Prevention of Oxidative Injury Associated with Thrombolysis for Ischemic Stroke

Abstract

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.

Editorial: Organization and Functional Properties of the Blood-Brain Barrier

“…There is now evidence that dysfunction of the blood-brain barrier accompanies several diseases involving the central nervous system (Sweeney et al, 2019 ). For instance, blood-brain barrier dysfunction has been associated with Alzheimer's disease, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, Parkinson's disease, stroke, and traumatic brain injury (Papadopoulos et al, 2001 ; Lo et al, 2003 ; Marroni et al, 2003 ; Minagar and Alexander, 2003 ; Lee and Bendayan, 2004 ; Kortekaas et al, 2005 ; Peterson and Sukowski, 2019 ). Alterations of the barrier include changes in its permeability, transport properties, and regulatory mechanisms.…”