title: Electrophilic nitro-fatty acids prevent astrocyte-mediated toxicity to motor neurons in a cell model of familial amyotrophic lateral sclerosis via nuclear factor erythroid 2-related factor activation.
abstract: Nitro-fatty acids (NO2-FA) are electrophilic signaling mediators formed in tissues during inflammation, which are able to induce pleiotropic cytoprotective and antioxidant pathways including up regulation of Nuclear factor erythroid 2-related factor 2 (Nrf2) responsive genes. Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons associated to an inflammatory process that usually aggravates the disease progression. In ALS animal models, the activation of the transcription factor Nrf2 in astrocytes confers protection to neighboring neurons. It is currently unknown whether NO2-FA can exert protective activity in ALS through Nrf2 activation. Herein we demonstrate that nitro-arachidonic acid (NO2-AA) or nitro-oleic acid (NO2-OA) administrated to astrocytes expressing the ALS-linked hSOD1(G93A) induce antioxidant phase II enzyme expression through Nrf2 activation concomitant with increasing intracellular glutathione levels. Furthermore, treatment of hSOD1(G93A)-expressing astrocytes with NO2-FA prevented their toxicity to motor neurons. Transfection of siRNA targeted to Nrf2 mRNA supported the involvement of Nrf2 activation in NO2-FA-mediated protective effects. Our results show for the first time that NO2-FA induce a potent Nrf2-dependent antioxidant response in astrocytes capable of preventing motor neurons death in a culture model of ALS.
authors.affiliation: Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay.
authors.forename: Pablo
authors.initials: P
authors.lastname: Diaz-Amarilla
authors.affiliation: Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Miquel
authors.affiliation: Departamento de Bioquímica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Andrés
authors.initials: A
authors.lastname: Trostchansky
authors.affiliation: Institut Pasteur of Montevideo, Montevideo, Uruguay.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Trias
authors.affiliation: Catedra de Inmunología, Facultad de Quimica y Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Ferreira
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.affiliation: Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Patricia
authors.initials: P
authors.lastname: Cassina
authors.affiliation: Institut Pasteur of Montevideo, Montevideo, Uruguay.
authors.forename: Luis
authors.initials: L
authors.lastname: Barbeito
authors.affiliation: Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Marcelo R
authors.initials: MR
authors.lastname: Vargas
authors.affiliation: Departamento de Bioquímica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. Electronic address: hrubbo@fmed.edu.uy.
authors.forename: Homero
authors.initials: H
authors.lastname: Rubbo
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism*; D016718:Arachidonic Acid / Q000737:chemistry / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry; D019301:Oleic Acid / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D000975:Antioxidants; D005227:Fatty Acids; D051267:NF-E2-Related Factor 2; D016718:Arachidonic Acid; D019301:Oleic Acid; D009569:Nitric Oxide; D013482:Superoxide Dismutase; D005978:Glutathione
keywords: ALS; Astrocytes; Heme oxygenase; Motor neurons; Nitro-fatty acids; Nitroarachidonic acid; Nitrooleic acid; Nrf2