Figure 5.

Schematic representation of the main sources of ROS and RNS during oxidative/nitrosative stress occurring after TBI. The severity of injury is quite well correlated with high or low oxidative/nitrosative stress and with protraction of intra- and extracellular ROS and RNS generation from the various potential sources. For instance, mild TBI rarely causes hematomas with hemoglobin extravasation and mobilization of ferritin iron, thus strongly decreasing the amount of iron used in the Haber–Weiss-sustained Fenton reaction. Conversely, severe TBI induces long-lasting conditions of metabolic derangement due to mitochondrial dysfunction. A vicious cycle is formed between the increased energy requirement, either to satisfy repairing processes or to counteract dangerous phenomena (glutamate excitotoxicity, ionic homeostatic disequilibrium), and the damaging molecules originating from mitochondrial ETC unable to manage the tetravalent reduction of molecular oxygen to water minimizing superoxide formation.