The novel therapeutic strategy of myricetin/chitooligosaccharide/astaxanthin, as potent multi-target-directed ligands for the potential treatment of Alzheimer's disease with comorbid depression.

OBJECTIVE: The mixed particles of Myricetin (MYR)/Chitooligosaccharide (COS)/Astaxanthin (AST) had not study to therapeutic effects on Alzheimer's disease (AD) combined with depression. In this study, the mixed particles of MYR/COS/AST were investigate the inhibitory activities against cholinesterase (ChE) and monoamine oxidase (MAO), possessing good activity were further assayed to inhibit β-amyloid1-42 (Aβ1-42) aggregation, beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1), the neuroprotective activity and cytotoxicity.

MATERIALS AND METHODS: ChE and MAO inhibitory activities by Ellman and Holts method. Aβ aggregation were evaluated by thioflavin T assay, BACE1 inhibition used the fluorescence resonance energy transfer (FRET)-based. The protective effect were tested by against L-Glutamate (L-Glu)-induced HT22 cell damage, Cu2+- and Fe3+-induced neuronal damage, the cytotoxicity were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. The antidepressant activities were measured by the forced swimming test (FST).

RESULTS: The results showed that the mass ratio of the mixed particles MYR/COS/AST was 10:10:3, which exhibited the best inhibitory activities on AChE, MAO, also exhibited inhibition against Aβ1-42 aggregation, BACE-1, Aβ1-42 disaggregation, exerted protective effects L-Glu-induced HT22 cell damage and on the cells against Cu2+ and Fe3+-induced damage in BV-2 cells. In the FST, the mixed particles of MYR/COS/AST (10:10:1) exhibited good antidepressant effect. None of three substances showed cytotoxicity against L929 cells. The molecular docking revealed important interactions between the active three substances and amino acid residues.

CONCLUSIONS: These studies provide the technical data for ensuring potential treatment of AD combined with depression of the mixed particles of MYR/COS/AST (10:10:3).