Nuclear Factor Erythroid 2 - Related Factor 2 Signaling in Parkinson Disease: A Promising Multi Therapeutic Target Against Oxidative Stress, Neuroinflammation and Cell Death

Hemant      Kumar; Sushruta      Koppula; In-Su      Kim; Sandeep      Vasant More; Byung-Wook      Kim; Dong-Kug      Choi

Abstract

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder with increased oxidative stress as central component. Till date, treatments related to PD are based on restoring dopamine either by targeting neurotransmitter and/or at receptor levels. These therapeutic approaches try to repair damage but do not address the underlying processes such as oxidative stress and neuroinflammation that contribute to cell death. The central nervous system maintains a robust antioxidant defense mechanism consisting of several cytoprotective genes and enzymes whose expression is controlled by antioxidant response element (ARE) which further depends on activation of nuclear factor erythroid 2-related factor 2 (Nrf2). In response to oxidative or electrophilic stress transcription factor Nrf2 binds to ARE and rescues the cells from oxidative stress and neuroinflammation. Recently, Nrf2 has been utilized as a drug target and some agents are currently under clinical trial. Owing to the potential role of Nrf2 in counteracting oxidative stress and neuroinflammation seen in PD, here we have focused on the molecular mechanism of the Nrf2/ARE antioxidant defense pathway in PD. Further, we also summarize published reports on the potential inducers of Nrf2 that demonstrate neuroprotective effects in experimental models of PD with possible future strategies to increase the transcriptional level of Nrf2 as a therapeutic strategy to provide neuroprotection of damaged dopaminergic neurons in PD.

Keywords: Antioxidant inflammation modulators, antioxidant response elements, apoptosis, nuclear factor erythroid 2-related factor 2, neuroinflammation, oxidative stress, Parkinson’s disease, dopaminergic neurons, neurotransmitter, robust antioxidant.