Increasing vulnerability of astrocytes to oxidative injury with age despite constant antioxidant defenses.

摘要

This paper investigates the vulnerability of astrocytes to oxidative injury as a function of age in culture in mice. Primary murine cortical astrocyte cultures of different ages were exposed to H2O2, combined oxygen-glucose deprivation or glucose deprivation. Astrocytes became more vulnerable to damage from each injury paradigm with age, showing transitions between 15 and 22 days. Both the antioxidant glutathione and superoxide dismutase activity increased after 30 days in culture, while catalase activity did not change up to 34 days. When the decrease in glutathione with injury was measured, young cells showed no change with H2O2 and decreases of < 20% after oxygen-glucose deprivation or glucose deprivation, while older cultures lost > 50% of their glutathione with the same insults. Since iron can be a catalyst for hydroxyl radical formation, we stained cultures and found both iron staining and ferritin immunoreactivity increased with age. Increased iron correlated with protection by deferoxamine against H2O2 injury. The three injury paradigms each had a unique pattern of protection by antioxidants. Dimethylthiourea, a hydrophilic antioxidant, protected from all three insults. Trolox, a lipophilic antioxidant, protected older astrocytes from oxygen-glucose deprivation and glucose deprivation. Deferoxamine provided near complete protection from H2O2, partial protection from oxygen-glucose deprivation and no protection from glucose deprivation. As evidence of increasing oxidative stress, lipid peroxidation resulting from oxygen-glucose deprivation increased with age, assessed with cis-parinaric acid. The increasing sensitivity of ageing astrocytes to oxidative injury occurs while antioxidant defenses are maintained. Increased sensitivity to H2O2 or oxygen-glucose deprivation correlates with iron accumulation.