EXPLORATION OF KEAP1-NRF2-ARE SIGNALING PATHWAY MODULATORS AS POTENTIAL NEUROPROTECTANTS

Abstract

Oxidative stress contributes to the pathogenesis of numerous neurodegenerative diseases (NDDs). Induction of the Keap1-Nrf2-ARE signaling pathway is a potentially feasible pharmacological intervention to mitigate the onset and progression of NDDs through alleviating oxidative stress and inducers of the Keap 1-Nrf2-ARE pathway have recently been explored as potential neuroprotectants. Nrf2 inducers are classified into two types: electrophilic small molecules that upregulate Nrf2 levels through causing chemical modifications to crucial cysteine residues in Keapl or molecules that disrupt the protein-protein interaction between Keapl and Nrf2. In this PhD study, (l) a series of ribisin compounds containing a pharmacophoric scaffold derived from naturally occurring ribisins found in Phellinus ribis, a white-rot fungus, and (2) a series of triazole-based compounds that were designed to inhibit Keap l-Nrf2 protein-protein interaction were evaluated for their Nrf2 inducing abilities. The identified lead compounds from both classes of compounds were found to display neuroprotective activities against oxidant-induced insult through at least partly activating the Keapl-Nrf2-ARE signaling pathway.