NDLI: The Flavonoid Derivative 2-(4′ Benzyloxyphenyl)-3-hydroxy-chromen-4-one Protects Against Aβ$_{42}$-Induced Neurodegeneration in Transgenic Drosophila: Insights from In Silico and In Vivo Studies

Content Provider	Springer Nature Link
Author	Singh, Sandeep Kumar Gaur, Ruchi Kumar, Akhil Fatima, Roshan Mishra, Lallan Srikrishna, Saripella
Copyright Year	2014
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 Aβ$_{42}$ peptide was expressed in the compound eye by driving UAS-Aβ$_{42}$ 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 Aβ$_{42}$ 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 Aβ$_{42}$-induced neurotoxicity in vivo and identify it as a future therapeutic agent against AD.
Starting Page	331
Ending Page	350
Page Count	20
File Format	PDF
ISSN	10298428
Journal	Neurotoxicity Research
Volume Number	26
Issue Number	4
e-ISSN	14763524
Language	English
Publisher	Springer US
Publisher Date	2014-04-05
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Alzheimer’s disease Aβ$_{42}$ Flavones Neuroprotection Molecular docking Confocal imaging Drosophila Neurosciences Neurology Neurochemistry Pharmacology/Toxicology Neurobiology Cell Biology
Content Type	Text
Resource Type	Article
Subject	Neuroscience Toxicology

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