FIG. 8. Working model that integrates the traditional view on the role of oxidative stress in ischemic tissue damage, and the new findings of the link between oxidative stress and pathological glutamate release.

Anoxic glutamate release is thought to initiate tissue damage via activation of ionotropic glutamate receptors (NMDA-R) and increases in cytosolic [Ca²⁺], which lead to terminal oxidative and nitrosative damage of neuronal cells. The relevant pathways are targeted by broad spectrum antioxidants, such as edaravone. New findings of the present study suggest that oxidative stress also acts upstream of pathological glutamate release via stimulation of glutamate permeability pathways by yet unidentified ROS intermediate (X, see text for detailed discussion). Amplification of glutamate release by the O₂^•− -derived ROS propagates tissue damage in the ischemic penumbra, and is preferentially targeted by the SOD mimetics tempol. Dohare et al.