Abstract
We studied the inhibitory activity of methylene blue (MB) γ-carbolines (gC) conjugates (MB-gCs) against human erythrocyte acetylcholinesterase (AChE), equine serum butyrylcholinesterase (BChE), and a structurally related enzyme, porcine liver carboxylesterase (CaE). In addition, we determined the ability of MB-gCs to bind to the peripheral anionic site (PAS) of Electrophorus electricus AChE (EeAChE) and competitively displace propidium iodide from this site. Moreover, we examined the ability of MB-gCs to scavenge free radicals as well as their influence on mitochondrial potential and iron-induced lipid peroxidation. We found that MB-gCs effectively inhibited AChE and BChE with IC50 values in the range 1.73–10.5 μM and exhibited low potencies against CaE (9.8–26% inhibition at 20 μM). Kinetic studies showed that MB-gCs were mixed-type reversible inhibitors of both cholinesterases. Molecular docking results showed that the MB-gCs could bind both to the catalytic active site and to the PAS of human AChE and BChE. Accordingly, MB-gCs effectively displaced propidium from the peripheral anionic site of EeAChE. In addition, MB-gCs were extremely active in both radical scavenging tests. Quantum mechanical DFT calculations suggested that free radical scavenging was likely mediated by the sulfur atom in the MB fragment. Furthermore, the MB-gCs, in like manner to MB, can restore mitochondrial membrane potential after depolarization with rotenone. Moreover, MB-gCs possess strong antioxidant properties, preventing iron-induced lipid peroxidation in mitochondria. Overall, the results indicate that MB-gCs are promising candidates for further optimization as multitarget therapeutic agents for neurodegenerative diseases.
Highlights
Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases
We studied the ability of methylene blue (MB)-gCs to bind to the peripheral anionic site (PAS) of AChE from Electrophorus electricus (EeAChE) and competitively displace propidium iodide from this site
We have shown that conjugates of MB with γ-carbolines are mixed-type AChE inhibitors, and according to molecular docking data can bind to the PAS of AChE
Summary
Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases. It is characterized by progressive loss of memory and higher cortical functions leading to total cognitive and intellectual decline[1]. It is widely believed that soluble oligomeric forms of amyloid-β aggregates containing 40–42 amino acid residues (Aβ 40–42) and preceding senile plaques formation are neurotoxic They are assumed to disrupt mitochondrial functions, induce apoptosis, and regulate stress-activated protein[6]. AChE plays an important role in the processing of Aβ through the interaction of its peripheral anionic site (PAS) with soluble amyloid-β peptides to promote their aggregation[8,9,10]. Based on these facts, drugs with such dual capabilities (i.e., inhibition of AChE catalytic activity and inhibition of AChE-induced Aβ aggregation) have been a subject of intensive research[11]. It is reasonable to expect that these kinds of agents could simultaneously enhance cognition and engender neuroprotection[12,13]
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