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
| Autor: | Akhil Kumar, Saripella Srikrishna, Roshan Fatima, Lallan Mishra, Sandeep Singh, Ruchi Gaur |
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| Rok vydání: | 2014 |
| Předmět: |
Pathology
medicine.medical_specialty Amyloid beta Plaque Amyloid Motor Activity Biology Toxicology Neuroprotection Animals Genetically Modified Capillary Permeability Alzheimer Disease In vivo medicine Animals Humans Compound Eye Arthropod Flavonoids Amyloid beta-Peptides Dose-Response Relationship Drug General Neuroscience Neurodegeneration Neurotoxicity Neurodegenerative Diseases Compound eye medicine.disease Survival Analysis Peptide Fragments Cell biology Molecular Docking Simulation Disease Models Animal Neuroprotective Agents Blood-Brain Barrier Docking (molecular) biology.protein Drosophila Alzheimer's disease |
| Zdroj: | Neurotoxicity Research. 26:331-350 |
| ISSN: | 1476-3524 1029-8428 |
| DOI: | 10.1007/s12640-014-9466-z |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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