Electrophiles And Michael Acceptors As NRF2 Modulators In A Caenorhabditis Elegans Model
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Date
2017-09
Authors
Lee, Elaine Hui Chen
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Journal ISSN
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Publisher
Universiti Sains Malaysia
Abstract
Amyloid-beta (Aβ) toxicity and oxidative stress have been demonstrated to be the causative factors of Alzheimer’s disease (AD). The present study hypothesized that modulation of oxidative stress via the stress response SKN-1/Nrf2 pathway may attenuate Aβ toxicity via the removal of oxidative stressors. This study aims to investigate the protective effect of seven selected electrophiles and Michael acceptors, namely curcumin (CUR) and its analogs (C1, C2, C3 and C4), dimethyl fumarate (DMF) and sulforaphane (SFN), against Aβ-induced toxicity in a transgenic Caenorhabditis elegans model. Pertinent to their potential as central nervous system (CNS) active drugs, the blood brain barrier (BBB) permeability of the study compounds were examined. Three curcumin analogs (C1, C2 and C3) of shortened linker moieties and reduced molecular size were designed with the notion that such structural modifications could improve the BBB permeability of CUR while exerting protective effect against Aβ. Using the PAMPA-BBB assay herein demonstrated for the first time the four analogs showed improved BBB permeability than CUR with the hemi-analog C4 having the highest permeability coefficient possibly owing to its reduced size. Four compounds (CUR, C4, DMF and SFN) were found to significantly delay Aβ-induced paralysis in the C. elegans at a concentration range of 1 – 100 μM. Mechanistic evaluation of the protective effect against Aβ toxicity on two AD-related events viz. Aβ aggregation and oxidative stress were investigated. The findings on Aβ inhibitory activity of the active
compounds showed that SFN displayed the highest Aβ aggregation inhibition (80%) followed by DMF (49.50%), whereas the CUR and C4 showed negligible Aβ aggregation inhibition. These findings suggested that direct inactivation of Aβ has minimal efficacy as mode of protection against Aβ as a weak correlation were observed between the in vivo paralysis reduction and the in vitro Aβ aggregation inhibitory properties. Using a developed RT-qPCR method, the involvement of skn-1 gene was probed. C4 and SFN induced the expression of skn-1 gene at both concentrations (10 and 100 μM) when evaluated at two different time points. Treatment of active compounds at 100 μM reduced the Aβ-induced intracellular reactive oxygen species (ROS) level. Taken together, these results suggested that the hemi analog C4, whilst having improved BBB permeability, may also have significant protective effect against Aβ-induced toxicity in C. elegans, partly through the induction of skn-1 gene expression and reduced accumulation of ROS. Hence C4 serves as a potential lead for further development as a neuroprotective agent for AD.
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Keywords
Electrophiles and michael acceptors as NRF2 , modulators in a caenorhabditis elegans model