Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8267770 | Free Radical Biology and Medicine | 2016 | 20 Pages |
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 hSOD1G93A induce antioxidant phase II enzyme expression through Nrf2 activation concomitant with increasing intracellular glutathione levels. Furthermore, treatment of hSOD1G93A-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.
Keywords
SOD1nitroarachidonic acidsulfiredoxin 1NO2-FAhemoxygenase-1tert-butylhydroquinoneNQO1GCLTBHQNrf2HO-1keap1Cu/Zn superoxide dismutaseNAD(P)H:quinone oxidoreductase 1Astrocytesamyotrophic lateral sclerosisArachidonic acidOleic acidnitro-oleic acidNitro-fatty acidsALSNuclear factor-erythroid 2-related factor 2antioxidant response elementglutamate-cysteine ligasemotor neuronsAREheme oxygenaseKelch-like ECH-associated protein 1
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Authors
Pablo Diaz-Amarilla, Ernesto Miquel, Andrés Trostchansky, Emiliano Trias, Ana M. Ferreira, Bruce A. Freeman, Patricia Cassina, Luis Barbeito, Marcelo R. Vargas, Homero Rubbo,