Protective effect of an Nrf2-ARE activator identified from a chemical library on 6-hydroxydopamine-induced dopaminergic neuronal death

Oxidative stress, which is caused by reactive oxygen species, contributes to the pathogenesis of Parkinson's disease. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway induces antioxidant enzymes in response to oxidative stress. We focused on the Nrf2-ARE activators as dopaminergic neuroprotective agents. Activators of the Nrf2-ARE pathway are often electrophilic compounds and they react with a specific thiol on Kelch-like ECH-associated protein 1 (Keap1), a suppressor of Nrf2. A general issue with electrophilic compounds is that they nonspecifically react with thiol groups, leading to cytotoxicity. In this study, we aimed to find novel compounds of Nrf2 activators with a wide safety margin and to demonstrate the protective effect of the activator against 6-hydroxydopamine (6-OHDA) -induced dopaminergic neuronal death.