Novel synthetic chalcone‐coumarin hybrid for Aβ aggregation reduction, antioxidation, and neuroprotection

• Published in: CNS neuroscience & therapeutics Vol. 24; no. 12; pp. 1286 - 1298
• Main Authors: Lee, Shin‐Ying, Chiu, Ya‐Jen, Yang, Shu‐Mei, Chen, Chiung‐Mei, Huang, Chin‐Chang, Lee‐Chen, Guey‐Jen, Lin, Wenwei, Chang, Kuo‐Hsuan
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2018; John Wiley and Sons Inc
• Subjects: Acetylcholinesterase; Acetylcholinesterase - metabolism; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Antioxidants; Antioxidants - pharmacology; antioxidation; Axonogenesis; Aβ aggregation reduction; Brain-derived neurotrophic factor; Cell culture; Cell Line, Tumor; Chalcone - chemistry; Chalcone - pharmacology; chalcone‐coumarin hybrid; Coumarin; Coumarins - chemistry; Coumarins - pharmacology; Cyclic AMP response element-binding protein; Dose-Response Relationship, Drug; Free radicals; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Humans; Inhibitory Concentration 50; Licochalcone A; Neuroblastoma - pathology; Neurodegenerative diseases; Neuronal Outgrowth - drug effects; Neuroprotection; Original; Oxidative stress; Protein Aggregates - drug effects; Reactive oxygen species; Reactive Oxygen Species - metabolism; RNA Interference - drug effects; RNA, Messenger - metabolism; Senile plaques; therapeutics; Toxicity; Transfection; chalcone‐coumarin hybrid; therapeutics; antioxidation; Alzheimer’s disease; neuroprotection; Aβ aggregation reduction
• ISSN: 1755-5930; 1755-5949; 1755-5949
• DOI: 10.1111/cns.13058

Background Aggregation of misfolded amyloid β (Aβ) in senile plaques causes oxidative stress and neuronal death in Alzheimer's disease (AD). Compounds possessing antiaggregation and antioxidant properties are promising candidate compounds for AD treatment. Methods We examined the potential of synthetic derivatives of licochalcone A and coumarin for inhibiting Aβ aggregation, scavenging reactive oxygen species (ROS), and providing neuroprotection by using biochemical assays and Tet‐On Aβ‐GFP 293/SH‐SY5Y cell models for AD. Results Among test compounds, LM‐031, a novel chalcone‐coumarin hybrid, inhibited Aβ aggregation and scavenged free oxygen radicals. LM‐031 markedly reduced Aβ misfolding and ROS as well as promoted neurite outgrowth and inhibited acetylcholinesterase in Tet‐On Aβ‐GFP 293/SH‐SY5Y cells. Mechanistic studies showed upregulation of the HSPB1 chaperone, NRF2/NQO1/GCLC pathway, and CREB/BDNF/BCL2 pathway. Decreased neurite outgrowth upon the induction of Aβ‐GFP was rescued by LM‐031, which was counteracted by knockdown of HSPB1, NRF2, or CREB. Conclusion Taken together, these findings demonstrate that LM‐031 exhibited antiaggregation, antioxidant, and neuroprotective effects against Aβ toxicity by enhancing HSPB1 and the NRF2‐related antioxidant pathway as well as by activating the CREB‐dependent survival and antiapoptosis pathway. These results imply that LM‐031 may be a new therapeutic compound for AD.