Fig. 2

Activation of the cellular antioxidative response system under normal and stress condition. a Under normal conditions, the response to injury is adaptive, designed to restore homoeostasis and to protect the cell from further injury. b In response to excessive oxidative stress promoted by chronic CS exposure, NADPH oxidase is activated, producing an excess of O2– which in the presence of nitric oxide (.NO; also abundant in CS and release in response to IR) results in formation of peroxinitrite (ONOO–). Furthermore, the excess of H₂O₂ (not neutralized by catalase or GPx) leads to the formation of hydroxyl radicals (OH; Fenton’s reaction). The Nrf2-ARE system becomes dysfunctional leading to imbalances in mitochondrial redox homeostasis and biogenesis, inflammation, vascular and cellular damage which are all prodromal to a large number of CNS and systemic/peripheral pathologies