The results of a new study show that …

Galantamine Reduces Alzheimer’s Genotoxicity
and helps prevent brain cell death

By Will Block

Biochemically, Alzheimer’s disease (AD) is characterized by the presence of abnormal deposition of beta amyloid peptide (Aβ(1-42)), which is generated by proteolytic processing from its precursor, the amyloid precursor protein (APP.) The presence of Aβ(1-42), in the brain is strongly correlated with cognitive impairment, cholinergic deficiency, bioenergetics disruption, cell death, and DNA damage.

Galantamine is an acetylcholinesterase inhibitor (AChEI) used for symptomatic treatment of AD. Several studies have showed that galantamine has antioxidant properties, offers anti-apoptotic action, and also promotes neurogenesis. However, it is unknown whether galantamine may present protection mechanisms against Aβ(1-42)-induced genomic instability. Genomic instability refers to a high frequency of mutations within the genome of a cellular lineage.

Effects of Galantamine on Cell Toxicity and DNA Strand Breaks

To understand the mechanisms of this neuroprotection, researchers at the University of São Paulo in Brazil studied the effects of galantamine on the cell toxicity and DNA strand breaks induced by Aβ(1-42).1 They used a set of biomarkers such as clonogenic assay (a cell biology technique for studying the effectiveness of specific agents on the survival and proliferation of cells), cytokinesis block micronucleus cytome (a comprehensive system for measuring DNA damage, cytostasis and cytotoxicity) and comet assay (an uncomplicated and sensitive technique for the detection of DNA damage at the level of the individual eukaryotic cell).


The presence of Aβ(1-42), in the
brain is strongly correlated with
cognitive impairment, cholinergic
deficiency, bioenergetics disruption,
cell death, and DNA damage.


Galantamine Exerts Antigenotoxic Properties

The results found that galantamine treatments were able to significantly reduce the Aβ(1-42)-induced cytotoxicity and genotoxicity. This study demonstrated that in addition to inhibition of acetylcholinesterase (AChE), galantamine exerts antigenotoxic properties. This property of galantamine is worthwhile exploring further because it may improve the discovery of new disease-modifying agents.

Several studies have showed that galantamine has antioxidant properties, anti-apoptotic action and also promotes neurogenesis.


Several studies have showed that
galantamine has antioxidant properties,
offers anti-apoptotic action, and also
promotes neurogenesis.


Dementia Worldwide

Worldwide, AD is the most common form of dementia. The etiology—cause, set of causes, or manner of causation of a disease—is multifactorial, and the pathophysiology of AD is complex. It has been estimated that 35.6 million people lived with dementia worldwide in 2010, with expectation to double these numbers every 20 years, to 65.7 million in 2030 and 115.4 million in 2050, due to the complexity of this disease and increase in the population with advanced age. AD is considered by many as the principal public health crisis of the 21st century.

Neurologically, AD patients’ brains are characterized by two classic hallmarks that define the pathological features of disease: accumulation of senile plaques (SPs) and the hyperphosphorylation of tau protein.


Aβ(1-42) has been reported to
generate reactive oxygen and nitrogen
species, such as hydrogen peroxide
(H
2O2) and nitric oxide (NO), lipid
peroxidation, protein oxidation, and
DNA and RNA damage.


SPs are extra cellular deposits composed of various peptide fragments—Aβ(1-40) and Aβ(1-42)—derived from the proteolytic processing of APP, an integral membrane protein. Evidence has shown that these proteins generate deposits in specific areas of the brain, and they are critical factors involved in memory loss and cognitive impairment in AD patients.

Although the etiological origin of AD remains unknown, growing evidence suggests that soluble oligomers of Aβ(1-42) are potentially toxic. In addition, Aβ(1-42) has been reported to generate reactive oxygen and nitrogen species, such as hydrogen peroxide (H2O2) and nitric oxide (NO), lipid peroxidation, protein oxidation, and DNA and RNA damage.

Nevertheless, the pathological changes include other biological alterations such as mitochondrial dysfunction, synapse loss and neuronal death, resulting from vulnerability to stress and oxidative damage, in parallel with a depletion of antioxidant system used to slow down the process of neurological degeneration.

The efficacy of galantamine has been shown for treatment of AD patients at different stages (mild, moderate and advanced) of the disease; however, recently, its efficacy has also been observed in patients with AD in the severe stage.2


The efficacy of galantamine
has been shown for treatment of AD
patients at different stages (mild,
moderate and advanced) of the
disease; however, recently, its efficacy
has also been observed in patients
with AD in the severe stage.


Galantamine Has a Weak AChEI Effect

Unlike other AChEIs such as donepezil, tacrine and rivastigmine, galantamine has a weak AChEI effect. Nevertheless, it has a dual mode of action, since it inhibits acetylcholinesterese and interacts allosterically with nAChRs to potentiate the sensitivity of acetylcholine receptors.

Also, galantamine modulates nonamyloidogenic processing of APP by inhibiting BACE (beta-site APP-cleaving enzyme) expression and inhibits the aggregation and toxicity of the β-amyloid (Aβ) peptide.

Purpose of Study

The purpose of the Brazilian study was to explore whether galantamine exerts antigenotoxic effects against Aβ(1-42)-induced DNA damages in undifferentiated human neuro­blastoma SHSY5Y cells. DNA damage was evaluated by the cytokinesis block micronucleus cytome (CBNM-cyt) and comet assays, which are highly sensitive and simple methods capable of providing relevant results regarding the antigenotoxicity potential of galantamine.

Preparation of Beta Amyloid Peptide and Galantamine

Aβ(1-42) peptide was prepared according to previously established techniques. The stock solution of Aβ(1-42) was dissolved at 1 mg/mL in 100% 1,1,1,3,3,3- exafluoro-2-propanol (HFIP), an efficient hydrogen-bond donor and highly polar solvent. This was sonicated in a water bath for 10 min, aliquoted into micro centrifuge tubes, dried under vacuum and stored at -20°C. Immediately prior to use, the HFIP-treated Aβ(1-42) was dissolved in 1mg/mL dimethylsulfoxide (DMSO). Galantamine stock solution was and the final methanol concentration in the culture medium was 1:100 (v/v).


Galantamine may not only decrease
AD progression due its AChEI activity,
but may also be involved in regulation
of DNA damage induced by Aβ(1-42).


Galantamine Exerted Protective Activity

The Brazilian study demonstrated that galantamine exerted protective activity against Aβ(1-42)-induced genotoxic and cytotoxic damages in SH-SY5Y cell line, indicating that this alkaloid compound may exert antigenotoxic properties and regulate cell loss in addition to AChEI and antioxidant activities as shown by its effects on the reduction of different biomarkers associated with DNA damage and cytotoxicity.

Following the aforementioned assays, it was determined that galantamine offered protective effects against (Aβ)1-42-induced inhibition of cell proliferation. Also that it decreased Aβ(1-42)-induced cell death and protected against Aβ(1-42)-induced genotoxicity.

Galantamine may not only decrease AD progression due its AChEI activity, but may also be involved in regulation of DNA damage induced by Aβ(1-42). We suggest that the antigenotoxic effects induced by galantamine might be related to the capacity of alkaloid to activate enzymes that stimulate detoxification and DNA repair, which might favor neuronal restoration.

References

  1. Castillo WO, Aristizabal-Pachon AF, de Lima Montaldi AP, Sakamoto-Hojo ET, Takahashi CS. Galantamine decreases genotoxicity and cell death induced by β-amyloid peptide in SH-SY5Y cell line. Neurotoxicology. 2016 Oct 25. pii: S0161-813X(16)30220-0. doi: 10.1016/j.neuro.2016.10.013. [Epub ahead of print] PubMed PMID: 27793617.
  2. Burns A, Bernabei R, Bullock R, Cruz Jentoft AJ, Frölich L, Hock C, Raivio M, Triau E, Vandewoude M, Wimo A, Came E, Van Baelen B, Hammond GL, van Oene JC, Schwalen S. Safety and efficacy of galantamine (Reminyl) in severe Alzheimer’s disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol. 2009 Jan;8(1):39-47.

Galantamine and Pneumonia

Persons with Alzheimer’s disease (AD) are at an increased risk for pneumonia. However, unlike most AD drugs, galantamine is not associated with an increase in pneumonia.1

  1. Lampela P, Tolppanen AM, Tanskanen A, Tiihonen J, Lavikainen P, Hartikainen S, Taipale H. Use of antidementia drugs and risk of pneumonia in older persons with Alzheimer’s disease. Ann Med. 2016 Oct 27:1-25.


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

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