Neuroprotectants: Reactive Oxygen Species (ROS) Based

Reactive oxygen species (ROS)-induced membrane lipid peroxidation (LP) is clearly one of the best validated secondary injury mechanisms in preclinical focal ischemic stroke and subarachnoid hemorrhage (SAH) models. Two main sources of LP-initiating free radicals are ferrous iron (Fe²⁺)-driven Fenton reactions, which give rise to the highly reactive hydroxyl radical (OH), and the reactive nitrogen species peroxynitrite (ONOO^-), which can similarly generate OH and the equally reactive nitrogen dioxide (NO₂) and carbonate (CO₃) radicals. After initiation of LP by these potent ROS, the process propagates through the membrane disrupting phospholipid structure and impairing the function of membrane-localized proteins. In addition, peroxidation of the LP-susceptible polyunsaturated fatty acids results in the formation of neurotoxic aldehyde-containing products, such as 4-hydroxynonenal (4-HNE) and 2-propenal (acrolein) that bind to cellular proteins, impairing their normal functions and leading to generation of additional ROS. This chapter summarizes the progress over the years with regard to the preclinical discovery and attempted clinical development of antioxidant drugs for focal ischemic stroke and SAH, as well as newer ROS-based pharmacologic strategies.