Exploration of Neuroprotective Properties of a Naturally Inspired Multifunctional Molecule (F24) against Oxidative Stress and Amyloid β Induced Neurotoxicity in Alzheimer’s Disease Models

Abstract

The pathological hallmarks of Alzheimer's disease (AD) are manifested as an increase in the level of oxidative stress and aggregation of the amyloid-β protein. <i>In vitro</i>, <i>in vivo</i>, and <i>in silico</i> experiments were designed and carried out with multifunctional cholinergic inhibitor, F24 (EJMC-<b>7a</b>) to explore its neuroprotective effects in AD models. The neuroprotection ability of F24 was tested in SH-SY5Y cells, a widely used neuronal cell line. The pretreatment and subsequent co-treatment of SH-SY5Y cells with different doses of F24 was effective in rescuing the cells from H₂O₂ induced neurotoxicity. F24 treated cells were found to be effective in the reduction of cellular reactive oxygen species, DNA damage, and Aβ_1-42 induced neurotoxicity, which validated its neuroprotective effectiveness. F24 exhibited efficacy in an <i>in vivo</i><i>Drosophila</i> model by rescuing eye phenotypes from degeneration caused by Aβ toxicity. Further, computational studies were carried out to monitor the interaction between F24 and Aβ_1-42 aggregates. The computational studies corroborated our <i>in vitro</i> and <i>in vivo</i> studies suggesting Aβ_1-42 aggregation modulation ability of F24. The brain entry ability of F24 was studied in the parallel artificial membrane permeability assay. Finally, F24 was tested at doses of 1 and 2.5 mg/kg in the Morris water maze AD model. The neuroprotective properties shown by F24 strongly suggest that multifunctional features of this molecule provide symptomatic relief and act as a disease-modifying agent in the treatment of AD. The results from our experiments strongly indicated that natural template-based F24 could serve as a lead molecule for further investigation to explore multifunctional therapeutic agents for AD management.