Multi-Target Actions of Flavonoid Derivatives from Mesua ferrea Linn Flower against Alzheimer’s disease Pathogenesis

Biomedical Sciences and Clinical Medicine Pub Date : 2023-12-01 DOI:10.12982/bscm.2023.17

Kusawadee Plekratoke, Pornthip Waiwut, C. Yenjai, O. Monthakantirat, Pitchayakarn Takomthong, N. Nualkaew, Suresh Awale, Yaowared Chulikhit, S. Daodee, Charinya Khamphukdee, Chantana Boonyarat

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Abstract

OBJECTIVE Kaempferol-3-O-rhamnoside (compound 1) and quercetin- 3-O-rhamnoside (compound 2), two flavonoids isolated from Mesua ferrea L. flowers, were examined for their activities related Alzheimer’s disease (AD) pathogenesis including antioxidant, acetylcholinesterase (AChE) inhibition, anti-beta amyloid (Ab) aggregation and neuroprotection. METHODS The two flavonoids were isolated from M. ferrea L. flowers using the column chromatography technique. Both compounds were evaluated for their effects on AD pathogenesis, including antioxidant action by ABTS assay, AChE inhibition by Ellman’s method, and anti-Ab aggregation by thioflavin T (ThT) assay and neuroprotection by cell base assay. To explain the mechanism of AChE inhibition and anti-Ab aggregation, binding interactions between the test compounds and AChE and Ab were studied in-silico. RESULTS Compounds 1 and 2 showed an ability to scavenge ABTS radicals, with IC50 values of 424.57±2.97 and 308.67±9.90 µM, respectively, and to inhibit AChE function with IC50 values of 769.23±6.23 and 520.64±5.94, respectively. ThT assay indicated that both compounds inhibited Ab aggregation with IC50 values of 406.43±9.95 and 300.69 ±1.18 µM, respectively. The neuroprotection study revealed that the two flavonoids could reduce human neuroblastoma (SH-SY5Y) cell death induced by H2O2. The in-silico study showed that both compounds bound AChE at catalytic anionic and peripheral anionic sites. In addition, the test compounds prevented Ab aggregation by interacting at the central hydrophobic core, the C-terminal hydrophobic region, and the important residues of Ile41. CONCLUSIONS Together, the results showed that kaempferol-3-O- rhamnoside and quercetin-3-O- rhamnoside exhibit multiple mechanisms of action that are involved in the pathogenesis of AD including antioxidant, AChE inhibition, anti-Ab aggregation, and neuroprotection. KEYWORDS flavonoid rhamnosides, Alzheimer’s disease, oxidation, beta amyloid, acetylcholinesterase, molecular docking

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阿魏花中的黄酮类衍生物对阿尔茨海默病发病机制的多靶点作用

目的研究了从铁线莲（Mesua ferrea L.）花中分离出的两种黄酮类化合物堪非醇-3-O-鼠李糖苷（化合物 1）和槲皮素-3-O-鼠李糖苷（化合物 2）与阿尔茨海默病（AD）发病机制有关的活性，包括抗氧化、抑制乙酰胆碱酯酶（AChE）、抗β淀粉样蛋白（Ab）聚集和神经保护作用。方法利用柱层析技术从阿魏花中分离出两种黄酮类化合物。评估了这两种化合物对AD发病机制的影响，包括ABTS法测定的抗氧化作用、Ellman法测定的乙酰胆碱酯酶抑制作用、硫黄素T（ThT）法测定的抗Ab聚集作用以及细胞基础法测定的神经保护作用。为了解释 AChE 抑制和抗 Ab 聚合的机制，对测试化合物与 AChE 和 Ab 之间的结合相互作用进行了室内研究。结果化合物 1 和 2 具有清除 ABTS 自由基的能力，其 IC50 值分别为 424.57±2.97 和 308.67±9.90 µM；具有抑制 AChE 功能的能力，其 IC50 值分别为 769.23±6.23 和 520.64±5.94。ThT 试验表明，这两种化合物都能抑制 Ab 的聚集，其 IC50 值分别为 406.43±9.95 µM 和 300.69 ±1.18 µM。神经保护研究表明，这两种黄酮类化合物能减少 H2O2 诱导的人神经母细胞瘤（SH-SY5Y）细胞死亡。分子内研究表明，这两种化合物都能与 AChE 的催化阴离子位点和外周阴离子位点结合。此外，测试化合物通过与 AChE 的中央疏水核心、C 端疏水区域以及 Ile41 的重要残基相互作用，阻止了 Ab 的聚集。结论研究结果表明，山奈酚-3-O-鼠李糖苷和槲皮素-3-O-鼠李糖苷具有多种作用机制，包括抗氧化、抑制 AChE、抗 Ab 聚合和神经保护等，参与了 AD 的发病机制。关键词：黄酮鼠李糖苷，阿尔茨海默病，氧化，β 淀粉样蛋白，乙酰胆碱酯酶，分子对接

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Biomedical Sciences and Clinical Medicine

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