A cerebroprotective dose of intravenous citrate/sorbitol-stabilized dehydroascorbic acid is correlated with increased cerebral ascorbic acid and inhibited lipid peroxidation after murine reperfused stroke
OBJECTIVE: Oxidative damage has been implicated in the pathogenesis of cerebral ischemia. We previously demonstrated that exogenously supplied dehydroascorbic acid (DHA), an oxidized, blood-brain barrier transportable form of the antioxidant ascorbic acid (AA), improves outcome after experimental stroke. METHODS: To investigate the neuroprotective effect of DHA therapy, we measured cerebral AA levels using a novel assay, quantified markers of lipid peroxidation, and evaluated infarct volume after reperfused stroke in a murine model. All experiments were performed using a new citrate/sorbitol-stabilized DHA formulation to improve the stability of the compound. RESULTS: Intraparenchymal AA levels declined after cerebral ischemia/reperfusion and were repleted in a dose-dependent fashion by postischemic administration of intravenous DHA (P < 0.01). Repletion of these levels was associated with reductions in cerebral malondialdehyde levels (P < 0.05), which were also elevated after reperfused stroke. DHA repletion of interstitial AA levels and reduction in cerebral lipid peroxidation was associated with dose-dependent reductions in infarct volume (P < 0.05). CONCLUSION: Together, these results indicate that an intravenous cerebroprotective dose of citrate/sorbitol-stabilized DHA is correlated with increased brain ascorbate levels and a suppression of excessive oxidative metabolism.
Medical Subject Headings
Animals; Antioxidants (pharmacology, therapeutic use); Ascorbic Acid (metabolism); Brain Ischemia (drug therapy, metabolism, physiopathology); Cerebral Cortex (drug effects, metabolism, physiopathology); Cerebral Infarction (drug therapy, physiopathology, prevention & control); Citric Acid (chemistry, pharmacology); Dehydroascorbic Acid (chemistry, pharmacology, therapeutic use); Disease Models, Animal; Excipients (chemistry, pharmacology); Infarction, Middle Cerebral Artery (drug therapy, metabolism, physiopathology); Injections, Intravenous; Lipid Peroxidation (drug effects, physiology); Mice; Mice, Inbred C57BL; Nerve Degeneration (drug therapy, physiopathology, prevention & control); Neuroprotective Agents (pharmacology, therapeutic use); Oxidative Stress (drug effects, physiology); Reperfusion Injury (drug therapy, metabolism, physiopathology); Sorbitol (chemistry, pharmacology); Treatment Outcome; Up-Regulation (drug effects, physiology)
8; discussion 383
Digital Object Identifier (DOI)
Mack, William J.; Mocco, J; Ducruet, Andrew F.; Laufer, Ilya; King, Ryan G.; Zhang, Yuan; Guo, Weijia; Pinsky, David J.; and Connolly, E Sander, "A cerebroprotective dose of intravenous citrate/sorbitol-stabilized dehydroascorbic acid is correlated with increased cerebral ascorbic acid and inhibited lipid peroxidation after murine reperfused stroke" (2006). Translational Neuroscience. 2049.