Identification and optimization of piperlongumine analogues as potential antioxidant and anti-inflammatory agents via activation of Nrf2

Oxidative stress and inflammation are significant risk factors for neurodegenerative disease. The Keap1-Nrf2-ARE pathway is one of the most promising defensive systems against oxidative stress. Here, dozens of piperlongumine analogues were designed, synthesized, and tested on PC12 cells to examine neuroprotective effects against H2O2 and 6-OHDA induced damage. Among them, 6d was found to be able to alleviate the accumulation of ROS, inhibit the production of NO and downregulate the level of IL-6, which indicated its potential antioxidant and anti-inflammatory activity. Further studies proved that 6d could activate Nrf2 signaling pathway, induce the translocation of Nrf2 from cell cytosol to nucleus and upregulate the related phase II antioxidant enzymes including NQO1, HO-1, GCLC, GCLM and TrxR1. These results confirmed that 6d exerted antioxidant and anti-inflammatory activities by activating Nrf2 signaling pathway. Moreover, the parallel artificial membrane permeability assay indicated that 6d can cross the blood-brain barrier. In general, 6d is promising for further development as a therapeutic drug against oxidative stress and inflammation related neurodegenerative disorders. (C) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

The study demonstrates that piperlongumine analogue 6d shows potential antioxidant and anti-inflammatory activities in PC12 cells by activating the Nrf2 signaling pathway to combat oxidative stress. Further research indicates that 6d has the potential to be a therapeutic drug for neurodegenerative disorders related to oxidative stress and inflammation.