Reperfusion damage following focal ischemia: pathophysiology and therapeutic windows.

Abstract

The mechanisms of reperfusion damage following focal cerebral ischemia are not known in detail. Recent results, however, strongly suggest that reactive oxygen species (ROS), generated during the reperfusion period, may trigger the reperfusion injury. Mitochondrial calcium overload and a permeability transition (PT) of the inner mitochondrial membrane have been shown to play an important role in production of ROS by the mitochondria. The immunosuppressant cyclosporin A (CsA), which inhibits mitochondrial PT, protects against delayed neuronal necrosis of the hippocampal CA1 sector following transient forebrain/global ischemia. In focal ischemia ("stroke"), expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) may lead to production of ROS by polymorphonuclear (PMN) leukocytes, which suggests the involvement of inflammatory and immunological reactions in reperfusion damage. The spin trap alpha-phenyl-N-tert-butyl nitrone (PBN) reduces infarct size and prevents a secondary mitochondrial dysfunction due to reperfusion, probably scavenging free radicals at the blood-endothelial cell interface.