Galantamine may be empowered by the rehabilitation of neurons …

Neuronal Restoration
Subdues Alzheimer’s

Through the supplemental use of an array of antioxidant,
anti-inflammatory, cofactors and other nutrients
By Will Block

W

e have long subscribed to the idea that there are many valid approaches to achieving, maintaining, and even restoring vigorous health—whether these involve the nervous, endocrine, integumentary, skeletal, muscular, cardiovascular, lymphatic, respiratory, digestive, urinary, or reproductive systems of the body. There is little doubt of the interactivity and internal adjustment constantly in play between these systems, meaning that if the requirements of any one of these systems are not met, the consequences will be reflected in the other systems, if not all the other systems. This adjusting of physiological systems within the body is called homeostatic regulation.

The proper functioning of the human organism involves trillions of cells all working together for the maintenance of the entire organism. While cells may perform very different functions, all cells are quite comparable in their metabolic requirements. Indeed, maintaining a continuous internal environment—with oxygen, glucose, mineral ions, waste removal, and so forth, which all cells need to survive—is absolutely necessary for the well-being of individual cells and the health of the entire body. All together, the diverse processes by which the body regulates its internal environment are referred to as homeostasis.

Truly, the many requirements of any system must be met to achieve optimality for any system, and the failure to do so will impact the others, in greater or lesser degree. Moreover, as Aristotle said, “The whole is more than the sum of its parts.” In biomedical terms, this means that even satisfying all of the known requirements of the identified parts (the systems) will not necessarily satisfy the requirements of the whole. This is because of the complexities involved, and relationships that have not yet been recognized.

Rehabilitating Neurons

Take the nervous system. A new report published in Clinical Interventions in Aging of work done at Universidad Veracruzana, Xalapa, Veracruz, México argues that the rehabilitation of neurons in the neurodegeneration process would enable Alzheimer’s disease (AD) drugs, along with the phytonutrient galantamine, to act more effectively on them and improve the effects of treatment in AD patients.1 As this paper proposes, the question to ask is, “Why do the drugs (including the natural galantamine compound) available to treat AD have limited efficacy?”

As readers of this publication are well aware, AD is a neurodegenerative disorder characterized by loss of memory combined with other cognitive dysfunctions, which progresses slowly. It is many years in the making. In at least 90% of cases, AD does not occur until after the age of 65. Thereafter, occurrence doubles every 10 years, from 10% at 60–70 years to 40% by the time a person reaches 80 years of age.

There are great differences in how long a person can survive, although death usually occurs within a decade after AD onset. The causes of death are frequently the result of infections. While several chromosomes have been found to be implicated in the likeliness of developing AD, most cases can’t be explained genetically. This has led to many hypotheses that have attempted to explain the complexities of this disease. Although some of these have gone so far as to suggest the presence of unidentified toxic or infectious agents as sufficient or necessary for AD development, there is agreement that of the main processes leading to AD, one entails the abnormal phosphorylation of tau, a microtubule-associated protein. In this generally accepted idea, tau is damaged through hyperphosphorylation. This causes the dissociation of tau from microtubules, following which structures called paired helical filaments begin to form within the cell bodies of neurons. Ultimately, this process generates neurofibrillary tangles, the main components of which are comprised by hyperphosphorylated tau thus loosening the cytoskeleton, with concomitant loss of the shape of the neuronal membrane.

The Answer to the Question

Considering just this, the answer to the question posed above might be a lot more simple than has previously been thought by scientists. Most of these drugs are acetylcholinesterase inhibitors (AChEIs) and allow the neurotransmitter acetylcholine to remain for longer in the synaptic cleft. Even the plant-derived nutrient galantamine is an AChEI. Galantamine also works by potentiating effects at nicotinic receptors. Accordingly, it affects not only cholinergic transmission, but also other neurotransmitter systems such as monoamines, glutamate, and γ-aminobutyric acid (GABA) through its allosteric mechanism. (See article on page 4.)

The Mexican researchers point out that these effects may result in additional beneficial effects. In their paper, the researchers suggest that, “degenerative neurons may not have their cholinergic receptors properly positioned on the damaged membrane, and there may even be some receptors not reaching the postsynaptic neuron during trafficking to the dendrite spine.”1 And furthermore, “Restoration of neuronal membranes before starting treatment with an [AChEI] might enhance the effects of the drugs to produce a prolonged improvement in symptomatology.” How can this be done? As Durk Pearson & Sandy Shaw have pointed out (see “Maintain your Brain the Durk Pearson & Sandy Shaw Way” in the May 2004 issue), there are numerous ways to preserve memory, and among these are the supplemental use of galantamine, choline, omega-3 fatty acids, folic acid, other B-vitamins, turmeric, quercetin, green tea (specifically EGCG), and lithium. Here follow the recommendations of the Mexican researchers and their reasoning, along with Durk & Sandy’s nutrient suggestions that the current paper did not cover.

Omega-3 Inhibits Tau Damage

Omega-3 fatty acids play a significant role in the inhibition of ischemic damage2 and also help to increase neurite* development, as demonstrated when hippocampal neurons are treated with docosahexaenoic acid (DHA), one of the principal omega-3 fatty acids. Omega-3s are also involved in the remodeling of membrane rafts3 and in neurogenesis.4


*Neurites are projections from the cell body of a neuron, such as axons and dentrites.


Lipid rafts are membrane domains that are rich in cholesterol (an essential structural component of cell membranes), and that help to stabilize membrane receptors. Membrane rafts have also been shown to participate in the stabilization of the synapse, AMPA25,5 and NMDA receptors.6 They also seem to help maintain dendritic spines. Finally, lipid rafts are needed for the ability of acetylcholine receptors to cluster at postjunctional membranes.7

Reactive oxygen species (ROS) damage to cell membranes, typical in AD, results in the redistribution of lipids, such as cholesterol and sphingomyelin, because of an increase in membrane fluidity.8 This, in turn, can lead to undesirable alterations in membrane receptor positioning.

Importantly, omega-3 acids have shown the ability to inhibit tau hyperphosphorylation, which would allow axonal transport restoration. Besides that, it has been shown that omega-3s are also capable of reducing amyloid plaque formation.9,10 Following the restoration of neuronal membranes, it might be necessary to reestablish the connections between neurons. This process could be aided by nutrients that promote the production of serotonin, such as tryptophan and 5-HTP, shown to play a role in the formation of new synapses and neuronal connections.

Folic Acid for Neuroplasticity and Neuronal Integrity

The B-vitamin folic acid has an important role in neuroplasticity and in the maintenance of neuronal integrity. Folate (its natural form) is a cofactor in one-carbon metabolism, which is centered around folate and promotes the methionine regeneration from homocysteine, a highly reactive sulfur-containing amino acid. Methionine can then be converted to S-adenosylmethionine (SAMe), the principal methyl donor in most biosynthetic methylation reactions.


This process could be aided by
nutrients that promote the production
of serotonin, such as tryptophan and
5-HTP, shown to play a role in the
formation of new synapses and
neuronal connections.


When folate is deficient at the cellular level, hyperhomocysteinemia can generate an assortment of harmful effects, including DNA damage, the detrimental misincorporation of uracil into DNA, and faulty DNA methylation. Also, low folate and high homocysteine levels stimulate the generation of ROS, while contributing to excitotoxicity and mitochondrial dysfunction. This can lead to apoptosis (cell suicide).

There is solid epidemiological and experimental evidence linking one-carbon metabolism derangements to neurodegenerative and neuropsychiatric disease, as well as vascular disease. Among the most likely are AD, cerebral ischemia, and depression.11 Folic acid is a strong candidate for incorporation into neuronal rehabilitation therapy.

Resveratrol: Protective Against Beta-Amyloid

Among the phytophenols (plant-derived phenols) are the bisphenols—which include the stilbenes—tricyclic phenols (flavonoids), and their subclasses, along with proanthocyanidins (see “Grape Seed Extract May Inhibit Fat Absorption” in the July 2007 issue) and anthocyanidins (see “Can Age-Related Macular Degeneration Be Prevented?” March 2007 issue). All of these should be familiar to Life Enhancement readers. The phytophenol precursors and stilbenes—a class that includes resveratrol—seem to play preventive and possibly therapeutic roles in atherosclerosis and certain neoplastic and inflammatory conditions. Probably through their free radical scavenger activity, they selectively interfere with the factors affecting cell division in rapidly and abnormally proliferative cells.


Folic acid is a strong candidate for
incorporation into neuronal
rehabilitation therapy.


Many studies have been published on resveratrol’s natural occurrence, bioavailability, and metabolism, as well as its effects on neurons cancer, the inflammation process, atherosclerosis, and more. Grape extracts are convenient source of these phytochemicals to supplement the diet, but higher levels are needed than are currently available through the fruit. High concentrated extraction from the Japanese knotweed (Polygonum cuspidatum) has proven to be more economical and effective.

Resveratrol and catechin, when use together, have been shown to be protective against β-amyloid (Aβ) in PC12 cells, a cell line useful as a model system for neuronal differentiation. Many environmental factors, including antioxidants, metal ions, and proteoglycans can modify Aβ toxicity in PC12 cells. Protection against ROS toxicity is concentration-dependent for both resveratrol and catechin. Moreover, this protective effect seems to be synergistic, and is unlikely to be due to antioxidant activity alone. Differences in chemical and biological activity by these compounds for the complex toxicity of Aβ may help explain this synergistic protective effect. When used together with different compounds with synergistic activity, they may yet again improve the protective effect against the complex toxic mechanisms of Aβ.12 A polyphenol-rich diet could help to maintain brain homeostasis, prevent oxidation, and keep neurons healthy.13 Best yet, it would be wise to supplement with epigallocatechin gallate (EGCG), undoubtedly the most potent of the catechins.

And now we turn to Durk & Sandy’s additional candidates for neuronal rescue:

Turmeric: Valuable for Neurodegenerative Disease

Inflammatory processes in the brain are at the base of the pathogenesis of AD, so nonsteroidal anti-inflammatory drugs have a protective effect in affected individuals. Better yet are anti-inflammatory nutrients such as turmeric, a powerhouse of active compounds that goes beyond the usual curcuminoids, and which, while effective in their own right, are matched by other components of whole ground turmeric.


The most persuasive hypothesis of how AD invades the brain is the so-called “amyloid beta protein cascade,” in which a protein called APP is clipped into shorter pieces by enzymes known as secretases. If the portion of APP clipped by the beta form of secretase is further clipped by a third form, gamma secretase, the resulting fragments are amyloid beta peptides, which are toxic and cause the formation of amyloid plaques.
From what we already know, turmeric can be valuable for neurodegenerative disease from mild cognitive impairment to dementias (including AD). Turmeric (or many of its active components) can also inhibit beta-secretase 1 (BACE1), also known as beta-site amyloid precursor protein (APP) cleaving enzyme 1 and reduce Aβ-induced ROS damage and the formation of beta-sheet structure. This is hospitable to protein aggregates and fibrils observed in many human diseases, notably the amyloidoses such as AD. If it turns out that there is such a thing as type 3 diabetes—or even if there isn’t such a disease—those who are concerned with the slippery slope that may take many of us into full-fledged diabetes or all-out AD (or both) will probably find no better place to start their personal defense than with the nutrients named in this article.

After all, turmeric is a whole set of antioxidants, and people who eat a lot of it in curry have a lower incidence of AD. Turmeric is also an anti-inflammatory. A lot of research has been done on the constituents of turmeric and much of this has been epidemiological. Researchers working with cholinergic neurons in vitro have found that turmeric and the various antioxidants in it are effective in protecting the neurons against damage or death caused by Aβ.14

Of the active components in turmeric, according to Durk & Sandy, “One of these is about twice as effective; one is 3 times, one is about 5 times, and one is about 10 to 15 times as effective. So if people are taking curcumin alone as a preventive for Alzheimer’s, they’ll probably be helping themselves (if they get the dose right), but taking the entire turmeric package will work better, because there are even more powerful antioxidants in there, and they have evolved together to work together as an integrated system.”

Continuing, “In turmeric, the root is the longest-lasting part of the plant, and it protects itself with a system of antioxidants whose collective action has been optimized by evolution. An example of what can happen if you isolate a single antioxidant from the turmeric root—curcumin, for example—can be found in some mouse experiments. Mice don’t normally develop Alzheimer’s disease, but if you genetically engineer them to produce the Alzheimer’s amyloid-beta preprotein that is then split to produce the human version of amyloid-beta, they do develop Alzheimer’s. As they get old, they develop memory losses; they develop plaques and tangles.”

Furthermore, and especially interesting, “There are some differences in the distribution of plaques and tangles in the brain, but they particularly go after the cholinergic areas, so in general, it’s a pretty good model. Researchers found that if they got the right dose of curcumin, they could slow down the development of memory loss dramatically and also reduce the size of the plaques at any age. If they used too high a dose of curcumin, however, it would actually speed up the deterioration.” [Emphasis added.]15,16

Curcumin and Galantamine Together

In more recent research on the use of turmeric and curcumin for AD, there was a study in which old mice were given both curcumin and galantamine treatment for 6 weeks and were found to have significantly improved cognitive tasks, locomotor activity, oxidative defense, and restored mitochondrial enzyme complex activity as compared to controls.17 Also, in another paper, treatment with curcumin enhanced neuronal survival in NMDA toxicity and long-term cultures.18 In yet another study, curcumin was found to be helpful in preventing Parkinsonism and has therapeutic potential in combating this devastating neurologic disorder.19

Quercetin: Good for Memory Impairment

Daily treatment with quercetin (2.5, 5 and 10mg/kg) showed a dose-dependent restoration of cerebral blood flow and ATP content following the administration of the toxin, streptozotocin (STZ).20 Furthermore, quercetin prevented induced memory impairment as assessed by Morris water maze and passive avoidance tests. Biochemical analysis revealed that STZ significantly increased malondialdehyde (MDA) and nitrite while depleting glutathione levels in the mice brain. Quercetin decreased oxidative and nitrosative stress as evidenced by a significant decrease in MDA, nitrite, and an increase in glutathione levels. It also reduced elevated acetylcholinesterase activity in the STZ-treated mice. Thus it was demonstrated that quercetin improves cerebral blood flow, along with preventing memory impairment, oxidative stress, altered brain energy metabolism and cholinergic dysfunction caused by STZ in mice. The use of quercetin should be encouraged to ward off dementia associated with vascular and neurodegenerative disorders.

Cell incubation with the antioxidant quercetin prevents 24-hydroxycholesterol (a major cholesterol metabolite) from exerting a pro-oxidant effect and the potentiation of Aβ-induced necrosis and apoptosis.21 Thus, the presence of 24-hydroxycholesterol in the close vicinity of amyloid plaques appears to enhance the adhesion of large amounts of Aβ to the plasma membrane of neurons and then to amplify the neurotoxic action of Aβ by locally increasing ROS steady-state levels. This report further supports a primary involvement of altered brain cholesterol metabolism in the complex pathogenesis of AD.

EGCG (Found in Green Tea) for Brain Benefit Synergy

Durk & Sandy report in a recent Life Extension News (Volume 13 No. 3, June 2010) on a 2010 paper22 finding that in a mouse model of Alzheimer’s disease, “oral co-treatment with fish oil (8 mg/kg/day) and EGCG (epigallocatechin gallate, 62.5 mg/kg/day or 12.5 mg/kg/day) at 8 months of age for 6 months enhanced the production of soluble amyloid precursor protein (sAPP).” [Emphasis added.] “That is produced via the non-amyloidogenic pathway where APP is cleaved by alpha secretase. The non-amyloidogenic pathway prevents the generation of amyloid beta and, therefore, is protective against AD. … [E]ach mouse ingested 0.25 mg of fish oil plus 1.875 mg of EGCG (high dose) or 0.25 mg of fish oil plus 0.375 mg of EGCG (low dose).


“… [M]oderate supplementation with
EGCG and fish oil [have]
significant therapeutic potential for
the treatment of AD.”


“The low oral dose of EGCG alone (12.5 mg/kg/day) does not itself reduce amyloid beta deposits. However, in the mice treated with this dose of EGCG plus the fish oil, there was a marked reduction of amyloid beta deposits. The researchers found significantly elevated plasma and brain levels of free EGCG in mice co-treated with fish oil, ‘suggesting a mechanism of increased bioavailability conferred by the addition of fish oil to EGCG.’ The authors further conclude that “moderate supplementation with EGCG and fish oil [have] significant therapeutic potential for the treatment of AD.” (Notice, they suggest TREATMENT of AD, not just risk reduction. The FDA forbids — in violation of the First Amendment — mention of any treatment effect for a dietary supplement in an ad or on a label, as that converts it magically into an unapproved new drug.)”

Lithium: For the Reduction of Aβ Neurotoxic Effects

Treatment with lithium has been found to offer neural protection against the insults of Aβ neurotoxicity in vitro. Rosiglitazone, a peroxisome proliferator activated receptor-gamma agonist (see “The Antidiabetes Trigger” in the March 2009 issue), has been shown to reduce Aβ neurotoxic effects, including the inflammatory response of microglia and astrocytes. Both lithium and rosiglitazone activate Wnt signaling, a pathway involving a complex network of proteins that has been shown to be related to AD.

In a recent study,23 a double transgenic mouse model was used to examine, in vivo, the effect of lithium and rosiglitazone on Aβ neurotoxicity. The mice were tested for spatial memory, and their brain samples were used for histochemical (relating to the the chemistry of cells and tissues) and biochemical analysis. The authors report that both lithium and rosiglitazone significantly reduced (1) spatial memory impairment induced by amyloid burden; (2) Aβ aggregates and Aβ oligomers; and (3) astrocytic and microglia activation. Also of benefit, lithium and rosiglitazone prevented changes in presynaptic and postsynaptic marker proteins. Finally, both substances independently activate Wnt signaling, which may be therapeutically beneficial in itself and thereby reduce various AD neuropathological markers.

Neuronal Rescue is Possible

All of the natural compounds covered in this article have abundant findings that they have benefit for significant neuronal repair and rescue. Some have even been directly shown to enhance the benefits of the natural AChEI, galantamine. As the Mexican authors conclude, once the neuronal membranes have been repaired, it would be important to induce the formation and maintenance of new synapses by an SSRI (or preferably a natural serotonin precursor such as 5-HTP or tryptophan), and folic acid. Serotonin regulates neuronal morphology and the reconnection between neurons. Its pathway interacts with that of acetylcholine, and it also has a role in memory impairment. A powerful antioxidant, such as resveratrol, along with other nutrients, would also improve the effects of membrane repair and formation of synapses.


The judicious use of neuronal rescue
nutrients might rehabilitate the AD
brain to enable the use of
galantamine for a better outcome.


Together, the judicious use of neuronal rescue nutrients might rehabilitate the AD brain to enable the use of galantamine for a better outcome. While the ongoing mechanisms of action of the AChEIs have failed to cure AD, the Mexican researchers believe this rehabilitating therapy with nutrients for neuronal repair and rescue, in combination with AChEIs such as galantamine can provide a high possibility for improving the quality of life of both AD patients and their relatives, who also suffer the consequences of the disease. Bear in mind that AD has a slow progression and the neuronal damage occurs over a long period of time, at some point to such an extent that it becomes impossible to prevent brain cell degeneration. Lastly, at a meeting of The Society of Neuroscience in 2009, the introduction of natural products to treat AD was recommended. The times, they are a changing!

References

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  2. Relton JK, Strijbos PJ, Cooper AL, Rothwell NJ. Dietary N-3 fatty acids inhibit ischaemic and excitotoxic brain damage in the rat. Brain Res Bull 1993;32:223-6.
  3. Fan YY, McMurray DN, Ly LH, Chapkin RS. Dietary (n-3) polyunsaturated fatty acids remodel mouse T-cell lipid rafts. J Nutr 2003;133:1913-20.
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  6. Hou Q, Huang Y, Amato S, Snyder SH, Huganir RL, Man HY. Regulation of AMPA receptor localization in lipid rafts. Mol Cell Neurosci 2008;38:213-23.
  7. Stetzkowski-Marden F, Recouvreur M, Camus G, Cartaud A, Marchand S, Cartaud J. Rafts are required for acetylcholine receptor clustering. J Mol Neurosci 2006;30:37-8.
  8. Clement AB, Gimpl G, Behl C. Oxidative stress resistance in hippocampal cells is associated with altered membrane fluidity and enhanced nonamyloidogenic cleavage of endogenous amyloid precursor protein. Free Radic Biol Med 2010;48:1236-41.
  9. Ma QL, Yang F, Rosario ER, et al. Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci 2009;29:9078-89.
  10. Amtul Z, Uhrig M, Rozmahel RF, Beyreuther K. Structural basis for the differential effects of omega-3 and omega-6 fatty acids on Abeta production and amyloid plaques. J Biol Chem 2010 Oct 22. [Epub ahead of print]
  11. Kronenberg G, Colla M, Endres M. Folic acid, neurodegenerative and neuropsychiatric disease. Curr Mol Med 2009;9:315-23.
  12. Conte A, Pellegrini S, Tagliazucchi D. Synergistic protection of PC12 cells from beta-amyloid toxicity by resveratrol and catechin. Brain Res Bull 2003;62:29-38.
  13. Rossi L, Mazzitelli S, Arciello M, Capo CR, Rotilio G. Benefits from dietary polyphenols for brain aging and Alzheimer’s disease. Neurochem Res 2008;33:2390-2400.
  14. Park SY, Kim DS. Discovery of natural products from Curcuma longa that protect cells from beta-amyloid insult: a drug discovery effort against Alzheimer’s disease. J Nat Prod 2002 Sep;65(9):1227-31.
  15. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosc 2001 Nov 1;21(21):8370-7.
  16. Frautschy SA, Hu W, Kim P, Miller SA, Chu T, Harris-White ME, Cole GM. Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology. Neurobiol Aging 2001 Nov-Dec;22(6): 993-1005.
  17. Kumar A, Prakash A, Dogra S. Protective effect of curcumin (Curcuma longa) against D-galactose-induced senescence in mice. J Asian Nat Prod Res 2011 Jan;13(1):42-55.
  18. Lin MS, Hung KS, Chiu WT, Sun YY, Tsai SH, Lin JW, Lee YH. Curcumin enhances neuronal survival in N-methyl-d-aspartic acid toxicity by inducing RANTES expression in astrocytes via PI-3K and MAPK signaling pathways. Prog Neuropsychopharmacol Biol Psychiatry 2011 Jan 1. [Epub ahead of print]
  19. Khuwaja G, Khan MM, Ishrat T, Ahmad A, Raza SS, Ashafaq M, Javed H, Khan MB, Khan A, Vaibhav K, Safhi MM, Islam F. Neuroprotective effects of curcumin on 6-hydroxydopamine-induced Parkinsonism in rats: behavioral, neurochemical and immunohistochemical studies. Brain Res 2011 Jan 12;1368:254-63. Epub 2010 Oct 15.
  20. Tota S, Awasthi H, Kamat PK, Nath C, Hanif K. Protective effect of quercetin against intracerebral streptozotocin induced reduction in cerebral blood flow and impairment of memory in mice. Behav Brain Res 2010 May 1;209(1):73-9. [Epub 2010 Jan 22]
  21. Gamba P, Leonarduzzi G, Tamagno E, Guglielmotto M, Testa G, Sottero B, Gargiulo S, Biasi F, Mauro A, Viña J, Poli G. Interaction between 24-hydroxycholesterol, oxidative stress, and amyloid-&βeta; in amplifying neuronal damage in Alzheimer’s disease: three partners in crime. Aging Cell 2011 Jan 27. doi: 10.1111/j.1474-9726.2011.00681.x. [Epub ahead of print]
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Will Block is the publisher and editorial director of Life Enhancement magazine.

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