An Intercellular Flow of Glutathione Regulated by Interleukin 6 Links Astrocytes and the Liver in the Pathophysiology of Amyotrophic Lateral Sclerosis

Abstract

Oxidative stress has been proposed as a major mechanism of damage to motor neurons associated with the progression of amyotrophic lateral sclerosis (ALS). Astrocytes are the most numerous glial cells in the central nervous system and, under physiological conditions, protect neurons from oxidative damage. However, it is uncertain how their reactive phenotype may affect motor neurons during ALS progression. In two different ALS mouse models (SOD1G93A and FUS-R521C), we found that increased levels of proinflammatory interleukin 6 facilitate glutathione (GSH) release from the liver to blood circulation, which can reach the astrocytes and be channeled towards motor neurons as a mechanism of antioxidant protection. Nevertheless, although ALS progression is associated with an increase in GSH efflux from astrocytes, generation of reactive oxygen species also increases, suggesting that as the disease progresses, astrocyte-derived oxidative stress could be key to motor-neuron damage.

N-Acetylcysteine Promotes Metastatic Spread of Melanoma in Mice

“…γ-glutamyl transpeptidase (GGT), superoxide dismutase (SOD) 1 and 2, catalase (CAT) and glutathione peroxidase (GPX) activities were measured as previously described in detail [ 22 ].…”

“…Levels of amino acids in arterial blood were determined as previously described [ 22 ] and using an LA8080 high-speed amino-acid analyzer (Hitachi, Tokyo, Japan).…”

“…Quantitative measurement of H 2 O 2 and O 2 · − generation followed previously described methodology [ 22 ].…”

“…O 2 concentration and consumption in isolated melanoma cells were measured using an oxygraph of OROBOROS Instruments (Innsbruck, Austria) and as previously described [ 22 ].…”

Astrocytes in Neurodegeneration: Inspiration From Genetics

“…Interestingly, decreasing NF-κB in astrocytes from the cortex of SOD1 G93A mice in the prodromal stage inhibited cortical inflammation (Gomes et al, 2019). Despite the fact that astrocytes in the motor cortex and spinal cord had different endurance in the early stage of the disease, widespread and excessive oxidative stress in astrocytes was activated in the late stage of the SOD1 G93A mouse model (López-Blanch et al, 2021). In the SOD1 G93A mouse models, astrocytes from both the motor cortex and the spinal cords were characterized by ERmitochondrial impairments, which were more pronounced in the mutated motor cortex than in the spinal cord cells (Marini et al, 2021).…”