Title

In vitro assessment to evaluate the potential effects of polyphenol extracts from sorghum on Alzheimer’s disease

Author Identifiers

Nasim Rezaee

https://orcid.org/0000-0001-5806-8591

Date of Award

2022

Degree Type

Thesis

Degree Name

Doctor of Philosophy

School

School of Medical and Health Sciences

First Advisor

Ralph N Martins

Second Advisor

W.M.A.D Binosha Fernando

Third Advisor

Eugene Hone

Fourth Advisor

Hamid R Sohrabi

Fifth Advisor

Stuart K Johnson

Sixth Advisor

Stuart Gunzburg

Abstract

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for most dementia cases. AD is characterised by extracellular deposition of amyloid-β (Aβ) protein plaques and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated tau. Other common hallmarks of the disease include neuroinflammation, oxidative stress and mitochondrial dysfunction. AD currently affects more than 55 million people worldwide and this number is increasingly growing. It is the second leading cause of death in Australia and the seventh leading cause of death worldwide. Despite its increasing economic, health and social burden, there are currently no effective treatments that substantially slow or reverse the progression of the disease. Because of the limited success of drug clinical trials, attention has focussed on natural products, particularly polyphenols (PPs) as possible alternative therapies mainly due to their multi-modal neuroprotective actions and fewer side effects. Sorghum is one such important candidate. It is a underutilized grain that grows widely in Australia. A wide range of PPs, including phenolic acids and flavonoids are present in sorghum grain. However, no study has investigated its neuroprotective activities to date.

Aim: The overall objective of the current study was the in vitro investigation of the neuroprotective effect of PP-rich extracts from six different sorghum varieties (Shawaya short black-1 (Black), IS1311C(Brown), QL33/QL36(Red), B923296(Red), QL12(White) and QL33(Red) on AD hallmarks.

Method and results: The PPs were extracted from sorghum and the polyphenolic content has been assessed. The sorghum Shawaya short black-1 and IS1311C showed the highest level of phenolic and flavonoid content compared to the other varieties. Nine different PPs have been identified through the HPLC-DAD assay. Then, we continued the experiments at the cellular level. First, the extracts were tested on human BE (2)-M17 neuroblastoma cells to determine the highest concentration which is non-toxic. The protective effects of these non-toxic doses of the extracts were then investigated for their ability to preserve cell viability in an Aβ42-induced cell model of AD. All six extracts (dissolved in DMSO) increased cell viability, but QL33(2000 μg/ml) was the most potent extract, increasing viability by 28%. To further evaluate whether there is a synergistic effect, these extracts were tested as paired combinations. However, no synergistic effect was noted. In addition, the extracts had significant anti-Aβ aggregation effects as assessed by the thioflavin T assay (Th-T). Shawaya short black-1 and B923296 demonstrated the highest and lowest inhibition effects, respectively. The extracts also affected Aβ42-induced reactive oxygen species (ROS), tau proteins and mitochondrial dysfunction. Except for B923296, the other five sorghum extracts showed a significant reduction of ROS and mitochondrial superoxide. Sorghum extracts also decreased the Aβ-induced total tau, tau phosphorylated at threonine- 231 (pT231) and Serine-199(pS199) (except for B923296). Furthermore, most of the sorghum extracts restored the mitochondrial membrane potential (Δψm) and adenosine triphosphate (ATP).

Conclusion: Overall, the sorghum extracts attenuated Aβ42-induced toxicity through multiple mechanisms. These extracts possess compounds that have the potential therapeutic value for AD. However, further studies using other in vitro and in vivo models of AD are required to validate these findings.

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