Nrf2 as a potential target for Parkinson's disease therapy

Parkinson's disease (PD) is a complex neurodegenerative disorder featuring both motor and nonmotor symptoms associated with a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Conventionally, PD treatment options have focused on dopamine replacement and provide only symptomatic relief. However, disease-modifying therapies are still unavailable. Mechanistically, genetic and environmental factors can produce oxidative stress which has been implicated as a core contributor to the initiation and progression of PD through the degeneration of dopaminergic neurons. Importantly, nuclear factor erythroid 2-related factor 2 (Nrf2) is essential for maintaining redox homeostasis by binding to the antioxidant response element which exists in the promoter regions of most genes coding for antioxidant enzymes. Furthermore, protein kinase C, mitogen-activated protein kinases, and phosphotidylinositol 3-kinase have been implicated in the regulation of Nrf2 activity during PD. Here, we review the evidence supporting the regulation of Nrf2 through Keap1-dependent and Keap1-independent mechanisms. We also address that targeting Nrf2 may provide a therapeutic option to mitigate oxidative stress-associated PD. Finally, we discuss currently known classes of small molecule activators of Nrf2, including Nrf2-activating compounds in PD.