholinergic hypofunction.

Long Expected

The establishment of a relationship between galantamine and a choline precursor that enhances both ACh synthesis and release is something that we have long thought about and the two primary papers cited in this article have finally offered more support. This is all the better for those who ardently seek to preserve their memory function, and all in good time before decline occurs.

GLOSSARY

ACh

acetylcholine

AChE

acetylcholinesterase

AChEI

acetylcholinesterase inhibitor

CA

choline alphoscerate

CHT

choline uptake transporter

DA

disease of Alzheimer’s

MCI

mild cognitive impairment

nAChRs

nicotinic Ach receptors

SHR

spontaneously hypertensive rats

VaD

vascular dementia

VAChT

vesicular Ach transporter

References

  1. Tayebati SK, Di Tullio MA, Tomassoni D, Amenta F. Neuroprotective effect of treatment with galantamine and choline alphoscerate on brain microanatomy in spontaneously hypertensive rats. J Neurol Sci 2009 Aug 15;283(1-2):187-9­­4.
  2. Amenta F, Tayebati SK, Vitali D, Di Tullio MA. Association with the cholinergic precursor choline alphoscerate and the cholinesterase inhibitor rivastigmine: an approach for enhancing cholinergic neurotransmission. Mech Ageing Dev 2006;127:173–9.
  3. Tomassoni D, Avola R, Mignini F, Parnetti L, Amenta F. Effect of treatment with choline alphoscerate on hippocampus microanatomy and glial reaction in spontaneously hypertensive rats. Brain Res
  4. Tomassoni D, Catalani A, Cinque C, Di Tullio MA, Tayebati SK, Cadoni A, Nwankwo IE, Traini E, Amenta F. Effects of cholinergic enhancing drugs on cholinergic transporters in the brain and peripheral blood lymphocytes of spontaneously hypertensive rats. Curr Alzheimer Res 2012 Jan 1;9(1):120-7.


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

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