Figure 1.

Schematic representation of neural redox reactions. Stress causes an increase in corticosterone which activates cytosolic glucocorticoid receptors (GR). These translocate into the nucleus to modulate gene transcription through glucocorticoid responsive elements (GRE), or co-localize with the anti-apoptotic Bcl-2 protein and translocate into the mitochondria. This increases mitochondrial membrane potential, calcium holding capacity, and mitochondrial oxidation. The increase in cellular metabolic rate promotes ATP synthesis in addition to spontaneous superoxide (O⁻₂) production via complex I and III of the electron transport chain. This is dismutated to hydrogen peroxide (H₂O₂) by manganese superoxide dismutase (Mn-SOD) and can be further converted to hydroxyl radical (OH⁻) or reduced to water by the mitochondrial antioxidant pathway. In the cytosol, a major source of superoxide production is via the oxidation of NADPH via NADPH oxidase. Cytosolic superoxide is dismutated to hydrogen peroxide by copper, zinc-superoxide dismutase (Cu, Zn-SOD). Hydrogen peroxide is neutralized by catalase (CAT) or glutathione peroxidase (GPx) which oxidizes the reduced form of glutathione (GSH) to oxidized glutathione (GSSG). GSH is then regenerated from GSSG via the glutathione reductase (GSR) enzymatic system. Hydrogen peroxide can also interact with superoxide radicals and/or transition metals such as Fe²⁺ or Cu²⁺ to produce the highly toxic hydroxyl radical by Haber-Weiss and Fenton chemistry. An increase in the production of superoxide, hydrogen peroxide, and hydroxyl radicals leads to a state of cellular oxidative stress which causes oxidative damage to DNA, protein carbonyl formation, and membrane lipid peroxidation (LPO). Hydrogen peroxide is membrane permeable and moves freely from mitochondrial to cytosolic compartments, in addition to traversing the extracellular space to affect neighboring neurons and glial cells. Superoxide radicals can also induce oxidative stress in neighboring cells by diffusing through membrane-bound anion channels. The majority of neuronal and astrocytic reactive oxygen species are produced by mitochondrial oxidation, while other cell types such as microglia rely heavily on the cytosolic NADPH-oxidase system to produce a respiratory burst in response to invading pathogens. However, in comparison to glial cells, neurons display a relatively poor expression of endogenous antioxidants, making them more vulnerable to oxidative stress.