Oxidative stress induced by ascorbate causes neuronal damage in an in vitro system

Of particular physiological interest, ascorbate, the ionized form of ascorb ic acid, possesses strong reducing properties. However, it has been shown t o induce oxidative stress and lead to apoptosis under certain experimental conditions. Ascorbate in the brain is released during hypoxia, including st roke, and is subsequently oxidized in plasma. The oxidized product (dehydro ascorbate) is transported into neurons via a glucose transporter (GLUT) dur ing a reperfusion period. The dehydroascorbate taken up by cells is reduced to ascorbate by both enzymatic and non-enzymatic processes, and the ascorb ate is stored in cells. This reduction process causes an oxidative stress, due to coupling of redox reactions, which can induce cellular damage and tr igger apoptosis. Ascorbate treatment decreased cellular glutathione (GSH) c ontent, and increased the rates of lipid peroxide production in rat cortica l slices. Wortmannin. a specific inhibitor of phosphatidylinositol (PI)-3-k inase (a key enzyme in GLUT translocation). prevented the ascorbate induced -decrease of GSH content, and suppressed ascorbate-induced lipid peroxide p roduction. However. wortmannin was ineffective in reducing hydrogen peroxid e (H2O2)-induced oxidative stress. The oxidative stress caused ceramide acc umulation. which was proportionally changed with lipid peroxides when the c ortical slices were treated with ascorbate. These differential effects supp ort the hypothesis that GLUT efficiently transports the dehydroascorbate in to neurons, causing oxidative stress. Crown Copyright (C) 2001 Published by Elsevier Science B.V. All rights reserved.