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

摘要

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.