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.

Pablo Diaz-Amarilla 1 Ernesto Miquel 2 Andrés Trostchansky 3 Emiliano Trias 4 Ana M Ferreira 3 Bruce A Freeman 5 Patricia Cassina 2 Luis Barbeito 4 Marcelo R Vargas 6 Homero Rubbo 3
1 IIBCE - Instituto de Investigaciones Biológicas Clemente Estable [Montevideo]
2 Departamento de Histologıa y Embriologıa, Facultad de Medicina [Montevideo]
3 UCUR - Universidad de la República [Montevideo]
4 Institut Pasteur de Montevideo
5 Department of Pharmacology and Chemical Biology [Pittsburgh]
6 MUSC - Medical University of South Carolina [Charleston]
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.
Keywords : Heme oxygenase Motor neurons Nitro-fatty acids Nitroarachidonic acid ALS Astrocytes Nitrooleic acid Nrf2
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Journal articles
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Submitted on : Wednesday, March 29, 2017 - 7:53:13 PM
Last modification on : Thursday, August 22, 2019 - 2:00:04 PM

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Pablo Diaz-Amarilla, Ernesto Miquel, Andrés Trostchansky, Emiliano Trias, Ana M Ferreira, et al.. 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.. Advances in Free Radical Biology & Medicine, Elsevier, 2016, 95, pp.112-20. ⟨10.1016/j.freeradbiomed.2016.03.013⟩. ⟨pasteur-01498339⟩

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