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Management of oxidative stress and other pathologies in Alzheimer’s disease
Open accessAbstract
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder, characterized by the formation, aggregation and accumulation of amyloid beta, perturbed metal (copper, iron and zinc) homeostasis, metal-induced oxidative stress, neuroinflammation, aberrant activity of acetylcholinesterase (AChE) and other pathologies. The aim of this review is to discuss the current therapies based on the "combination-drugs-multitargets" strategy to target multiple pathologies to block the progression of pathogenesis of AD. In addition to cholinergic and amyloid targets, a significant effort is focused on targeting the metal-induced oxidative stress component of the disease. The main focus of research is based on modifications of existing drugs with specific biological activity. Tacrine was the first AChE inhibitor to be introduced into clinical practice and has been frequently used for the design of multitarget-directed ligands. A number of hybrid compounds containing tacrine and structural moieties derived from natural sources such as flavonoids [quercetin, rutin, coumarin, gallamine, resveratrol, scutellarin, anisidine, hesperetin, (-)-epicatechin] and other molecules (melatonin, trolox) have also been applied to function as multitarget-directed ligands. Most of these hybrids are potent inhibitors of AChE and butyrylcholinesterase and also of amyloid-beta aggregation. In addition, the antioxidant functionality, represented by coumarins, melatonin and other antioxidant molecules reduces the level of oxidative stress via ROS-scavenging mechanisms, as well as via chelation of redox-active Cu and Fe, thus suppressing the formation of ROS via the Fenton reaction. Various medicinal plants are under investigation for their ability to ameliorate symptoms of AD. The therapeutic potency of huperzine A and B, ginseng, curcumin and other compounds is manifested predominantly by the inhibitory action toward AChE, antioxidant or radical-scavenging and redox metal-chelating activity, inhibition of amyloid-beta aggregation and tau-protein hyperphosphorylation and antiinflammatory activity. Flavonoids not only function as antioxidants and metal-chelating agents, but also interact with protein kinase and lipid kinase signaling pathways, and others involving mitogen-activated protein kinase, NF-kappaB and tyrosine kinase. Among the most promising group of substances with potential activity against AD are the flavonoids, including myricetin, morin, rutin, quercetin, fisetin, kaempferol, apigenin and glycitein, which have been shown, in vitro, to possess antiamyloidogenic and fibril-destabilization activity, as well as being able to act as metal chelators and to suppressing oxidative stress. In terms of the clinical use of multifunctional hybrids, herbal drugs or flavonoids against AD, some remaining challenges are to establish the ideal dose to develop effective formulations to preserve bioavailability and to determine the stage when they should be administered. If the onset of the disease could be delayed by a decade, the number of AD victims would be significantly reduced.
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“β-amyloid (Aβ) protein is the principal component of AD-associated amyloid plaques, and is produced by protease cleavage of the type I transmembrane amyloid precursor protein (APP) [16, 17].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [16]
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Metadata
- Authors
- Simunkova, M., Alwasel, S. H., Alhazza, I. M., Jomova, K., Kollar, V., Rusko, M., & Valko, M.
- Affiliations
- King Saud University (SA)
- Slovak University of Technology in Bratislava (SK)
- Venue
- Archives of Toxicology
- Published
- 2019-08-22
- Volume
- 93
- Issue
- 9
- Pages
- 2491-2513
- ISSN
- 0340-5761 (ISSN-L)
- 1432-0738
- OpenAlex
- W2969291614
- Cited by
- 303
- References
- 164
- Citations by year
- 2026: 31 · 2025: 50 · 2024: 43 · 2023: 56 · 2022: 55 · 2021: 34 · 2020: 29 · 2019: 4
- FWCI
- 3.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Archives of Toxicology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Agentúra Ministerstva Školstva, Vedy, Výskumu a Športu SR (APVV-15-0079, 1/0686/17)
- DSF Program
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
- Keywords
- Alzheimer's disease, oxidative stress, acetylcholinesterase inhibitors, amyloid-beta aggregation, flavonoids, metal-induced oxidative stress, neuroinflammation, tau hyperphosphorylation, huperzine A, curcumin, ginseng, medicinal plants, antioxidant activity, redox-active metals
- MeSH terms
- Acetylcholinesterase, Alzheimer Disease, Antioxidants, Butyrylcholinesterase, Chelating Agents, Cholinesterase Inhibitors, Copper, Humans, Iron, Amyloid beta-Peptides, Oxidative Stress, Plant Preparations
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