The Flavonoid Derivative 2-(4′ Benzyloxyphenyl)-3-hydroxy-chromen-4-one Protects Against Aβ42-Induced Neurodegeneration in Transgenic Drosophila: Insights from In Silico and In Vivo Studies

Abstract

In the pathogenesis of Alzheimer's disease (AD), it is well established that the self-association of Aβ peptides into amyloid fibrils and/or plaque like aggregates causes neurotoxicity. As there is no cure for AD till date, identification of specific compounds that either inhibit the formation of Aβ-fibrils or help in the dissolution of already formed amyloid plaques makes an appealing therapeutic and preventive strategy in the development of drugs. In the present study, four synthetic flavonoid derivatives (1, 2, 3 and 4) were examined for docking studies with Amyloid beta (PDB Code: 1IYT) and Amyloid fibril (PDB Code: 2BEG). Of these, compound 1 and 4 were found to be potential inhibitors, as supported by computational molecular docking studies with adequate pharmacokinetic properties. Compound 1 was further tested in vivo in transgenic AD model of Drosophila. The disease causing human Aβ42 peptide was expressed in the compound eye by driving UAS-Aβ42 with ey-GAL4, which caused severe degeneration in eye tissues ranging from loss of bristles, ommatidial holes to severe ommatidial disruption as revealed by digital camera imaging and scanning electron microscopy. When the Aβ42 expressing larvae were grown in medium containing Compound 1, ~70 % rescue of the rough eye phenotype was observed at 75 and 100 μM concentrations. This is further corroborated by significant reduction in amyloid plaques in eye imaginal disks of compound 1 treated larvae as revealed by immuno-confocal imaging studies. Further, rescue of locomotor deficit and improved life span in compound 1 treated Aβ flies also confirm the neuroprotective activity of this compound. Thus, our results support the neuroprotective efficacy of compound 1 in preventing Aβ42-induced neurotoxicity in vivo and identify it as a future therapeutic agent against AD.

Overview of Alzheimer’s Disease and Some Therapeutic Approaches Targeting Aβ by Using Several Synthetic and Herbal Compounds

“…Nevertheless, due to their limited absorption and their low bioavailability in the brain, increasing evidence demonstrates that they are able to interact with the cellular and molecular components of the brain responsible for memory, having the potential to protect vulnerable neurons, enhance existing neuronal function, stimulate neuronal regeneration, and induce neurogenesis [ 194 , 195 ]. Recent study from our lab showed the neuroprotective property of a novel synthetic flavonoid derivative against A β -induce neurotoxicity in Drosophila model of AD [ 196 ].…”

Neuroprotective and Antioxidant Effect of Ginkgo biloba Extract Against AD and Other Neurological Disorders

“…Several drug treatments are available to help prevent various symptoms in the disease, and researchers around the world are focusing on finding better treatments, preventive strategies, and ultimately a cure. Researchers are using different synthetic and/or herbal compounds to test their potential efficacy against AD [3][4][5][6]. In this milieu, polyphenolic compounds from medicinal plants are key sources of neuroprotective agents against AD.…”

Characterisation of twelve newly synthesised N-(substituted phenyl)-2-chloroacetamides with QSAR analysis and antimicrobial activity tests

“…Veber ( 31 ) demonstrated that molecules with TPSA≤140 Å 2 display efficient permeability. Higher partition coefficient log P will allow biologically active chloroacetamides higher efficiency by passive diffusion as well as effective binding to the active receptor sites ( 32 ). Besides, almost no divergence in log P (-Br, -CN) was observed for compounds with the same substituent in different positions ( 3 ).…”