xanthohumol and Protein-Aggregation--Pathological

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).. 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.. We designed and synthesized a novel series of 9 xanthohumol derivatives. Their inhibitory effect on amyloid-β (1-42), Aβ1-42, oligomerization and fibrillation as well as neuroprotection against amyloid-β induced toxicities, were explored.. Among the 9 xanthohumol derivatives, some of them exhibited a moderate to high inhibitory effect on Aβ1-42 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.. Two derivatives have been identified to be biocompatible, non-toxic, neuroprotective against Aβ-induced toxicities and blood-brain barrier permeable highlighting their promising potential as AD drug candidates for future clinical use.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Calcium; Capillary Permeability; Cell Line, Tumor; Cell Survival; Drug Evaluation, Preclinical; Flavonoids; Humans; Mice; Neuroprotective Agents; Propiophenones; Protein Aggregation, Pathological; Random Allocation; Reactive Oxygen Species

Alzheimer's disease (AD) is a neurodegenerative disease. The molecular mechanisms of AD are not yet clear, and no effective treatments are available to cure AD. Because of the huge number of patients and related costs, it is urgent to discover new medicines to prevent or cure AD. In this study, xanthohumol (XN), a natural botanic compound, is found to inhibit tau protein aggregation and disaggregate tau fibrils. XN directly interacts with tau protein at sites sporadically located in all four repeating domains with a Kd value of 52 μM. Binding with XN does not alter the secondary structures of tau protein. Cellular experiments showed that XN exhibits little cytotoxicity and attenuates apoptosis induced by tau oligomers. The results provide preliminary experimental data to develop XN into medicines, food products, or nutritional supplements for AD. The findings also provide data for computational drug design.

Topics: Animals; Apoptosis; Flavonoids; Kinetics; Mice; Neurons; Propiophenones; Protein Aggregates; Protein Aggregation, Pathological; tau Proteins