Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke Journal Article
| Authors: | Huang, J.; Agus, D. B.; Winfree, C. J.; Kiss, S.; Mack, W. J.; McTaggart, R. A.; Choudhri, T. F.; Kim, L. J.; Mocco, J.; Pinsky, D. J.; Fox, W. D.; Israel, R. J.; Boyd, T. A.; Golde, D. W.; Connolly, E. S. Jr |
| Article Title: | Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke |
| Abstract: | Neuronal injury in ischemic stroke is partly mediated by cytotoxic reactive oxygen species. Although the antioxidant ascorbic acid (AA) or vitamin C does not penetrate the blood-brain barrier (BBB), its oxidized form, dehydroascorbic acid (DHA), enters the brain by means of facilitative transport. We hypothesized that i.v. DHA would improve outcome after stroke because of its ability to cross the BBB and augment brain antioxidant levels. Reversible or permanent focal cerebral ischemia was created by intraluminal middle cerebral artery occlusion in mice treated with vehicle, AA, or DHA (40, 250, or 500 mg/kg), either before or after ischemia. Given before ischemia, DHA caused dose-dependent increases in postreperfusion cerebral blood flow, with reductions in neurological deficit and mortality. In reperfused cerebral ischemia, mean infarct volume was reduced from 53% and 59% in vehicle- and AA-treated animals, respectively, to 15% in 250 mg/kg DHA-treated animals (P < 0.05). Similar significant reductions occurred in nonreperfused cerebral ischemia. Delayed postischemic DHA administration after 15 min or 3 h also mediated improved outcomes. DHA (250 mg/kg or 500 mg/kg) administered at 3 h postischemia reduced infarct volume by 6- to 9-fold, to only 5% with the highest DHA dose (P < 0.05). In contrast, AA had no effect on infarct volumes, mortality, or neurological deficits. No differences in the incidence of intracerebral hemorrhage occurred. Unlike exogenous AA, DHA confers in vivo, dose-dependent neuroprotection in reperfused and nonreperfused cerebral ischemia at clinically relevant times. As a naturally occurring interconvertible form of AA with BBB permeability, DHA represents a promising pharmacological therapy for stroke based on its effects in this model of cerebral ischemia. |
| Keywords: | controlled study; treatment outcome; dose response; nonhuman; mouse; animals; mice; animal model; dose-response relationship, drug; time factors; brain; cerebrovascular disease; stroke; blood brain barrier; antioxidants; ascorbic acid; antioxidant activity; brain ischemia; brain blood flow; cerebrovascular circulation; sucrose; dehydroascorbic acid; biological transport; cerebrovascular accident; neuroprotective agents; tritium; experimental model; carbon 14; reperfusion; priority journal; article; brain protection; middle cerebral artery occlusion; middle cerebral artery |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 98 |
| Issue: | 20 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2001-09-25 |
| Start Page: | 11720 |
| End Page: | 11724 |
| Language: | English |
| DOI: | 10.1073/pnas.171325998 |
| PUBMED: | 11573006 |
| PROVIDER: | scopus |
| PMCID: | PMC58796 |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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