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).


CONCLUSIONS
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.
Mack
William J
WJ
Department of Neurological Surgery, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA. wjm32@columbia.edu
Mocco
J
J
Ducruet
Andrew F
AF
Laufer
Ilya
I
King
Ryan G
RG
Zhang
Yuan
Y
Guo
Weijia
W
Pinsky
David J
DJ
Connolly
E Sander
ES
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001205:Ascorbic Acid / Q000378:metabolism*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D019343:Citric Acid / Q000737:chemistry / Q000494:pharmacology; D003683:Dehydroascorbic Acid / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005079:Excipients / Q000737:chemistry / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007275:Injections, Intravenous; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013012:Sorbitol / Q000737:chemistry / Q000494:pharmacology; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000975:Antioxidants; D005079:Excipients; D018696:Neuroprotective Agents; D019343:Citric Acid; D013012:Sorbitol; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid