DEHYDROASCORBIC ACID AS THERAPY FOR ISCHEMIC STROKE

DESCRIPTION(adapted from applicant's abstract): A major goal of stroke research is the development of new treatment modalities to limit the extent of brain injury following acute ischemic injury. Ischemic stroke is associated with a rapid increase in free radical content in the brain and a depletion of natural antioxidants such as ascorbic acid. Delivery of ascorbic acid to the site of ischemic injury is limited by its inability to cross the blood-brain barrier. Dehydroascorbic acid, the oxidized form of ascorbic acid, readily crosses the blood-brain barrier via a facilitative transport mechanism and is converted into ascorbic acid after entering the brain. Dehydroascorbic acid has shown preliminary evidence of efficacy in a murine stroke model. This compound thus has significant potential as a therapeutic agent for stroke. The first aim of this Phase I project is to prepare an adequate supply of pure dehydroascorbic acid for testing. As large quantities of pure compound are not presently available, a new preparative, large-scale route will be developed. New analytical methods will be developed for determining the compound's identity and purity and for quantitating levels of unwanted impurities. The second aim is to formulate a convenient and stable solution for injection. This is feasible provided the buffer components are tightly optimized and the stability is confirmed by analytical testing. The final aim is to demonstrate in a small animal model that ehydroascorbic acid decreases neuronal injury after an occlusive infarct. This will be done in the mouse middle cerebral artery occlusion model. Dehydroascorbic acid will be administered intravenously at various doses and intervals following the onset of ischemia, and its effects on infarct volume, neurological function, cerebral blood flow, and mortality will be determined. A significant beneficial effect in this model in comparison with either vehicle or ascorbic acid controls will provide in vivo proof-of concept of the approach and will confine the value of additional studies of dehydroascorbic acid as a therapeutic agent in ischemic stroke. PROPOSED COMMERCIAL APPLICATIONS: Dehydroascorbic acid is a novel treatment for patients who have suffered an ischemic stroke. Dehydroascorbic acid has a unique ability to enter the brain and to elevate tissue levels of ascorbic acid, a natural antioxidant. This project seeks to demonstrate that dehydroascorbic acid is efficacious in a murine stroke model in the interval of time immediately following an ischemic event, a critical period for patients with ischemic stroke. These studies will support eventual clinical testing of the compound.