1. Usnic acid derivatives as tau-aggregation and neuroinflammation inhibitors.
- Author
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Shi CJ, Peng W, Zhao JH, Yang HL, Qu LL, Wang C, Kong LY, and Wang XB
- Subjects
- Alzheimer Disease metabolism, Animals, Benzofurans chemical synthesis, Benzofurans chemistry, Cell Line, Tumor, Disease Models, Animal, Dose-Response Relationship, Drug, Humans, Inflammation metabolism, Lipopolysaccharides antagonists & inhibitors, Lipopolysaccharides pharmacology, Male, Mice, Models, Molecular, Molecular Structure, Nitric Oxide antagonists & inhibitors, Nitric Oxide biosynthesis, Protein Aggregates drug effects, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, tau Proteins metabolism, Alzheimer Disease drug therapy, Benzofurans pharmacology, Inflammation drug therapy, Maze Learning drug effects, tau Proteins antagonists & inhibitors
- Abstract
Accumulation of tau protein aggregation plays a crucial role in neurodegenerative diseases, such as Alzheimer's disease (AD). Uncontrollable neuroinflammation and tau pathology form a vicious circle that further aggravates AD progression. Herein, we reported the synthesis of usnic acid derivatives and evaluation of their inhibitory activities against tau-aggregation and neuroinflammation. The inhibitory activity of the derivatives against the self-fibrillation of the hexapeptide AcPHF6 was initially screened by ThT fluorescence assay. Using circular dichroism and transmission electron microscopy, compound 30 showed the most potent inhibitory activity against AcPHF6 self-fibrillation. Compound 30 was further confirmed to inhibit the aggregation of full-length 2N4R tau protein by a heparin-induced mechanism. In addition, we investigated the anti-inflammatory activity of compound 30, and showed that compared with sodium usnate, it reduced NO release in LPS-stimulated mouse microglia BV2 cells. More importantly, 30 showed significant protective effects against okadaic acid-induced memory impairment in rats. Thus, 30 was a novel tau-aggregation and neuroinflammation inhibitor that represented a potential therapeutic candidate for AD., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
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