The third mechanism of galantamine

Galantamine as Antioxidant
New evidence demonstrates a largely undisclosed power for new health benefits

By Will Block

I am amazed that you drank this potion
And are not bewitched. No other man
Has ever resisted this drug once it’s past his lips.
But you have a mind that cannot be beguiled.
You must be Odysseus, the man of many wiles.

— Circe to Odysseus, The Odyssey,
Book X (Trans. Stanley Lombardo)

Translater Stanley Lombardo opens The Odyssey with “Speak, Memory.” This underscores that the ‘”Odyssey” is, at its core, about preserving memory.

Then—in what is perhaps the first mention of a nootropic phytonutrient in recorded history (if epic tales are included)—Homer’s Greek hero Odysseus is protected from the memory-stealing poison of Circe by eating a galantamine-containing flower and its bulb, the snowdrop.

Circe’s poison was Datura stamonium, a mind-altering plant now known to contain atropine, hyoscyamine, and scopolamine. Aside from atropine’s ability to antagonize acetylcholine receptors and thus degrade memory (as do hyoscyamine and scopolamine), all substances cause cerebral oxidative damage because they abolish the antioxidant effects of acetylcholine, an important memory molecule. There are other reasons as well, as we shall see.

Galantamine and Oxidative Stress

To date, there have been few overt notices of the antioxidant properties of galantamine. But a very recent paper—published by researchers from the Medical University of Sofia, Bulgaria and Sapienza University in Rome, Italy—develops a strong argument that accumulated research demonstrates that galantamine has powerful antioxidant effects.1 The two generally accepted mechanisms of galantamine, as readers of this publication well know, are its cholinesterase inhibitor effect, which increases the utility of acetylcholine, and its nicotinic receptor enhancement effect in the cholinergic system, which increases sensitivity to acetylcholine. With the publication of this new paper, galantamine’s ability to protect against oxidative damage through its antioxidant properties may represent a third major mechanism.

Disease and Oxidation

As we are increasingly learning, oxidative stress is implicated in the pathogenesis of many different human diseases: Alzheimer, Parkinson, Huntington, amyotrophic lateral sclerosis (Lou Gehrig’s disease), Down’s syndrome, atherosclerosis, vascular disease, cancer, diabetes mellitus type 1 and type 2, age-related macular degeneration, psoriatic arthritis, and others.


Galantamine’s ability to protect
against oxidative damage through its
antioxidant properties may represent
a third major mechanism.


Quoting the new Bulgarian/Italian study, “Alzheimer’s disease is a chronic neurodegenerative disorder causing progressive impairment of memory and cognitive function, as a result of extensive dendritic spine loss and synaptic alterations. Synaptic dysfunction is [characterized by] the presence of abnormal [deposits] of Aβ [amyloid-beta] protein in senile plaques and formation of neurofibrillary tangles and neuropil threads, which are composed of abnormal and hyperphosphorylated microtubule-associated tau protein, aggregated into paired helical filaments. Free radicals are [ ] causative factor[s] of the inflammatory injury and oxidative stress, which have been implicated in pathogenesis of this chronic neurodegenerative disease. [Emphasis added; references ­excluded]”

The Vulnerability of Brains

Simply put, oxidative damages are among the earliest neuronal and pathological changes of Alzheimer’s disease. Our brains are especially sensitive to oxidative damage because they are comprised of large amounts of easily oxidized fatty acids. They also consume high amounts of oxygen while possessing low levels of endogenous antioxidants. Thus, oxidative stress plays a major role in the pathogenesis of neuron degeneration in the brains of patients with Alzheimer’s disease due to the production of reactive oxygen species that mediate the dysfunction of cell membranes and cell damage. This subsequently leads to nerve cell death activation (apoptosis) by:

  1. Oxidation of proteins, lipids and nucleic acids (RNA, DNA)
  2. DNA strand breaks
  3. Increased membrane rigidity
  4. Decreased energy production by disturbed glucose metabolism

The major biomarkers of the brain damage induced by the reactive oxygen species, are:

  1. Protein carbonyls, which are an index of protein oxidation
  2. Generation of markers of lipid peroxidation
  3. 3-nitrotyrosine, formed by reaction between peroxynitrite and tyrosine
  4. Activity loss of sensitive enzymes through oxidation
  5. Oxidized DNA

Plants as a Source of Antioxidants

Owing to their free-radical scavenging properties, plant antioxidants have potential to prevent, delay or ameliorate many human disorders, including Alzheimer’s disease. In traditional Ayurvedic, Chinese, European, and Japanese medicine, plants have been used for treatment of cognitive disorders, including neurodegenerative diseases such as Alzheimer’s disease and other memory related disorders.

For example, Ginkgo biloba, Salvia officinalis and Melissa officinalis possess memory-improving properties. Also, Curcuma longa (turmeric) is one of the most popular species in tropical areas of Asia and Central America, containing many natural antioxidants that have radical scavenging activity. Bulgarian medicinal plants include Silibum marianum, Tribulus terrestris, Galantus nivalis, and Leucojum aestivum (the last two are snowdrops). These are rich sources of compounds with free radical scavenging activity.

Galantamine’s Pharmacological Activity as an Acetylcholinesterase Inhibitor

Galantamine is a natural alkaloid, isolated from bulbs and aerial parts of plants from the family Amaryllidaceae, of which Galanthus nivalis, Leucojum aestivum, and Lycoris radiata are representative. Galantamine is a long-acting specific centrally active cholinergic phytonutrient with antioxidant and neuroprotective properties through an antiapoptotic (apoptosis is cell suicide) action. It stimulates choline-acetyltransferase activity and potentiates the release of the neurotransmitter acetylcholine and sensitivity to it via its dual mechanism of action (see above).


Free radicals are causative factors of
the inflammatory injury and oxidative
stress, which have been implicated in
pathogenesis of [Alzheimer’s] disease.


A deficit in cholinergic function has been identified in schizophrenia, major depression, bipolar disorder and alcohol abuse. Galantamine has been shown to improve cognitive dysfunctions in these diseases, and also possesses an antipsychotic effect in patients and in animal models of psychiatric disorders. Galantamine enhances dopaminergic neurotransmission in vivo, increases dopamine concentrations in the prefrontal cortex and midbrain, significantly increases noradrenaline release from hippocampal slices, and potentiates nicotine-evoked noradrenaline release.

Galantamine is a nootropic agent, which benefits performance in all domains of mild to moderate Alzheimer’s disease, Alzheimer’s plus cerebrovascular disease, vascular dementia, ischemic insult, and stroke. It improves attention, behavior, cognition, concentration, memory retention, mental retardation, functional ability, and both short-term (3–12 months) and long-term (36 months) memory improvement. It also slows the clinical progression of Alzheimer’s disease by decreasing the cognitive decline over 36 months of continuous treatment.

Galantamine possesses morphine-like activity, acts as a morphine antagonist (blocking the prolongation of sleeping time), reverses the respiratory depression induced by dextromoramide (a powerful opioid analgesic approximately three times more potent than morphine, but shorter acting), improves cell-mediated immunity, suppresses the abnormal release of inflammatory cytokines, and reduces smoking rates. It crosses the blood-brain barrier, has a broad therapeutic index, stable pharmacokinetics, good tolerability, and moderate to negligible toxicity.

Antioxidant Properties of Galantamine

Galantamine is a natural alkaloid with antioxidant properties. It is a scavenger of reactive oxygen species and exerts neuroprotection mainly by inhibition of the oxidative damage. The capability of galantamine and galantamine hydrobromide to scavenge the reactive oxygen species is related to the enol group* in the molecule.


* An organic compound containing a hydroxyl group bonded to a carbon atom, which in turn is doubly bonded to another carbon atom.



Galantamine in a concentration-
dependent manner prevents
neuronal oxidative damage,
induced by Aβ1–40.


When galantamine is changed to galantamine ­hydrobromide there is a significant increase of the ­radical-scavenging effect. The presence of enol group and quaternary nitrogen improves the antioxidant activity.

Neuroprotective Effect of Galantamine Against Beta Amyloid Peptide

The neuroprotective effect of galantamine is mediated through its allosteric modulation of α7-subtype of nicotinic acetylcholine receptors (α7SNAR). The most important hallmarks of Alzheimer’s disease are oxidative stress, amyloid-β ­peptide 1–42 (Aβ1–42) increase, neurofibrillary tangles, synapse loss, and neurodegeneration.

In the pathogenesis of Alzheimer’s disease the activity of Aβ1–42 plays a central role when it is deposited in senile plaques and aggregated in fibrillar networks. In hippocampal neuronal cultures Aβ1–42 induces free radical oxygen species formation, protein oxidation, lipid peroxidation and cell apoptosis. Galantamine in a concentration-dependent manner prevents neuronal oxidative damage, induced by Aβ1–40. One study found that galantamine reduces apoptotic cell death induced by Aβ in a culture of human neuroblastoma cells. Galantamine helped prevent apoptosis and cholinergic neuronal stress. [All refs omitted; see ref 1.]


† Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy.


Another study found that galantamine prevents human neuroblastoma neuronal damage induced by Aβ-peptide through the activation of α7SNAR. In a related study, pretreatment of human neuroblastoma cells with galantamine for 24 hours provided inhibition of Aβ1–40 toxicity. The phytonutrient affords neuroprotective effects against Aβ1–40, and this protection could be attributed to galantamine’s anti-aggregation properties. In other experimental investigations, galantamine protected the human neuroblastoma cell line against apoptosis. In another study, pretreatment with galantamine for 24 hours prior to Aβ25–35 exposure, protected PC12 cells against Aβ25–35-induced loss of cell viability and apoptosis. All of the Aβ peptides are destructive, but to different degrees.

Neuroprotective Effect of Galantamine Against Glutamate-Induced Toxicity

Glutamate-induced toxicity is believed to be one of the central mechanisms that result in Alzheimer’s disease by attacking and killing the cortical neurons. In one study, galantamine in a concentration-dependent manner activated α7SNAR that led to blocking glutamate neurotoxicity in rat cultured cortical neurons. In another study, it was demonstrated that the suppression of α7SNAR expression inhibits galantamine phosphorylation of serine/threonine protein kinase thus decreasing the neuroprotective effect of the phytonutrient.

The antiapoptotic activity of galantamine against glutamate toxicity is concentration-dependent, with maximum protection produced at 300 nM. Also, galantamine prevents Aβ induced glutamate cell death due to: 1) allosteric activation of α7SNAR; 2) induction of antiapoptotic protein B-cell leukemia/lymphoma 2 expression.

Neuroprotective Effect of Galantamine against Hydrogen Peroxide-Induced Toxicity

Hydrogen peroxide is produced by mitochondrial dysfunction and the autoxidation of dopamine, which in turn generates hydroxyl radicals in the presence of iron (as Fe2+). It is known that the hydroxyl radical is one of the most potent neurotoxic factors in dopaminergic neurodegeneration. Experiments have shown that in an in vivo hemi-Parkinsonian rat model galantamine possessed synergistic effect on nicotine-induced neuroprotection. It can be inferred that galantamine synergistically enhances the neuroprotective activity of nicotine against induced dopaminergic neuronal loss through an allosteric modulation of α7SNAR activation. In another study, it was demonstrated that galantamine enhances phagocytosis by sensitizing the microglial α7SNAR to choline and inducing calcium ion (Ca2+) influx into microglia.


‡ The process of engulfing and ingesting particles by the cell or a phagocyte (e.g. macrophage).


Galantamine has been found to protect against an in vitro model of hydrogen peroxide-induced oxidative injury in human neuroblastoma cell lines by the following mechanisms:

  1. Decreasing nitrogen oxide and superoxide anion overproduction
  2. Prevention of membrane fluidity disturbances
  3. Restoring mitochondrial membrane potential and mitochondrial impairment
  4. Increasing of availability of acetylcholine due to concentration-dependently acetylcholinesterase inhibition
  5. Subsequent activation of α7SNAR. A close relationship between acetylcholinesterase inhibition and reduced oxidative injury exist.

Heme oxygenase-1 is an inducible antioxidative enzyme that degrades heme§ to carbon monoxide and biliverdin (a product of heme catabolism). Experiments have demonstrated that oxygenase-1 has a strong cytoprotective effect in neurons and cerebral microvascular endothelial cells. Because oxidative stress is implicated in the mechanism, leading to cellular injury in cerebrovascular disease, the pharmacological induction of heme oxygenase-1 in the brain cerebral circulation provides complete protection against cerebral vascular dysfunction. Other investigations show that galantamine in a dose dependent manner within a specific range in concentration significantly reduces hydrogen peroxide-induced cell death of rat cerebral microvascular endothelial cells, in association with heme oxygenase-1 induction, leading to improvement of cerebral microcirculation.


§ Heme is the deep red, nonprotein, iron-containing component of hemoglobin that carries oxygen throughout the body.


Neuroprotective Effect of Galantamine against Oxygen and Glucose Deprivation-Induced Toxicity

Galantamine in a concentration-dependent manner confers neuroprotective activity in vitro on brain rat hippocampal slices subjected to oxygen and glucose deprivation, followed by reoxygenation. By activation of the α7SNAR, galantamine stimulates cytoplasmic Janus protein tyrosine kinases.|| This effect mediates the following mechanisms that inhibit the induction of inducible nitric oxide synthase, nitric oxide production and cell death. These results show that cytoplasmic Janus protein tyrosine kinases are the initial kinases, which are activated by galantamine through the allosteric modulation of α7SNAR, and mediate the induction of neuroprotective effect and anti-inflammatory action under brain ischemia-reoxygenation conditions.


|| Cytoplasmic Janus protein tyrosine kinases are crucial components of diverse signal transduction pathways that govern cellular survival, proliferation, differentiation and apoptosis.


Neuroprotective Effect of Galantamine against Induced Transient Global Cerebral Ischemia

Because it can lead to neuronal cell death, ischemic brain injury—as a secondary result from cardiovascular disease and cerebrovascular diseases—is a common cause of dementia and cognitive decline in Alzheimer’s disease.

The cognitive deficits induced by global cerebral ischemia revealed a close relationship with the neuronal death in the hippocampus. Global cerebral ischemia mediates a cascade of damaging processes that contribute to ischemic cell damage. In one experiment, it was shown that the continuous administration of galantamine, given 30 minutes before transient global ischemia in gerbils, attenuates the cognitive deficits and hippocampal neurons loss.

The neuroprotective action of galantamine results from its indirect choline mimetic effect, leading to preserving the autoregulation of the cerebral blood flow and to the reduction of excitotoxicity. In experiments with gerbils, strokes were stimulated by ligation of their carotid arteries for 5 minutes. This deprived their brains of blood and oxygen (transient global cerebral ischemia). In the periods of ischemia and reperfusion, when blood flows freely again, free oxygen radicals are generated, far in excess of the norm. Before cells can respond by producing of large amounts of the antioxidant enzyme superoxide dismutase (SOD), serious damage is done to cellular proteins, lipids and nucleic acids. The damage done by the ischemia and the reperfusion is called ischemia-reperfusion injury.


A recent study showed that galantamine, given 24 hours before ischemia and continuing application for 3 days, in a dose-dependent manner significantly increases the number of living pyramidal neurons after transient global cerebral ischemia-reperfusion injury in gerbils. In the hippocampus of the gerbils, which were not treated with galantamine, a massive loss of neurons is observed. The remarkable result is that 10 mg/kg of galantamine, administered 3 hours post-ischemia, provided in vivo neuroprotection and memory recovery against global cerebral ischemia, reduced DNA fragmentation in a dose-dependent manner and decreased SOD2 concentrations. This finding is very important, because in humans, 3 hours is the therapeutic window of the opportunity for the effective treatment of acute ischemic stroke with thrombolytic drugs. The inhibition of DNA fragmentation is dependent in part on nicotinic receptors.

In another study, galantamine significantly decreased active caspase-3# in pyramidal neurons after transient ischemia. This is consistent with the in vitro antiapoptotic effect. Galantamine reduced caspase-3 activation, independently of nicotinic receptors.This caspase-3 independent mechanism also is involved in galantamine’s neuroprotective action. Animals treated with galantamine prior to or post-ischemia-reperfusion injury show restored superoxide dismutase 2 immunoreactivity. All these results suggest again, that the α7SNAR-mediated effect of galantamine could play an important role in prevention of the detrimental effects of superoxide anion. In another investigation, it was found that 25 min. post-ischemic single administration of galantamine improved learning ability in rats.


# Caspase 3 is an enzyme that plays a key role in programmed cell death, or apoptosis.


Neuroprotective Effect of Galantamine against Ethanol Induced Oxidative Stress and Cytotoxicity

α7SNAR-mediated protection of galantamine was demonstrated against ethanol-induced oxidative stress and cytotoxicity in rat adrenal medulla cells. In other experiments, the neuroprotective activity of galantamine in vivo was shown in anti-nerve growth factor mice. After an application for 2 months, galantamine was effective in decreasing of the deposition of amyloid precursor protein in vessels in Alzheimer’s mice.

Neuroprotective Effect of Galantamine against Kainic Acid Oxidative Damage

Intrahippocampal Kainic acid (an excitatory neurotoxin, which stimulates glutamate receptors) administration causes oxidative damage indicated by the rise in lipid peroxidation, nitrite concentration and depletion of superoxide dismutase in the hippocampus. Kainic acid-induced neurodegeneration in the hippocampus is accompanied by a decrease in the concentration of acetylcholine and by an increase in the activity of acetylcholinesterase.

Intrahippocampal administration of Kainic acid produces significant impairment of the activity of mitochondrial complex and decreases the number of viable cells, as a result of intracellular calcium overload. The calcium overload induces the activation of a number of calcium dependent cellular enzymes. This effect promotes the activation of astrocytes, which produce the inflammatory mediators leading to neurodegeneration.

In a recent investigation, it was demonstrated that after 14 days of simultaneous application with a nonsteroidal anti-inflammatory drug (NSAID) and caffeic acid, galantamine significantly potentiated the protective effect of the NSAID and caffeic acid against intrahippocampal kainic acid-induced oxidative damages, cognitive impairment and mitochondrial respiratory enzyme alterations in rats. The results also showed that reduced glutathione was restored and that acetylcholinesterase activity was reduced.

Improved locomotor activity, memory retention and oxidative defense result by decreasing lipid peroxidation and nitrite and increasing SOD activity in the hippocampus. The prior experimental results also showed that galantamine and the NSAID significantly enhanced their protective effect in comparison to their separate effects by reducing the elevated levels of acetylcholinesterase, stimulating choline acetyltransferase activity, and elevating acetylcholine levels, reducing glutathione levels and activity of an enzyme complex in mitochondria, reducing levels of inflammatory mediators.

A complex interaction between α7SNAR, Aβ peptide and acetylcholinesterase causes cholinergic depletion and neuronal death in Alzheimer’s disease brain, in which α7SNAR are significantly reduced. Aβ peptide causes neuronal death by inhibition of the release of acetylcholine and reuptake of choline and by enhancing of calcium influx. High concentrations of acetylcholinesterase exist in the core of the amyloid plaques. The complex between Aβ plaques and acetylcholinesterase is significantly more toxic than Aβ plaques alone.


Among the points to remember
is that one of the earliest neuronal
and pathological changes of
Alzheimer’s disease is increased
oxidative damage.


Galantamine enhances synaptic transmission by its action as an allosteric modulator of α7SNAR, thereby increasing the amount of acetylcholine in the synapses, by preventing its breakdown, leading to modulation of the muscarinic transmission. Due to chronic stimulation of α7SNAR, acetylcholine enhances their numbers. As a result of these mechanisms, it has been demonstrated that galantamine significantly increases excitability of hippocampal pyramidal neurons, and improves the deficits in learning and memory, attention and cognition in patients with Alzheimer’s disease by affecting the information flow through the hippocampus. Galantamine also inhibits disease progression by enhancing the function of pathways involved with neuroprotection.

Synergistic Relationship of Galantamine and Choline Donors

The simultaneous application of the acetylcholinesterase inhibitor galantamine and acetylcholine precursor choline alphoscerate (a choline donor) elicits neuroprotective activity on brain in spontaneously hypertensive rats. There is synergy and the combination is higher than the sum of the separate effects observed with single administration of the compounds. These results demonstrate that the combination between an acetylcholine breakdown inhibitor, galantamine and an acetylcholine precursor (such as choline alphoscerate or choline), not only more effectively increases brain acetylcholine levels, but also possesses a stronger neuroprotective action (see “Alzheimer’s Breakthrough” in the April 2012 issue of Life Enhancement.

Galantamine is a Powerful Alzheimer’s Oxidative Damage Scavenger

Among the points to remember is that one of the earliest neuronal and pathological changes of Alzheimer’s disease is increased oxidative damage. This occurs in selective brain regions, but especially those that are involved in the governance of cognitive performance. Here galantamine ought to be seen as a powerful scavenger of reactive oxygen species (ROS). The major biomarkers of the brain damage, induced by the ROS are: 1) protein carbonyls, which are an index of protein oxidation; 2) lipid peroxidation markers; 3) 3-nitrotyrosine, formed by reaction between peroxynitrite and tyrosine; 4) loss of activity of oxidatively sensitive ­enzymes; and 5) oxidized DNA. Galantamine defends against each of these.

Galantamine’s Neuroprotective Effects

Galantamine exerts neuroprotective effect by lowering oxidative neuronal damage, through mechanisms which involve:

  1. Decreasing H2O2-induced superoxide anion and nitric oxide overproduction, resulting from the increased availability of acetylcholine due to acetylcholinesterase inhibition and the subsequent activation of α7SNAR
  2. Preventing the activation of the P2X7 receptors, implicated in ATP-mediated cell death.
  3. Protection of mitochondrial membrane potential. A close relationship between acetylcholinesterase inhibition and reduced oxidative injury is observed.

The neuroprotective activity of galantamine against a variety of cytotoxic agents, Aβ and glutamate, hydrogen peroxide, oxygen and glucose deprivation) is mediated through the allosteric potentiation of α7SNAR. Galantamine reduces the Aβ induced neuronal apoptosis through inhibition of Aβ-peptide aggregation. Galantamine improves memory and other cognitive functions in patients with combination of dementia, hypertension, and insomnia.

As Your Epic Tale Continues

If you are concerned about memory loss, as your years unfold, it may be a good idea to consider the benefits of galantamine, and make this extraordinary phytonutrient a regular part of your life. Then perhaps, you too can “Speak, Memory.”

Reference

  1. Tsvetkova D, Obreshkova D, Zheleva-Dimitrova D, Saso L. Antioxidant Activity of Galantamine and some of its Derivatives. Curr Med Chem. 2013 Jun 25. [Epub ahead of print]


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

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