title: NRF2-regulation in brain health and disease: implication of cerebral inflammation.
abstract: The nuclear factor erythroid 2 related factor 2 (NRF2) is a key regulator of endogenous inducible defense systems in the body. Under physiological conditions NRF2 is mainly located in the cytoplasm. However, in response to oxidative stress, NRF2 translocates to the nucleus and binds to specific DNA sites termed "anti-oxidant response elements" or "electrophile response elements" to initiate transcription of cytoprotective genes. Acute oxidative stress to the brain, such as stroke and traumatic brain injury is increased in animals that are deficient in NRF2. Insufficient NRF2 activation in humans has been linked to chronic diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. New findings have also linked activation of the NRF2 system to anti-inflammatory effects via interactions with NF-κB. Here we review literature on cellular mechanisms of NRF2 regulation, how to maintain and restore NRF2 function and the relationship between NRF2 regulation and brain damage. We bring forward the hypothesis that inflammation via prolonged activation of key kinases (p38 and GSK-3β) and activation of histone deacetylases gives rise to dysregulation of the NRF2 system in the brain, which contributes to oxidative stress and injury.
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Sandberg
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
authors.forename: Jaspal
authors.initials: J
authors.lastname: Patil
authors.affiliation: Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
authors.forename: Barbara
authors.initials: B
authors.lastname: D'Angelo
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, United States.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Weber
authors.affiliation: Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden. Electronic address: carina.mallard@neuro.gu.se.
authors.forename: Carina
authors.initials: C
authors.lastname: Mallard
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology / Q000502:physiology* / Q000503:physiopathology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology
chemical_list: D051267:NF-E2-Related Factor 2
keywords: Anti-oxidants; NRF2; Neuroinflammation