Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75NTR-dependent motor neuron apoptosis

Journal of Neurochemistry
Marcelo R VargasLuis Barbeito

Abstract

Astrocytes may modulate the survival of motor neurons in amyotrophic lateral sclerosis (ALS). We have previously shown that fibroblast growth factor-1 (FGF-1) activates astrocytes to increase secretion of nerve growth factor (NGF). NGF in turn induces apoptosis in co-cultured motor neurons expressing the p75 neurotrophin receptor (p75NTR) by a mechanism involving nitric oxide (NO) and peroxynitrite formation. We show here that FGF-1 increased the expression of inducible nitric oxide synthase and NO production in astrocytes, making adjacent motor neurons vulnerable to NGF-induced apoptosis. Spinal cord astrocytes isolated from transgenic SOD1G93A rats displayed increased NO production and spontaneously induced apoptosis of co-cultured motor neurons. FGF-1 also activates the redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in astrocytes. Because Nrf2 increases glutathione (GSH) biosynthesis, we investigated the role of GSH production by astrocytes on p75NTR-dependent motor neuron apoptosis. The combined treatment of astrocytes with FGF-1 and t-butylhydroquinone (tBHQ) increased GSH production and secretion, preventing motor neuron apoptosis. Moreover, Nrf2 activation in SOD1G93A astrocytes a...Continue Reading

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Citations

Jun 17, 2010·Journal of Neural Transmission·Ana G BarbeitoSéverine Boillée
Apr 11, 2012·Neurotoxicity Research·Derek A DrechselJoseph S Beckman
Oct 1, 2010·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Marcelo R Vargas, Jeffrey A Johnson
Jun 6, 2009·Expert Reviews in Molecular Medicine·Marcelo R Vargas, Jeffrey A Johnson
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Oct 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Pablo Díaz-AmarillaLuis Barbeito
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Nov 1, 2007·Biochemical and Biophysical Research Communications·Paweł JałoszyńskiMasayuki Yamamoto
Aug 7, 2008·Journal of Neuroscience Research·Marcelo R VargasLuis Barbeito
Sep 24, 2008·Journal of Neurochemistry·Lynsey G BilslandMichael R Duchen

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