Diaportheone A Analogues Instigate a Neuroprotective Effect by Protecting Neuroblastoma SH-SY5Y Cells from Oxidative Stress.

Abstract

Simple SummaryAlzheimer’s disease is a progressive neurodegenerative illness affecting mostly elderly people. Preventing the neurotoxicity caused by the formation of amyloid-beta plaques and oxidative stress is one of the key strategies to minimize the effects of this disease. Hence, our study aims to search for compounds which may exhibit neuroprotective potential using the human neuroblastoma SH-SY5Y cells induced with oxidative stress as our cellular model. Our library of compounds showed that diaportheones A1 and A2 protected the formation of amyloid-beta plaques using the ThT assay and exhibited neuroprotective effects in damaged SH-SY5Y cells. The preventive effect of the compounds on the aggregation of amyloid-beta was also shown by molecular modelling. Thus, diaportheones A1 and A2 could be potential compounds for further studies against Alzheimer’s disease.Alzheimer’s disease (AD) remains an incurable neurodegenerative illness. Oxidative stress resulting in the formation of reactive oxygen species (ROS) and the abnormal deposition of amyloid-beta (Aβ) are the major pathological hallmarks associated with AD. In search for small molecules targeting multiple pathways of AD and of no known molecular targets, the neuroprotective effects of the synthetic chromones diaportheone A1 and diaportheone A2, analogues of the natural product diaportheone A, were investigated. Chromones are heterocyclic compounds bearing the benzoannelated γ-pyrone moiety and were regarded as an important class of organic molecules due to their diverse pharmacological activities. The influence of the compounds on the inhibition of Aβ aggregation was determined by Thioflavin T (ThT) assay, and the cell viability, ROS, and mitochondrial membrane potential were evaluated with human neuroblastoma SH-SY5Y cells. Results showed that both compounds inhibited the Aβ aggregation at 80.41% and 73.68% for diaportheone A1 and diaportheone A2, respectively. Increased cell viabilities were observed from the protection by both compounds using Aβ- or H2O2-induced SH-SY5Y cells. Both compounds also reduced the intracellular ROS level in Aβ- or H2O2-induced SH-SY5Y cells at 10 and 20 μM concentrations, and increased the mitochondrial membrane potentials in Aβ-induced SH-SY5Y cells at 20 μM concentration. Molecular docking experiments using the Aβ protein models 2MXU and 2BEG also indicated a good agreement with the experimental data. The results demonstrated for the first time the oxidative stress effects associated with the chromones diaportheone A1 and diaportheone A2 as potential neuroprotective therapeutic agents against AD.