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

Shin Ying Lee, Ya Jen Chiu, Shu Mei Yang, Chiung Mei Chen, Chin Chang Huang, Guey Jen Lee-Chen*, Wenwei Lin, Kuo Hsuan Chang

*此作品的通信作者

研究成果: 雜誌貢獻期刊論文同行評審

12 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
頁(從 - 到)1286-1298
頁數13
期刊CNS Neuroscience and Therapeutics
24
發行號12
DOIs
出版狀態已發佈 - 2018 十二月

ASJC Scopus subject areas

  • 藥理
  • 精神病學和心理健康
  • 生理學(醫學)
  • 藥學(醫學)

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