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  • Title: Involvement of oxidative stress in ascorbate-induced proapoptotic death of PC12 cells.
    Author: Song JH, Shin SH, Wang W, Ross GM.
    Journal: Exp Neurol; 2001 Jun; 169(2):425-37. PubMed ID: 11358456.
    Abstract:
    Ascorbate is a reducing agent, but it is also known to oxidize cellular components under specific conditions. The mechanism of this oxidative action, however, is not well established. Ascorbate treatment increased lipid peroxide content in PC12 cells, but did not increase quantities of lipid peroxide when homogenates of PC12 cells were treated with ascorbate, suggesting that cellular integrity is required for ascorbate to generate lipid peroxidation. However, dehydroascorbate increased lipid peroxide production in both intact PC12 cells and the cell homogenates. These differential effects of ascorbate and dehydroascorbate on intact cells versus homogenates suggest that the dehydroascorbate in cytosol induces an oxidative stress. Ascorbate in culture medium is rapidly oxidized to dehydroascorbate, which is transported into cells by a glucose transporter (GLUT). The GLUT antagonists wortmannin and cytochalasin B, or a high concentration of glucose, blocked (14)C uptake (from ascorbate) in a time-dependent manner and suppressed lipid peroxide production in PC12 cells. These observations support the concept that ascorbate is oxidized to dehydroascorbate, which is transported into cells via GLUT. The dehydroascorbate induces oxidative stress. The oxidative stress triggered apoptosis according to ceramide production, caspase-3 activation, and TUNEL. We have concluded that ascorbate is taken up after oxidation to dehydroascorbate via a "dehydroascorbate transporter" (GLUT), and the dehydroascorbate generates an oxidative stress which triggers apoptosis. These studies have significant implications for conditions under which a high concentration of ascorbate in a tissue is released during a period of hypoxia (e.g., stroke) and taken up during a reperfusion period as dehydroascorbate. Inhibiting uptake of dehydroascorbate may offer novel therapeutic strategies to alleviate brain damage during a reperfusion period.
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