amyloid-beta-peptides and ebselen

Cumulative evidence suggests that β-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Antioxidants; Aspartic Acid Endopeptidases; Azoles; Binding Sites; Blood-Brain Barrier; Cyclic S-Oxides; Drug Design; Humans; Interleukin-6; Isoindoles; Ligands; Mitochondria; Molecular Docking Simulation; Neuroprotective Agents; NF-E2-Related Factor 2; Organoselenium Compounds; Oxidative Stress; Peptide Fragments; Reactive Oxygen Species; Selenium; Signal Transduction; Thiadiazines

A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer's disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one of the most potent acetylcholinesterase inhibitors (IC50 values of 0.042 μM for Electrophorus electricus acetylcholinesterase and 0.097 μM for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC50 = 1.586 μM), to possess rapid H2O2 and peroxynitrite scavenging activity and glutathione peroxidase-like activity (ν0 = 123.5 μM min(-1)), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood-brain barrier model, 7d is able to penetrate the central nervous system.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Azoles; Butyrylcholinesterase; Chemistry Techniques, Synthetic; Cholinesterase Inhibitors; Donepezil; Electrophorus; Glutathione Peroxidase; Humans; Indans; Isoindoles; Kinetics; Ligands; Mice; Molecular Docking Simulation; Molecular Targeted Therapy; Organoselenium Compounds; Peptide Fragments; Peroxynitrous Acid; Piperidines; Protein Multimerization; Protein Structure, Secondary; Thioredoxin-Disulfide Reductase; Toxicity Tests, Acute

Amyloid peptides (AbetaPs) are implicated in neuronal death associated with Alzheimer's disease. Their toxicity involves disruption cellular Ca(2+) homeostasis, leading to activation of caspases and cell death. Antioxidants can prevent such cell death and show beneficial clinical effects in Alzheimer's disease patients. Using the model neurosecretory cell line, PC12, we have shown that AbetaPs cause enhancement of evoked exocytosis via formation of a Cd(2+) -resistant Ca(2+) influx pathway, and also cause selective, functional up-regulation of current through L-type Ca(2+) channels. The involvement of reactive oxygen species (ROS) in these effects were investigated by examining the ability of various antioxidants to interfere with these responses. Both melatonin and ascorbic acid fully blocked the enhancement of catecholamine secretion caused by application of AbetaP((1-40)), as monitored in real time amperometrically, but inhibition of the transcriptional regulator NF-kappaB with SN-50 did not affect secretion. Enhanced immunofluorescence, observed in AbetaP-treated cells using a monoclonal antibody raised against the N-terminus of AbetaP, was also suppressed by melatonin. Ascorbic acid, melatonin and ebselen also fully prevented augmentation of whole-cell Ca(2+) currents caused by application of AbetaP((1-40)). By contrast, inhibitors of NF-kappaB (sulfasalazine and SN-50) were able to prevent AbetaP induced Ca(2+) channel current enhancement, whilst inhibitors of mitogen-activated protein kinase and protein kinase C could not. Our results indicate that augmentation or induction by AbetaPs of two important, distinct factors regulating Ca(2+) homeostasis is mediated by increased ROS production, but only one of these (up-regulation of native Ca(2+) channels) requires activation of NF-kappaB.

Topics: Amyloid beta-Peptides; Animals; Antioxidants; Ascorbic Acid; Azoles; Cadmium; Calcium; Calcium Channels, L-Type; Catecholamines; Enzyme Inhibitors; Exocytosis; Fluorescent Antibody Technique; Indoles; Isoindoles; Maleimides; Melatonin; NF-kappa B; Organoselenium Compounds; Patch-Clamp Techniques; PC12 Cells; Peptide Fragments; Peptides; Rats; Reactive Oxygen Species; Signal Transduction; Sulfasalazine