title: Activation of the astrocytic Nrf2/ARE system ameliorates the formation of demyelinating lesions in a multiple sclerosis animal model.
abstract: Oxidative stress critically contributes to the pathogenesis of a variety of neurodegenerative diseases such as multiple sclerosis. Astrocytes are the main regulators of oxidative homeostasis in the brain and dysregulation of these cells likely contributes to the accumulation of oxidative damage. The nuclear factor erythroid 2-related factor 2 (Nrf2) is the main transcriptional regulator of the anti-oxidant stress defense. In this study, we elucidate the effects of astrocytic Nrf2-activation on brain-intrinsic inflammation and lesion development. Cells deficient for the Nrf2 repressor kelch-like ECH-associated protein 1 (Keap1) are characterized by hyperactivation of Nrf2-signaling. Therefore, wild type mice and mice with a GFAP-specific Keap1-deletion were fed with 0.25% cuprizone for 1 or 3 weeks. Cuprizone intoxication induced pronounced oligodendrocyte loss, demyelination and reactive gliosis in wild type animals. In contrast, astrocyte-specific Nrf2-activation was sufficient to prevent oligodendrocyte loss and demyelination, to ameliorate brain intrinsic inflammation and to counteract axonal damage. Our results highlight the potential of the Nrf2/ARE system for the treatment of neuroinflammation in general and of multiple sclerosis in particular. © GLIA 2016;64:2219-2230.
authors.affiliation: Faculty of Medicine, Institute of Neuroanatomy, Uniklinik RWTH Aachen, Aachen, 52074, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Draheim
authors.affiliation: Faculty of Medicine, Institute of Neuroanatomy, Uniklinik RWTH Aachen, Aachen, 52074, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Liessem
authors.affiliation: Faculty of Medicine, Institute of Neuroanatomy, Uniklinik RWTH Aachen, Aachen, 52074, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Scheld
authors.affiliation: Faculty of Medicine, Institute of Neuroanatomy, Uniklinik RWTH Aachen, Aachen, 52074, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Wilms
authors.affiliation: Faculty of Medicine, Institute of Neuroanatomy, Uniklinik RWTH Aachen, Aachen, 52074, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Weißflog
authors.affiliation: Interdisciplinary Centre for Clinical Research (IZKF) Aachen, Uniklinik RWTH Aachen, Aachen, 52074, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Denecke
authors.affiliation: Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: T W
authors.initials: TW
authors.lastname: Kensler
authors.affiliation: Faculty of Medicine, Institute of Neuroanatomy, Uniklinik RWTH Aachen, Aachen, 52074, Germany.|Department of Anatomical Sciences, Faculty of Medicine, Giulan University of Medical Sciences, Rasht, Iran.
authors.forename: A
authors.initials: A
authors.lastname: Zendedel
authors.affiliation: Faculty of Medicine, Institute of Neuroanatomy, Uniklinik RWTH Aachen, Aachen, 52074, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Beyer
authors.affiliation: Faculty of Medicine, Institute of Neuroanatomy, Uniklinik RWTH Aachen, Aachen, 52074, Germany.|Department of Anatomy II, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kipp
authors.affiliation: Department of Anatomy and Cell Biology, Faculty of Medicine, Uniklinik RWTH Aachen, Aachen, 52074, Germany.
authors.forename: C J
authors.initials: CJ
authors.lastname: Wruck
authors.affiliation: Department of Anatomy and Cell Biology, Faculty of Medicine, Uniklinik RWTH Aachen, Aachen, 52074, Germany.|Department of Orthopaedic Surgery, Faculty of Medicine, Uniklinik RWTH Aachen, Aachen, 52074, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Fragoulis
authors.affiliation: Faculty of Medicine, Institute of Neuroanatomy, Uniklinik RWTH Aachen, Aachen, 52074, Germany. tclarner@ukaachen.de.
authors.forename: T
authors.initials: T
authors.lastname: Clarner
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000209:etiology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D054481:Thioredoxin Reductase 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; D005904:Glial Fibrillary Acidic Protein; D000072019:Kelch-Like ECH-Associated Protein 1; D008565:Membrane Proteins; D008996:Monoamine Oxidase Inhibitors; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D003471:Cuprizone; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D054481:Thioredoxin Reductase 1; C516125:Txnrd1 protein, mouse; D005721:Glutamate-Cysteine Ligase
keywords: Nrf2; astrocytes; multiple sclerosis; oxidative stress