Preclinical Evaluation of Postischemic Dehydroascorbic Acid Administration in a Large-Animal Stroke Model

Abstract

Dehydroascorbic acid (DHA), a blood-brain barrier transportable form of ascorbic acid, confers robust neuroprotection following murine stroke. In an effort to translate this promising neuroprotective strategy into human clinical trial, we evaluated postischemic DHA administration in a large-animal stroke model. Thirty-six adult male baboons were initially randomized to undergo transorbital craniectomy to induce transient cerebral artery occlusion and to receive postischemic dosing of either 500 mg/kg of DHA or vehicle. Primary outcomes included infarct volume, determined by magnetic resonance imaging, as well as neurological function evaluated on the day of sacrifice. The midpoint interim analysis (n = 9 per cohort) revealed that DHA administration did not significantly improve either infarct volume or neurological function. The study was terminated after a determination of statistical futility. We were unable to confirm a neuroprotective effect for postischemic DHA administration in our large-animal model using a dosing scheme that was previously successful in rodents. Further analysis of the efficacy of DHA administration must thus be undertaken prior to clinical translation.

Oxidative Stress in Ischemia/Reperfusion Injuries following Acute Ischemic Stroke

“…Observational studies in human patients showed that increases in plasma levels of vitamin C were correlated with reduced incidence of stroke [123]. In animal studies, although 4 weeks pre-treatment with vitamins C and E diminished the degree of lipid peroxidation and reduced infarct volume after middle cerebral artery occlusion [124], administering dehydroascorbic acid after arterial occlusion in baboons with transient cerebral artery occlusion was not able to significantly decrease lesion volume [125]. Similarly, human stroke trials with antioxidant vitamin supplements showed no benefits, neither in the acute setting [126] nor in prevention [127].…”

Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion

“…In contrast, high-dose vitamin E supplements have been suggested to increase all-cause mortality [124,125]. Administration of dehydroascorbic acid (DHA), a blood-brain barrier transportable form of vitamin C, and EPC-K1, a phosphate diester of vitamins C and E, ameliorated outcomes in a mouse MCAO model, while preclinical administration did not show a neuroprotective effect [126][127][128]. Apart from antioxidant vitamins, other studies based on free radical scavengers such as edaravone, N-acetylcysteine, and NXY-059 have revealed improved neurological outcomes in rodent and primate models, but the performance of exogenous antioxidants in recent clinical trials has been inconsistent [129][130][131][132].…”

Oxidative Stress and the Use of Antioxidants in Stroke

“…One form of vitamin C, ascorbic acid, was found to protect newborn rat brain from HI injury [ 173 ]. In a large animal stroke model, the administration of dehydroascorbic acid did not significantly decrease infarct volume or improve neurological outcome and the study was terminated early [ 174 ]. In a recent study however, it was found that 4 weeks of pre-treatment of stroke-prone spontaneously hypertensive rats with vitamins C and E lowered levels of lipid peroxidation and significantly lowered infarct volume following MCAO [ 175 ].…”