Preclinical Evaluation of Postischemic Dehydroascorbic Acid Administration in a Large-Animal Stroke Model
- PDF / 153,217 Bytes
- 5 Pages / 595.276 x 790.866 pts Page_size
- 75 Downloads / 173 Views
ORIGINAL ARTICLE
Preclinical Evaluation of Postischemic Dehydroascorbic Acid Administration in a Large-Animal Stroke Model Andrew F. Ducruet & William J. Mack & J. Mocco & Daniel J. Hoh & Alexander L. Coon & Anthony L. D’Ambrosio & Christopher J. Winfree & David J. Pinsky & E. Sander Connolly Jr.
Received: 13 January 2011 / Revised: 1 April 2011 / Accepted: 26 April 2011 / Published online: 17 May 2011 # Springer Science+Business Media, LLC 2011
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. Keywords Antioxidants . Brain ischemia . Animal models . Neuroprotection . Acute stroke A. F. Ducruet : W. J. Mack : J. Mocco : D. J. Hoh : A. L. Coon : A. L. D’Ambrosio : C. J. Winfree : D. J. Pinsky : E. S. Connolly Jr. Department of Neurological Surgery, Columbia University, New York, NY, USA E. S. Connolly Jr. (*) Department of Neurological Surgery, Neurological Institute of New York, 710 West 168th Street, New York, NY 10032, USA e-mail: [email protected]
Introduction The occlusion and subsequent reperfusion of a cerebral blood vessel induces a myriad of deleterious molecular cascades that culminate in cerebral injury [1, 2]. A critical component of this cerebral “reperfusion injury” is the accumulation of toxic by-products of oxidative stress [3]. These reactive oxygen species are not only directly toxic to neurons and glias, but may also exacerbate leukocyte infiltration, microvascular thrombosis, and nitric oxidemediated injury [4]. Prior investigations have established the neuroprotective efficacy of a variety of antioxidant strategies following experimental stroke [5]. Despite this initial promise, however, subsequent clinical trials evaluating antioxidants in stroke have been disappointing [6]. Among the numerous explanations proposed for these translational failures, the limited permeability of antioxidant compounds at the blood–brain barrier has been cited as a primary concern.
Data Loading...
