Investigating the binding interactions of galantamine with β-amyloid peptide

Rao, Praveen P.N.; Mohamed, Tarek; Osman, Wesseem

doi:10.1016/j.bmcl.2012.10.111

Cited by 22 publications

(11 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on the MD simulation results for Ab 1-42 with galanthamine, galanthamine binds to Ab 1-42 in two different manners: the aromatic ring of galanthamine interacts with Lys 28 of Ab 1-42 via p-cation interactions, and the protonated tertiary amine interacts with Asp 23 via electrostatic interactions, preventing the formation of the salt bridge that was shown to form before the Ab 1-42 conformational change. Both types of interactions are capable of preventing the Ab 1-42 conformational change from a-helix to b-sheet; according to previous reports, 28 galanthamine interacts with the amino acids located at the turn portion of Ab 1-42 , such as Lys 28. However, the affinity of Ab 1-42 for galanthamine is lower than that for Cu 21 , as revealed by the higher concentration of galanthamine (100 mM) necessary to inhibit the oligomerization process 13 compared with Cu 21 (20 mM).…”

Section: Discussionmentioning

confidence: 77%

“…Importantly, some authors have reported that Cu 21 is associated with Ab 1-42 in the b-folded structure and is tetracoordinate with three amino acid residues, including His 6, His 13, and His 14, and a fourth component Additionally, the RMSD plots and rotation of the C a revealed the presence of significant instability in the Ab 1-42 chain, implying that this type of interaction promotes the destabilization of the peptide and prevents the formation of the salt bridge necessary for the transition to a b-sheet conformation. In fact, the 28 galanthamine interacts with the amino acids located at the turn portion of Ab , such as Lys 28. However, the affinity of Ab 1-42 for galanthamine is lower than that for Cu 21 , as revealed by the higher concentration of galanthamine (100 mM) necessary to inhibit the oligomerization process 13 compared with Cu 21 (20 mM).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

et al. 2013

View full text Add to dashboard Cite

The formation of fibrils and oligomers of amyloid beta (Aβ) with 42 amino acid residues (Aβ1–42) is the most important pathophysiological event associated with Alzheimer's disease (AD). The formation of Aβ fibrils and oligomers requires a conformational change from an α‐helix to a β‐sheet conformation, which is encouraged by the formation of a salt bridge between Asp 23 or Glu 22 and Lys 28. Recently, Cu2+ and various drugs used for AD treatment, such as galanthamine (Reminyl®), have been reported to inhibit the formation of Aβ fibrils. However, the mechanism of this inhibition remains unclear. Therefore, the aim of this work was to explore how Cu2+ and galanthamine prevent the formation of Aβ1–42 fibrils using molecular dynamics (MD) simulations (20 ns) and in vitro studies using fluorescence and circular dichroism (CD) spectroscopies. The MD simulations revealed that Aβ1–42 acquires a characteristic U‐shape before the α‐helix to β‐sheet conformational change. The formation of a salt bridge between Asp 23 and Lys 28 was also observed beginning at 5 ns. However, the MD simulations of Aβ1−42 in the presence of Cu2+ or galanthamine demonstrated that both ligands prevent the formation of the salt bridge by either binding to Glu 22 and Asp 23 (Cu2+) or to Lys 28 (galanthamine), which prevents Aβ1−42 from adopting the U‐characteristic conformation that allows the amino acids to transition to a β‐sheet conformation. The docking results revealed that the conformation obtained by the MD simulation of a monomer from the 1Z0Q structure can form similar interactions to those obtained from the 2BGE structure in the oligomers. The in vitro studies demonstrated that Aβ remains in an unfolded conformation when Cu2+ and galanthamine are used. Then, ligands that bind Asp 23 or Glu 22 and Lys 28 could therefore be used to prevent β turn formation and, consequently, the formation of Aβ fibrils.

show abstract

Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Also, galantamine has been shown to enhance microglial Aβ clearance [16]. Another possible explanation could be that galantamine binds to amyloid oligomers leading to a significant conformational change at the turn region (Asp23-Gly29) disrupting interactions between individual β strands and promoting a nontoxic conformation of Aβ (1–40) to prevent the formation of neurotoxic oligomers [55]. A previous study by Unger et al [56] reported that galantamine at a concentration of 2mg/kg injected subcutaneously for 10 days had no effect on the levels of soluble or insoluble forms of Aβ in 10 months old Tg2576 mice.…”

Section: Discussionmentioning

confidence: 99%

Galantamine Slows Down Plaque Formation and Behavioral Decline in the 5XFAD Mouse Model of Alzheimer’s Disease

Bhattacharya

Haertel

Maelicke³

et al. 2014

PLoS ONE

112

View full text Add to dashboard Cite

The plant alkaloid galantamine is an established symptomatic drug treatment for Alzheimer’s disease (AD), providing temporary cognitive and global relief in human patients. In this study, the 5X Familial Alzheimer’s Disease (5XFAD) mouse model was used to investigate the effect of chronic galantamine treatment on behavior and amyloid β (Aβ) plaque deposition in the mouse brain. Quantification of plaques in untreated 5XFAD mice showed a gender specific phenotype; the plaque density increased steadily reaching saturation in males after 10 months of age, whereas in females the density further increased until after 14 months of age. Moreover, females consistently displayed a higher plaque density in comparison to males of the same age. Chronic oral treatment with galantamine resulted in improved performance in behavioral tests, such as open field and light-dark avoidance, already at mildly affected stages compared to untreated controls. Treated animals of both sexes showed significantly lower plaque density in the brain, i.e., the entorhinal cortex and hippocampus, gliosis being always positively correlated to plaque load. A high dose treatment with a daily uptake of 26 mg/kg body weight was tolerated well and produced significantly larger positive effects than a lower dose treatment (14 mg/kg body weight) in terms of plaque density and behavior. These results strongly support that galantamine, in addition to improving cognitive and behavioral symptoms in AD, may have disease-modifying and neuroprotective properties, as is indicated by delayed Aβ plaque formation and reduced gliosis.

show abstract

“…Galantamine also reduces significantly the production and release of Tumor Necrosis Factor‐α in rats with polysaccharide‐induced inflammation (Liu et al ) and can suppress the induction of iNOS, resulting in lowered NO production during hypoxia (Egea et al ). Galantamine is an efficient anti‐oxidant agent, preventing cell damage caused by hydrogen peroxide (Triana‐Vidal and Carvajal‐Varona ) or amyloid‐β (Melo et al ), this possibly being one of the mechanisms by which the drug protects against neuronal damage by β‐amyloid (Matharu et al, ; Li et al ; Rao et al ) and the toxic compounds kainic acid and caffeic acid (Kumar et al ). There is, therefor, a plethora of actions which, independently or combined, provide galantamine with a complex pharmacology which make it even more inappropriate as a tool to define the pharmacological specificity of a compound such as kynurenic acid.…”

Section: Galantamine As a Pharmacological Toolmentioning

confidence: 99%

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

Stone

2019

Journal of Neurochemistry

View full text Add to dashboard Cite

As a major metabolite of kynurenine in the oxidative metabolism of tryptophan, kynurenic acid is of considerable biological and clinical importance as an endogenous antagonist of glutamate in the central nervous system. It is most active as an antagonist at receptors sensitive to N‐methyl‐D‐aspartate (NMDA) which regulate neuronal excitability and plasticity, brain development and behaviour. It is also thought to play a causative role in hypo‐glutamatergic conditions such as schizophrenia, and a protective role in several neurodegenerative disorders, notably Huntington’s disease. An additional hypothesis, that kynurenic acid could block nicotinic receptors for acetylcholine in the central nervous system has been proposed as an alternative mechanism of action of kynurenate. However, the evidence for this alternative mechanism is highly controversial, partly because at least eight earlier studies concluded that kynurenic acid blocked NMDA receptors but not nicotinic receptors and five subsequent, independent studies designed to repeat the results have failed to do so. Many studies considered to support the alternative ‘nicotinic’ hypothesis have been based on the use of analogs of kynurenate such as 7‐chloro‐kynurenic acid, or putatively nicotinic modulators such as galantamine, but a detailed analysis of the pharmacology of these compounds suggests that the results have often been misinterpreted, especially since the pharmacology of galantamine itself has been disputed. This review examines the evidence in detail, with the conclusion that there is no confirmed, reliable evidence for an antagonist activity of kynurenic acid at nicotinic receptors. Therefore, since there is overwhelming evidence for kynurenate acting at ionotropic glutamate receptors, especially NMDAR glutamate and glycine sites, with some activity at GPR35 sites and Aryl Hydrocarbon Receptors, results with kynurenic acid should be interpreted only in terms of these confirmed sites of action.

show abstract

Investigating the binding interactions of galantamine with β-amyloid peptide

Cited by 22 publications

References 26 publications

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

Galantamine Slows Down Plaque Formation and Behavioral Decline in the 5XFAD Mouse Model of Alzheimer’s Disease

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

Contact Info

Product

Resources

About

Investigating the binding interactions of galantamine with β-amyloid peptide

Cited by 22 publications

References 26 publications

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

Galantamine Slows Down Plaque Formation and Behavioral Decline in the 5XFAD Mouse Model of Alzheimer’s Disease

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

Contact Info

Product

Resources

About

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process