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

Departamento de Neurobiología Celular y Molecular, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay.
Journal of Neurochemistry (Impact Factor: 4.24). 06/2006; 97(3):687-96. DOI: 10.1111/j.1471-4159.2006.03742.x
Source: PubMed

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 abolished their apoptotic activity. The protection exerted by increased Nrf2 activity was overcome by adding the NO donor DETA-NONOate to the co-cultures or by inhibiting GSH synthesis and release from astrocytes. These results suggest that activation of Nrf2 in astrocytes can reduce NO-dependent toxicity to motor neurons by increasing GSH biosynthesis.

  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Meningitis is an inflammation of the membranes that surround the brain and spinal cord, thereby involving the arachnoid, the pia and the cerebrospinal fluid (CSF). It is divided into viral and bacterial meningitis. For different reasons the diagnosis of bacterial meningitis is very important. The examination of CSF samples may provide information about causative microorganism. The sensivity of Gram-stained specimen of CSF ranges from 60% to 90%. CSF is continuously secreted by the choroids plexus and contains growth factors which are present under specific pathological conditions. As CSF is in close contact with the extracellular space of the brain, biochemical brain modifications could be reflected in the CSF and study of growth factor expression in the CSF might identify biomarkers of meningitis. As fibroblast growth factor-1 (FGF-1) is important in neural cell survival, we studied the changes in the total protein concentration (TPC) and FGF-1 expression in the CSF of normal control and patients with meningitis using Western blott. No significant increase in the CSF TPC in the patients with bacterial meningitis has been seen when compared to control group. However, significant increase in the CSF FGF-1 expression in the patients with meningitis has been seen as compared to control group. It is suggested that FGF-1 could be significantly involved in the pathophysiology of meningitis. we have also conclude that the FGF level in the CSF may provide additional information in the differential diagnosis of meningitis.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Astrocytes have a pivotal role in brain as partners of neurons in homeostatic and metabolic processes. Astrocytes also protect other types of brain cells against the toxicity of reactive oxygen species and are considered as first line of defence against the toxic potential of xenobiotics. A key component in many of the astrocytic detoxification processes is the tripeptide glutathione (GSH) which serves as electron donor in the GSH peroxidase-catalyzed reduction of peroxides. In addition, GSH is substrate in the detoxification of xenobiotics and endogenous compounds by GSH-S-transferases which generate GSH conjugates that are efficiently exported from the cells by multidrug resistance proteins. Moreover, GSH reacts with the reactive endogenous carbonyls methylglyoxal and formaldehyde to intermediates which are substrates of detoxifying enzymes. In this article we will review the current knowledge on the GSH metabolism of astrocytes with a special emphasis on GSH-dependent detoxification processes.
    Neurochemical Research 11/2014; DOI:10.1007/s11064-014-1481-1 · 2.55 Impact Factor

Full-text (2 Sources)

Available from
Feb 5, 2015