Galantamine reduces the devastating effects of dementia by …

Decelerating Alzheimer’s Disease
Thus enabling a stop prior to the edge of oblivion’s cliff
By Will Block

While galantamine may not provide a cure for Alzheimer’s disease (AD), it may help prevent it. Furthermore, it has recently been learned that it can decelerate the progression of AD and provide relief of symptoms for this disorder.1 This is great news because progress is being made on this memory-stealing disease on many fronts, and as a result a combination therapy may provide a cure in the not so distant future. Additionally, the longer we remain intact cognitively, the greater our chance of defeating it in the long run and adding a great deal of life to our years.

Nerve Growth Factor Gene Therapy

What’s more, a potent combination therapy has already arrived, bringing together abundant amounts of choline, omega-3 fish oil, lithium, green tea’s EGCG, turmeric, hesperidin, and quercetin, along with protein refolding nutrients. Will Big Pharma play a role in this? That’s unlikely because the FDA frowns on combination therapies.

In one recent study, researchers have found that nerve growth factor gene (NGF) therapy activates neuronal responses in Alzheimer disease.2 These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer and is likely to be potent when induced by supplements. Growth factor therapy appears safe over extended periods, and merits continued testing as a means of treating neurodegenerative disorders. If we slow down AD’s progression, the greater will be our chance to avoid the cliff—off of which lies oblivion (as even Santa should know).

Galantamine and Nerve Growth Factor Rescue Memory

Of interest, both NGF and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice (see “Galantamine Rescues Damaged Brain Cells: Study using transgenic mice reveals galantamine’s unique mode of action” in the March 2003 issue). Also, mice genetically altered to have reduced amounts of NGF, have deficits in cholinergic neurons in the basal forebrain resulting in impaired cholinergic function, manifested as behavioral memory-related deficits. In medical terms, treatment with galantamine significantly “rescued” the cholinergic deficit in these transgenic NGF-deficient mice by preventing the loss of cholinergic neurons (see “Galantamine Helps Protect Your Neurons” in the April 2005 issue).

In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor, NGF, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain.3 Lithium has been reported to be beneficial in animal models of brain injury, stroke, Alzheimer’s, Huntington's, and Parkinson’s diseases, amyotrophic lateral sclerosis (ALS), spinal cord injury, and other conditions.

Galantamine Treatment Benefits

In the new study, Chinese researchers set out to investigate the effect of chronic galantamine treatment on cognitive performance, amyloid-beta (Aβ) deposition and astrocyte activation in a transgenic mouse model of AD.1 Astrocytes are characteristic star-shaped glial cells in the brain. They perform an elaborate array of support functions for neurons, but if they get out of hand, they can lead to trouble. For example, at the later stages of AD, astrocytes become activated and contribute to the neuroinflammatory component of neurodegeneration.


If we slow down AD’s progression,
the greater will be our chance to
avoid the cliff—off of which lies
oblivion (as even Santa should know).


AD is a neurodegenerative disease characterized by cholinergic deficiency and deposition of Aβ in brain tissue. So it follows that considerable effort has been directed toward therapeutic approaches involving the prevention and treatment of these changes.

Galantamine, an acetylcholinesterase inhibitor, has been approved for symptomatic treatment of AD and functions to alleviate symptoms of AD by preventing the breakdown of the neurotransmitter acetylcholine. Galantamine also functions as an allosterically potentiating ligand (APL) for nicotinic acetylcholinesterase receptors (nAChRs), enabling the herbal extract to facilitate synaptic transmission in the mammalian central nervous system.

To repeat, the aim of the current study was to observe the effect of chronic galantamine administration on behavior/cognition, Aβ reduction, astrocyte stimulation and levels of pro-inflammatory cytokines in AD transgenic mice. Each of two groups of mice was given either galantamine (5 mg/kg) or 0.9% saline twice daily for eight weeks in 10-month-old mice. In protected environments such as a laboratory, mice often live two to three years, so 10-month-old mice have entered middle age.

Getting to the Platform Faster

Compared with saline treated mice, galantamine treated mice displayed significantly improved escape latencies on Days 6 and 7 of the testing period which began after 8 weeks of saline or galantamine treatments. Also, there were significantly decreased numbers of platform crossings as assessed in the Morris water maze. In the Morris test, mice are trained to find a submerged platform in a tank of water. Around the sides of the tank are symbols, and the goal entails (pun intended) that the rats remember the location of the platform, to save themselves (not really; they’re pulled out after 60 seconds) from exerting energy to stay afloat by refinding the platform and emerging from the water.

Galantamine Reduces Amyloid in Hippocampus

Galantamine reduced the total area of amyloid load within the hippocampus of the transgenic mice, inhibited astrocyte activation surrounding Aβ plaques and decreased the intracellular pro-inflammatory markers TNF-α and IL-6. Thus, galantamine may be involved in modifying AD pathophysiological mechanisms by alleviating Aβ deposition and neuroinflammation.

Mimicking Clinical Use in Humans

In the Chinese study, galantamine was chronically administered to the transgenic mice in a way that mimics clinical use in human patients. A daily administration of galantamine ranging from 1-10 mg/kg (daily treatment) has been used extensively in preclinical investigations.

Results from a previous report indicated that a subcutaneous injection of galantamine (2 mg/kg) for ten days produced an increase in cortical levels of synaptophysin (an integral membrane glycoprotein found in many types of active neurons, involved in the uptake of neurotransmitters).4


Galantamine plays an essential role in
restoring cognitive function,
reducing Aβ deposition and
inhibiting astrocyte activation and the
intracellular expressions of
TNF-α and IL-6.


In the new study, the Chinese researchers used a higher daily dose of galantamine (10 mg/kg/day, administered twice daily at 5 mg/kg) for eight weeks, to assess its effects in the transgenic mouse model of AD. With this regimen, the mice in the study displayed good tolerability with no obvious gastrointestinal side effects. Clinically, galantamine is known to have side effects that include gastrointestinal symptoms, such as abdominal pain, diarrhea, nausea and vomiting. In humans, these can be largely avoided if galantamine dosing is slowly increased to the desired level.

Faster Escape and Increased Platform Crossings with Galantamine

The behavioral data from the Morris water maze test confirmed that transgenic mice treated with saline showed clear impairments in learning and memory, which was consistent with previous studies. However, the regimen of galantamine significantly reduced these learning and memory deficits specifically with regard to important measures of decreased escape latencies (they got to the platforms faster) and increased numbers of platform crossings after the platform was removed, indicating they knew where it had been, as compared with those mice given saline.

Galantamine’s Dual Role

Galantamine (3 mg/kg, subcutaneous) also ameliorated Aβ-impaired working and reference memories when administered to the intracerebroventricular infused Aβ (10 nmol) mouse model of AD. In addition to its capacity to function as an acetylcholinesterase inhibitor, galantamine also acts as a potentiating ligand for nAChRs. This represents a double beneficial role.

Accordingly, pretreatment with Methyllycaconitine (1 mg/kg, i.p.), an α-nAChR antagonist, reverses the beneficial effects of galantamine as seen in the Morris water maze test. Such findings serve as a basis for considering agonists of α7 nAChRs as therapeutic approaches for managing cognitive deficits in AD.

Reductions in Amyloid Deposits Lessen AD Symptoms

While the precise mechanisms of Aβ toxicity have not been fully elucidated, there is clear evidence that reductions in amyloid deposits alleviate AD symptoms. Prevention of amyloid formation and clearance of existing amyloid at early stages in the disease are currently considered as promising disease-modifying therapeutic strategies in AD.

The greater levels of Aβ and development of plaques at earlier ages (10 weeks) within transgenic mice makes them a particularly relevant model for AD. In these mice, significant amounts of plaques are localized within the hippocampus by 6-8 months of age, which is much delayed as compared to that of the cortex.

Galantamine Significantly Reduced Plaque Burden

While the transgenic mice treated with saline showed obvious Aβ plaques within the cortex and hippocampus at 12 months of age, the galantamine regimen significantly reduced this plaque burden. Within 10-month old transgenic mice, a substantially reduced galantamine administration consisting of 2mg/kg subcutaneously injected for ten days had no effect on Aβ levels.1

In another AD mouse model, a high daily dose treatment of galantamine at 26 mg/kg delayed Aβ plaque formation and reduced gliosis (a nonspecific reactive change of glial cells in response to damage to the central nervous system).5 Along with the Chinese study’s eight week administration of galantamine at 10 mg/kg/day showing a positive effect on reducing Aβ plaques, both of these studies provide new evidence for use of galantamine in the treatment of AD.


While the transgenic mice treated
with saline showed obvious Aβ
plaques within the cortex and
hippocampus at 12 months of age,
the galantamine regimen significantly
reduced this plaque burden.


Morphological Changes Have Functional Impact

The astrocytes present, both within the vicinity and surrounding Aβ plaques in the hippocampus, displayed a swollen and irregular morphology and hypertrophic proximal processes that were in intimate contact with plaques. The reduction in Aβ pathology within these transgenic mice correlated with their improved behavioral/cognitive performance resulting from galantamine, thus demonstrating that the observed morphological changes exert a corresponding functional impact. Reducing Aβ burden may be obtained by increasing Aβ degradation and/or decreasing Aβ42 synthesis through increasing alpha-secretase (a family of proteolytic enzymes that cleave amyloid precursor protein).

Another study demonstrated that treatment of rat microglia with galantamine significantly enhanced microglial Aβ phagocytosis (“cell eating”), an effect which requires the combined actions of an acetylcholine competitive agonist and an APL for nAChRs, but also facilitated Aβ clearance in the brains of rodent AD models.6


The results from this study provide
new evidence for use of galantamine
in the treatment of AD.


Galantamine as Anti-Inflammatory

It has been suggested that inflammation may be a key factor in the pathophysiology of AD. Transgenic mice over-expressing Aβ, show significant inflammation and astrogliosis around areas of Aβ deposition.7,8 In these two studies, the hippocampus of transgenic mice showed substantial astrocytic activation both in the vicinity and surrounding Aβ deposition. And, in these activated astrocytes, significant increases in TNF-α and IL-6 expression were present as revealed. As the brains of these transgenic mice are under active inflammatory stress, the increased levels of pro-inflammatory TNF-α and IL-6 expression may be directly related to the amount of soluble and insoluble Aβ present in the brain. TNF-α is thought to amplify brain inflammation and cognitive impairment in AD models and IL-6 expression is increased around amyloid plaques and in cerebrospinal fluid in the brains of AD patients.

IL-6 also increases neuronal damage induced by Aβ peptide in cultured rat cortical neurons. However, IL-6 may also show a beneficial effect in transgenic AD models resulting from a massive gliosis, which can attenuate Aβ deposition and enhance plaque clearance. The chronic administration of galantamine as used in this study inhibited astrocyte activation and the expression of TNF-α and IL-6 in astrocytes. In this way, the galantamine reducing plaque burden may be correlated with this decreased glial activation.

The Dual Edge of Benefit or Detriment

The impact of astrocyte activation and reactive gliosis on the pathogenesis of AD represent dual processes that can potentially be beneficial or detrimental to this disorder. On the beneficial side, astrocyte activation may limit the lesion size, thereby providing neuroprotection and regulation of the CNS homeostasis.

Yet, the improved performance in context memory and spatial learning tests has been reported to be associated with reductions in plaque formation and gliosis in transgenic mouse models. Galantamine was ineffective in altering hippocampal levels of TNF-α and IL-6 in transgenic mice as compared with their saline treated controls. Peripheral administration of galantamine significantly reduces serum TNF levels through vagus nerve signaling and protects against lethality during murine endotoxemia.


Galantamine plays an essential
role in restoring cognitive function,
reducing Aβ deposition and inhibiting
astrocyte activation and
the intracellular expressions of
TNF-α and IL-6.


In another study, administration of galantamine to α7nAChR knockout mice failed to suppress TNF-α levels. Galantamine can up-regulate IFγ expression and down-regulate IL-6 expression in plasma samples of tularemia-infected laboratory mice. IFNγ is a cytokine that is critical for innate and adaptive immunity against viral, some bacterial and protozoal infections. Tularemia is a severe infectious bacterial disease of animals transmissible to humans.

Thus, galantamine can significantly influence the immune response via the cholinergic anti-inflammatory pathway. While results from animal studies suggest that AChEIs can acquire a modulatory anti-inflammation role, in AD patients taking AChEIs (including galantamine), inflammatory blood markers and function remained unaltered.

Pre-Treatment with Galantamine Reduces Brain Damage

Importantly, galantamine has been shown to influence proinflammatory cytokine levels in other animal model disease conditions. Pre-treatment with galantamine is effective in reducing brain damage via an inhibitory effect on microglial activation and IL-1β production as demonstrated in a newborn rat model of hypoxia-ischemia.

The data presented in the Chinese paper suggest that galantamine plays an essential role in restoring cognitive function, reducing Aβ deposition and inhibiting astrocyte activation and the intracellular expressions of TNF-α and IL-6.

Galantamine may not only decelerate AD progression and provide symptomatic relief, but may also be involved in modifying pathophysiological mechanisms by alleviating Aβ deposition and neuroinflamation. The results from this study provide new evidence for use of galantamine in the treatment of AD.

References

  1. Wu Z, Zhao L, Chen X, Cheng X, Zhang Y. Galantamine attenuates amyloid-β deposition and astrocyte activation in APP/PS1 transgenic mice. Exp Gerontol. 2015 Oct 28. pii: S0531-5565(15)30077-2. doi: 10.1016/j.exger.2015.10.015. [Epub ahead of print] PubMed PMID: 26521029.
  2. Tuszynski MH, Yang JH, Barba D, U HS, Bakay RA, Pay MM, Masliah E, Conner JM, Kobalka P, Roy S, Nagahara AH. Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease. JAMA Neurol. 2015 Oct 1;72(10):1139-47.
  3. Young W. Review of lithium effects on brain and blood. Cell Transplant. 2009;18(9):951-75.
  4. Unger C, Svedberg MM, Yu WF, Hedberg MM, Nordberg A. Effect of subchronic treatment of memantine, galantamine, and nicotine in the brain of Tg2576 (APPswe) transgenic mice. J Pharmacol Exp Ther. 2006 Apr;317(1):30-6.
  5. Bhattacharya S, Haertel C, Maelicke A, Montag D. Galantamine slows down plaque formation and behavioral decline in the 5XFAD mouse model of Alzheimer’s disease. PLoS One. 2014 Feb 21;9(2):e89454. doi: 10.1371/journal.pone.0089454. eCollection 2014. PubMed PMID: 24586789; PubMed Central PMCID: PMC3931790.
  6. Takata K, Kitamura Y, Saeki M, Terada M, Kagitani S, Kitamura R, Fujikawa Y, Maelicke A, Tomimoto H, Taniguchi T, Shimohama S. Galantamine-induced amyloid-{beta} clearance mediated via stimulation of microglial nicotinic acetylcholine receptors. J Biol Chem. 2010 Dec 17;285(51):40180-91. doi:10.1074/jbc.M110.142356. Epub 2010 Oct 14. PubMed PMID: 20947502; PubMed Central PMCID: PMC3001000.
  7. Lewis TL, Cao D, Lu H, Mans RA, Su YR, Jungbauer L, Linton MF, Fazio S, LaDu MJ, Li L. Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer disease. J Biol Chem. 2010 Nov 19;285(47):36958-68.
  8. Weitz TM, Gate D, Rezai-Zadeh K, Town T. MyD88 is dispensable for cerebral amyloidosis and neuroinflammation in APP/PS1 transgenic mice. Am J Pathol. 2014 Nov;184(11):2855-61.


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

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