Oxygen radicals in cerebral ischemia - The 2001 Willis Lecture

The sequential univalent reduction of oxygen generates superoxide, hydrogen peroxide, and hydroxyl radical. The generation of hydroxyl radical is depe ndent on catalysis by ferrous iron. In addition, superoxide and nitric oxid e produce peroxynitrite, which spontaneously generates hydroxyl radical ind ependently of iron-mediated catalysis. These agents have a variety of cellu lar actions, which render them suitable candidates as mediators of tissue d estruction and cellular death. In the intact brain, superoxide and its deri vatives cause vasodilation, mediated by opening of potassium channels, alte red vascular reactivity, breakdown of the blood-brain barrier, and focal de structive endothelial lesions. These abnormalities are also seen in early r eperfusion following brain ischemia. During reperfusion there is a marked t ransient increase in superoxide production. Vasodilation, abnormal vascular reactivity, and blood-brain barrier breakdown are inhibited by eliminating superoxide. Superoxide production during reperfusion may be initiated by g lutamate via activation of alpha -amino-3-hydroxy-5-methylisoxasolepropioni c acid (AMPA) receptors. These experimental findings have important implica tions for human cerebral ischemia. Agents directed at eliminating oxygen ra dicals must be administered before or in the early stages of reperfusion fo llowing ischemia. The therapeutic window appears to be narrow and limited t o, at most, a few hours. The inhibition of AMPA receptors may be a promisin g approach to inhibit the production of oxygen radicals during ischemia-rep erfusion of the brain.