Amyloid-β Aggregation Inhibitory and Neuroprotective Effects of Xanthohumol and its Derivatives for Alzheimer’s Diseases

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Author(s): Xueli Wang , See-Lok Ho , Chung-Yan Poon , Ting Yan , Hung-Wing Li* , Man Shing Wong* .

Journal Name: Current Alzheimer Research

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Background: Xanthohumol has been reported to have cytoprotection through activation of Nrf2−ARE signaling pathway and; it has capability of scavenging free radicals, suggesting its potential for the prevention of neurodegeneration. However, the bio-incompatibility and blood-brain barrier impermeability of xanthohumol hindered its in vivo efficacy potential for treating Alzheimer’s disease (AD).

Objective: We designed and prepared a series of xanthohumol derivatives to enhance the desirable physical, biological and pharmacological properties in particular the blood-brain barrier permeability for intervention of AD.

Method: We designed and synthesized a novel series of 9 xanthohumol derivatives. Their inhibitory effect on amyloid-β (1-42), A β 1-42 , oligomerization and fibrillation as well as neuroprotection against amyloid- β induced toxicities, were explored.

Results: Among the 9 xanthohumol derivatives, some of them exhibited a moderate to high inhibitory effect on Aβ 1-42 oligomerization and fibrillation. They were biocompatible and neuroprotective to the SH-SY5Y cells by reducing the ROS generation and calcium uploading that were induced by the amyloid- β. Importantly, two of the derivatives were found to be blood-brain barrier permeable showing promising potential for AD treatment.

Conclusion: Two derivatives have been identified to be biocompatible, non-toxic, neuroprotective against A β -induced toxicities and blood-brain barrier permeable highlighting their promising potential as AD drug candidates for future clinical use.

Keywords: Derivatives of xanthohumol; neuroprotective; amyloid aggregation inhibition; blood brain barrier permeable

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(E-pub Ahead of Print)
DOI: 10.2174/1567205016666190827123222
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