Abstract 12601: Oral Xe-Cyclodextrin Provides Neuroprotection for Ischemic Stroke Treatment

Abstract

Introduction: Ischemic stroke is one of the main causes of long-term morbidity/mortality and early treatment is key. Xenon (Xe) has demonstrated powerful neuroprotective effects on both ischemic and hemorrhagic stroke, but its clinical and long-term outpatient administration is limited by currently available delivery methods. Development of an oral Xe formulation is an attractive strategy for stroke treatment in the field. We developed a Xenon (Xe)-cyclodextrin (CD) oral formulation. Hypothesis: Xe-CD formulation can be delivered orally for acute stroke treatment. Methods: A stable, oral Xe-CD clathrate (Xe solid gas) was formed by pressurizing Xe (3 atm) into 14% alpha-cyclodextrin at room temperature. Xe concentration was measured by GC-MS. Rat middle cerebral artery occlusion (MCAO) was induced by intraluminar suture. The animals were divided into groups: stroke (n=4); stroke with CD (n=3); stroke with 0.5 ml Xe-CD (n=3); stroke with 1.0 ml Xe-CD (n=3); and stroke with 1.5 ml Xe-CD (n=3). Treatments were administered by gavage once a day for 3 days. At day 3, neurological behavior testing was conducted. The infarct size and neuronal death were assessed and normalized by total brain volume. Results: There are 1.56 mM Xe clathrate per 0.6 mM alpha-cyclodextrin. MCAO for 2 hours induced 21% ± 3.6% infarct volume. Xe-CD treatment dose-dependently reduced the infarct size to 18.9% ± 2.3% by 0.5 ml Xe-CD, 6.7% ± 1.8% by 1.0 ml Xe-CD, and 4.8% ± 1.2% by 1.5 ml Xe-CD (Fig. 1A). Behavioral test assessment using forelimb placement rate and Rotarod score matched infarct size. TUNEL staining demonstrated significant decreases in apoptosis in stroke rats treated with 1.5 ml Xe-CD (Fig. 1B). Conclusions: We have demonstrated oral Xe-CD formulation ameliorates neuronal apoptosis and reduces infarct size. Xe-CD represents a promising therapeutic for ischemic stroke treatment.