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

Kusawadee  Plekratoke; Pornthip  Waiwut; Chavi  Yenjai; Orawan  Monthakantirat; Pitchayakarn  Takomthong; Natsajee  Nualkaew; Suresh  Awale; Yaowared  Chulikhit; Supawadee  Daodee; Charinya  Khamphukdee; Chantana  Boonyarat

Authors

Kusawadee Plekratoke Biomedical Science Program, Graduate School, Khon Kaen University, Thailand https://orcid.org/0000-0003-0028-9855
Pornthip Waiwut Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Thailand https://orcid.org/0000-0001-9776-4397
Chavi Yenjai Department of Chemistry, Faculty of Science, Khon Kaen University, Thailand https://orcid.org/0000-0002-5803-0312
Orawan Monthakantirat Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand https://orcid.org/0000-0002-7331-8373
Pitchayakarn Takomthong Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand
Natsajee Nualkaew Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand https://orcid.org/0000-0002-7375-7093
Suresh Awale Natural Drug Discovery Lab, Institute of Natural Medicine, University of Toyama, Japan https://orcid.org/0000-0002-5299-193X
Yaowared Chulikhit Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand https://orcid.org/0000-0001-7317-8721
Supawadee Daodee Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand https://orcid.org/0000-0003-2051-9953
Charinya Khamphukdee Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand https://orcid.org/0000-0002-9927-0670
Chantana Boonyarat Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand https://orcid.org/0000-0003-4065-6090

Keywords:

flavonoid rhamnosides, Alzheimer’s disease, oxidation, beta amyloid, acetylcholinesterase, molecular docking

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 (Aβ) 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-Aβ aggregation by thioflavin T (ThT) assay and neuroprotection by cell base assay. To explain the mechanism of AChE inhibition and anti-Aβ aggregation, binding interactions between the test compounds and AChE and Aβ 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 Aβ 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 Aβ 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-Aβ aggregation, and neuroprotection.

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