Oxidative Stress-Mediated Blood-Brain Barrier (BBB) Disruption in Neurological Diseases

Figure 1

Schematic diagram of common pathological mechanisms that trigger oxidative stress. Primary mechanisms: (A) Formation of ROS. They are the main biomarkers of oxidative stress. A variety of enzymes including superoxide anion (O^2-), hydrogen peroxide (H₂O₂), nitric oxide (NO), and glutathione peroxidase (GPx) all belong to a group of molecules called ROS. (B) Mitochondrial dysfunction. ROS are mainly derived from oxidative phosphorylation (OXPHOS) occurring in the mitochondria. Secondary mechanisms: (C) Excitotoxicity. This occurs mainly through the excessive release of glutamate and the influx of Ca²⁺ to cause calcium overload in neurons, leading to the production of ROS. (D) Iron metabolism. When the amount of iron exceeds the cell’s detoxification systems, the iron content increases, especially the ferrous (Fe²⁺) content, and will promote the conversion of H₂O₂ to IOH through the Fenton reaction leading to an amplification of oxidative stress. (E) Cytokines. Inflammatory cells can release harmful compounds or cytokines, exacerbating oxidative stress. (F) Pyroptosis. ROS generation triggers the NLRP3 inflammasome to induce cell pyrolysis. (G) Necroptosis. The accumulation of intracellular ROS can cause necroptosis. In turn, TNF-induced necroptosis could also lead to ROS generation. Abbreviations: TCA cycle: tricarboxylic acid cycle; NLRP3: NLR pyrin domain-containing 3; RIP3: receptor-interacting protein 3; MLKL: mixed lineage kinase domain-like pseudokinase.