A Synergistic Combination of DHA, Luteolin, and Urolithin A Against Alzheimer's Disease

Dona P W Jayatunga; Eugene Hone; W M A D Binosha Fernando; Manohar L Garg; Giuseppe Verdile; Ralph N Martins

doi:10.3389/fnagi.2022.780602

A Synergistic Combination of DHA, Luteolin, and Urolithin A Against Alzheimer's Disease

Front Aging Neurosci. 2022 Feb 16:14:780602. doi: 10.3389/fnagi.2022.780602. eCollection 2022.

Authors

Dona P W Jayatunga¹, Eugene Hone^{1

2}, W M A D Binosha Fernando¹, Manohar L Garg^{3

4}, Giuseppe Verdile^{1

5}, Ralph N Martins^{1

6

7}

Affiliations

¹ Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.
² Cooperative Research Centre for Mental Health, Carlton, VIC, Australia.
³ School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia.
⁴ Riddet Institute, Massey University, Palmerston North, New Zealand.
⁵ School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.
⁶ Australian Alzheimer's Research Foundation, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia.
⁷ Department of Biomedical Sciences, Macquarie University, Sydney, NSW, Australia.

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common form of dementia worldwide. The classical AD brain is characterized by extracellular deposition of amyloid-β (Aβ) protein aggregates as senile plaques and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated forms of the microtubule-associated protein Tau. There has been limited success in clinical trials for some proposed therapies for AD, so attention has been drawn toward using alternative approaches, including prevention strategies. As a result, nutraceuticals have become attractive compounds for their potential neuroprotective capabilities. The objective of the present study was to derive a synergistic nutraceutical combination in vitro that may act as a potential preventative therapy for AD. The compounds of interest were docosahexaenoic acid (DHA), luteolin (LUT), and urolithin A (UA). The cell viability and cytotoxicity assays MTS and LDH were used to evaluate the compounds individually and in two-compound combinations, for their ability to inhibit Aβ_1-42-induced toxicity in human neuroblastoma BE(2)-M17 cells. The LDH-derived% protection values were used in the program CompuSyn v.1.0 to calculate the combination index (CI) of the two-compound combinations. The software-predicted potentially synergistic (CI < 1) two-compound combinations were validated using CellTiter Glo assay. Finally, a three-compound combination was predicted (D₅L₅U₅) and shown to be the most effective at inhibiting Aβ_1-42-induced toxicity. The synergistic combination, D₅L₅U₅ warrants further research for its mechanism of action; however, it can serve as a basis to develop an advanced functional food for the prevention or co-treatment of AD.

Keywords: Alzheimer’s disease; Luteolin; docosahexaenoic acid; in vitro; synergistic nutraceutical combinations; urolithin A.