The Nrf2/ARE Pathway as a Potential Therapeutic Target in Neurodegenerative Disease

Abstract

Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor known to induce expression of a variety of cytoprotective and detoxification genes. Several of the genes commonly regulated by Nrf2 have been implicated in protection from neurodegenerative conditions. Work from several laboratories has uncovered the potential for Nrf2-mediated transcription to protect from neurodegeneration resulting from mechanisms involving oxidative stress. For this reason, Nrf2 may be considered a therapeutic target for conditions that are known to involve free radical damage. Because common mechanisms of neurodegeneration, such as mitochondrial dysfunction and build-up of reactive oxygen species, are currently being uncovered, targeting Nrf2 may be valuable in combating conditions with variable causes and etiologies. Most effectively to target this protein in neurodegenerative conditions, a description of the involvement of Nrf2 and potential for neuroprotection must come from laboratory models. Herein, we review the current literature that suggests that Nrf2 may be a valuable therapeutic target for neurodegenerative disease, as well as experiments that illustrate potential mechanisms of protection. Antioxid. Redox Signal. 11,[497][498][499][500][501][502][503][504][505][506][507][508]

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition: Robust New Target or Another Big Bust for Stroke Therapeutics?

“…One general approach of increasing interest to clinical neuroscientists, aided by the molecular and genomic revolutions, is the use of drugs that activate endogenous adaptive programs. Indeed, activators of the Nrf2-mediated antioxidant response (Calkins et al, 2009;Smirnova et al, 2011), peroxisome proliferator-activated receptor g-mediated metabolic adaptation and antiinflammatory programs (Zhao et al, 2006), and histone deacetylases inhibitor-induced neuroprotective and repair cassettes (Sleiman et al, 2009;Langley et al, 2009) are examples of how this general approach has been applied. Excitingly, with each of these targets, there is a clear trajectory toward the human bedside.…”

SCF/β-TrCP Promotes Glycogen Synthase Kinase 3-Dependent Degradation of the Nrf2 Transcription Factor in a Keap1-Independent Manner

“…Because ROS play a role as intracellular signaling molecules for many physiological processes, Nrf2 can have an impact on numerous cell functions, ranging from differentiation and development to proliferation and inflammation. Therefore, Nrf2 activity influences neurodegenerative disease, cardiovascular disease, and cancer (3,4,14,16,17,49,53).…”

Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A

“…The role of Nrf2 in regulating cell-cell crosstalk is less appreciated. Neuroprotective strategies based on Nrf2's cell-intrinsic properties have focused on neurodegenerative conditions (8,9), but have also been demonstrated in the Significance Delayed revascularization of ischemic neural tissue is a major impediment to preservation of function in central nervous system (CNS) diseases including stroke and ischemic retinopathies. The key mechanisms governing vascular recovery in ischemic CNS, including regulatory molecules governing transition from tissue injury to repair, are largely unknown.…”