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

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Abstract

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.

Original languageEnglish
Pages (from-to)1286-1298
Number of pages13
JournalCNS Neuroscience and Therapeutics
Volume24
Issue number12
DOIs
Publication statusPublished - 2018 Dec

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Keywords

  • Alzheimer’s disease
  • Aβ aggregation reduction
  • antioxidation
  • chalcone-coumarin hybrid
  • neuroprotection
  • therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Physiology (medical)
  • Pharmacology (medical)

Cite this

Lee, S. Y., Chiu, Y. J., Yang, S. M., Chen, C. M., Huang, C. C., Lee-Chen, G. J., Lin, W., & Chang, K. H. (2018). Novel synthetic chalcone-coumarin hybrid for Aβ aggregation reduction, antioxidation, and neuroprotection. CNS Neuroscience and Therapeutics, 24(12), 1286-1298. https://doi.org/10.1111/cns.13058