Neuroprotective effects of verbascoside against Alzheimer’s disease via the relief of endoplasmic reticulum stress in Aβ-exposed U251 cells and APP/PS1 mice

Journal of Neuroinflammation, Journal Year: 2020, Volume and Issue: 17(1)

Published: Oct. 18, 2020

Abstract Background Endoplasmic reticulum (ER) stress is involved in the progression of Alzheimer’s disease (AD). Verbascoside (VB), an active phenylethanoid glycoside that was first isolated from Verbascum sinuatum (the wavyleaf mullein), possesses anti-inflammatory, antioxidative, and anti-apoptotic effects. The purpose this study to elucidate beneficial effects VB amyloid β (Aβ) 1–42 -damaged human glioma (U251) cells APPswe/PSEN1dE9 transgenic (APP/PS1) mice. Methods U251 were co-incubated with 10 μM Aβ 1-42 treated VB. protective investigated by using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay, flow cytometry, fluorescence staining, transmission electron microscopy. APP/PS1 mice for 6 weeks Learning memory evaluated a Morris water maze test. Immunohistochemistry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, thioflavin-S proteomics analysis performed potential neuroprotective mechanism. Enzyme-linked immunosorbent assays western blot analyze altered protein levels brain lysates and/or cells. Results In cells, significantly improved cell viability, inhibited apoptosis, reduced calcium accumulation intracellular concentrations reactive oxygen species, morphology mitochondria ER. mice, 6-week administration cognition. deposition Aβ, formation neurofibrillary tangles formed hyperphosphorylated tau protein, downregulated expression 4-hydroxynonenal mesencephalic astrocyte-derived neurotrophic factor brains Proteomics mouse hippocampus suggested effect may be related reduction ER stress. This indicated fact three branches unfolded response, thereby attenuating preventing apoptosis. Conclusions results confirmed significant effects, which are These findings support status as potentially effective treatment AD warrant further research.

Language: Английский

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Investigating 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole as scaffold of butyrylcholinesterase-selective inhibitors with additional neuroprotective activities for Alzheimer's disease

European Journal of Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 177, P. 414 - 424

Published: May 28, 2019

Language: Английский

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Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer’s disease

European Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 198, P. 112257 - 112257

Published: April 11, 2020

Language: Английский

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Isoquinoline alkaloids from the roots of Zanthoxylum rigidum as multi-target inhibitors of cholinesterase, monoamine oxidase A and Aβ1-42 aggregation

Bioorganic Chemistry, Journal Year: 2020, Volume and Issue: 98, P. 103722 - 103722

Published: March 4, 2020

Language: Английский

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Rational drug design strategies for the development of promising multi-target directed indole hybrids as Anti-Alzheimer agents

Bioorganic Chemistry, Journal Year: 2022, Volume and Issue: 127, P. 105941 - 105941

Published: June 10, 2022

Language: Английский

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Nature's toolbox against tau aggregation: An updated review of current research

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 87, P. 101924 - 101924

Published: March 31, 2023

Language: Английский

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Enhancing the Therapeutic Effect in Alzheimer's Disease Drugs: The role of Polypharmacology and Cholinesterase inhibitors

ChemistrySelect, Journal Year: 2023, Volume and Issue: 8(10)

Published: March 7, 2023

Abstract Alzheimer's disease (AD) is a devastating syndrome that accounts for 60–70 % of all dementia cases, putting an enormous burden on global healthcare and economy. Unfortunately, there no cure AD, the currently approved drugs are limited in their effects. Given various pathological mechanisms behind “one‐target, one‐drug” paradigm drug design became obsolete, new paradigm, polypharmacology, emerged. Consequently, greater focus has been put towards multi‐target directed ligands (MTDLs), as these can regulate several targets operating network. Parallel to that, cholinesterase inhibitors have regained popularity after decades being considered only symptomatic agents with disease‐modifying properties. In this review, current AD hypotheses therapeutic targets, concept polypharmacology pathology importance cholinesterases pathogenesis biochemical processes discussed, final overview development cholinesterase‐based MTDLs.

Language: Английский

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Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study

Bioorganic & Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 101, P. 117649 - 117649

Published: Feb. 18, 2024

Language: Английский

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Novel Molecular Hybrids of N-Benzylpiperidine and 1,3,4-Oxadiazole as Multitargeted Therapeutics to Treat Alzheimer’s Disease

ACS Chemical Neuroscience, Journal Year: 2019, Volume and Issue: 10(10), P. 4361 - 4384

Published: Sept. 6, 2019

Multitargeted hybrids of N-benzylpiperidine and substituted 5-phenyl-1,3,4-oxadiazoles were designed, synthesized, evaluated against Alzheimer's disease (AD). Tested compounds exhibited moderate to excellent inhibition human acetylcholinesterase (hAChE), butyrylcholinesterase (hBChE), beta-secretase-1 (hBACE-1). The potential leads 6g 10f balanced inhibitory profiles all the targets, with a substantial displacement propidium iodide from peripheral anionic site hAChE. Hybrids also elicited favorable permeation across blood-brain barrier devoid neurotoxic liability toward SH-SY5Y neuroblastoma cells. Both remarkably disassembled Aβ aggregation in thioflavin T-based self- AChE-induced experiments. Compounds ameliorated scopolamine-induced cognitive dysfunctions Y-maze test. ex vivo studies rat brain homogenates established reduced AChE levels antioxidant activity both compounds. Compound noteworthy improvement Aβ-induced Morris water maze test downregulation expression BACE-1 proteins corroborated by Western blot immunohistochemical analysis. pharmacokinetic study showed oral absorption characteristics compound 6g. silico molecular docking dynamics simulation lead affirmed their consensual binding interactions PAS-AChE aspartate dyad BACE-1.

Language: Английский

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Design, synthesis, and evaluation of N-benzylpyrrolidine and 1,3,4-oxadiazole as multitargeted hybrids for the treatment of Alzheimer’s disease

Bioorganic Chemistry, Journal Year: 2021, Volume and Issue: 111, P. 104922 - 104922

Published: April 17, 2021

Language: Английский

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