Antioxidant defense of the brain: a role for astrocytes

Partially reduced forms of oxygen are produced in the brain during cellular respiration and, at accelerated rates, during brain insults. The most reactive forms, such as the hydroxyl radical, are capable of oxidizing proteins, lipids, and nucleic acids. Oxidative injury has been implicated in degenerative diseases, epilepsy, trauma, and stroke. It is a threshold phenomenon that occurs after antioxidant mechanisms are overwhelmed. Oxidative stress is a disparity between the rates of free radical production and elimination. This imbalance is initiated by numerous factors: acidosis; transition metals; amyloid beta-peptide; the neurotransmitters dopamine, glutamate, and nitric oxide; and uncouplers of mitochondrial electron transport. Antioxidant defenses include the enzymes superoxide dismutase, glutathione peroxidase, and catalase, as well as the low molecular weight reductants alpha-tocopherol (vitamin E), glutathione, and ascorbate (reduced vitamin C). Astrocytes maintain high intracellular concentrations of certain antioxidants, making these cells resistant to oxidative stress relative to oligodendrocytes and neurons. Following reactive gliosis, the neuroprotective role of astrocytes may be accentuated because of increases in a number of activities: expression of antioxidant enzymes; transport and metabolism of glucose that yields reducing equivalents for antioxidant regeneration and lactate for neuronal metabolism; synthesis of glutathione; and recycling of vitamin C. In the latter process, astrocytes take up oxidized vitamin C (dehydroascorbic acid, DHAA) through plasma membrane transporters, reduce it to ascorbate, and then release ascorbate to the extracellular fluid, where it may contribute to antioxidant defense of neurons.