Although treatment of ischemic stroke focuses on re-establishing blood flow to the brain (e.g., thrombolysis), delayed reperfusion may be associated with oxidative damage to brain capillary endothelial cells, resulting in cerebral bleeding and death (hemorrhagic transformation). The goal of this study was to define cellular mechanisms responsible for reperfusion injury to brain capillaries, and to provide a rationale for more effective treatment of stroke. Mechanisms of oxidative injury to cerebral capillary endothelial cells were measured in the presence and absence of experimental inhibitors to define the roles of transport and metabolic pathways. In vitro experiments provided evidence that: (1) intracellular calcium is elevated in brain capillary endothelial cells following simulated transient ischemia and reperfusion, due to reverse movement of Na/Ca exchange; (2) a simultaneous increase of calcium and reactive oxygen species (ROS) during re-oxygenation causes mitochondrial dysfunction, thus initiating apoptosis and loss of brain capillary integrity. In vivo studies showed that γ-glutamylcysteine (an antioxidant precursor of glutathione) and the experimental compound KB-R7943 (inhibits reverse movement of Na/Ca exchange) protect brain capillary endothelial cells when co-administered just before reperfusion following transient ischemia. The data indicate that these agents may be useful in preventing oxidative injury associated with thrombolysis for ischemic stroke.
Part of the book: Antioxidants