title: The role of modulation of antioxidant enzyme systems in the treatment of neurodegenerative diseases.
abstract: Oxidative stress is a much-appreciated phenomenon associated with the progression of neurodegenerative diseases (NDDs) due to imbalances in redox homeostasis. The poor correlations between the in vitro benefits and clinical trials of direct radical scavengers have prompted research into indirect antioxidant enzymes such as Nrf2. Activation of Nrf2 leads to the upregulation of a myriad of cytoprotective and antioxidant enzymes/proteins. Traditionally, early Nrf2-activators were studied as chemoprotective agents. There is a consequential lack of clinical trials testing Nrf2 activation in NDDs. However, there is abundant evidence of their utility in pre-clinical studies. Herein, we review the endogenous Nrf2 regulatory pathway and avenues for targeting this pathway. Furthermore, we provide updated information on pre-clinical studies for natural and synthetic Nrf2 activators. On the basis of our findings, we posit that successful therapeutics for NDDs rely on the design of potent synthetic Nrf2 activators with a careful combination of other neuroprotective activities.
authors.affiliation: a Department of Pharmacy , National University of Singapore , Singapore.
authors.forename: Sybil
authors.initials: S
authors.lastname: Obuobi
authors.affiliation: a Department of Pharmacy , National University of Singapore , Singapore.
authors.forename: Sanzhar
authors.initials: S
authors.lastname: Karatayev
authors.affiliation: a Department of Pharmacy , National University of Singapore , Singapore.
authors.forename: Christina Li Lin
authors.initials: CL
authors.lastname: Chai
authors.affiliation: a Department of Pharmacy , National University of Singapore , Singapore.
authors.forename: Pui Lai Rachel
authors.initials: PL
authors.lastname: Ee
authors.affiliation: b Department of Organic Chemistry , Semmelweis University , Budapest , Hungary , and.|c Bionics Innovation Center Nonprofit Ltd , Budapest , Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Mátyus
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents
keywords: Keap 1; Nrf2; ROS; neurodegeneration; oxidative stress