Abstract W P219: Delivery of an Oral Formulation of Angiotensin-(1-7) After Stroke is Neuroprotective
Background: The renin angiotensin system has become the focus of recent interest in stroke research as accumulating evidence indicates that activation of the angiotensin converting enzyme 2/angiotensin-(1-7)/mas (ACE2-Ang-(1-7)-Mas) axis exerts neuroprotective benefit in animal stroke models. Pre- and post-stroke activation of this axis by intracerebroventricular infusion of Ang-(1-7) reduces infarct size and improves neurological function in rats. The recent development of an orally active formulation of Ang-(1-7) in hydroxypropylβ-cyclodextrin [HPβCD/Ang-(1-7)] provides a non-invasive avenue for testing the efficacy of systemic post-stroke administration of Ang-(1-7). We tested the hypothesis that post-stroke oral gavage of HPβCD/Ang-(1-7) exerts neuroprotection in a rat model of ischemic stroke.
Methods: Male SD rats underwent ischemic stroke by endothelin-1-induced middle cerebral artery occlusion and were randomly divided into 2 groups of 12 each that received oral gavages of dH2O or HPβCD/Ang-(1-7) (50 ug/kg) at 4, 24, and 48h after stroke, as well as blinded neurological assessments at 4, 24, and 72h after stroke. Immediately after the 72h tests, animals were euthanized and cerebral infarct sizes were assessed by TTC staining. Data are expressed as mean ± SEM with significance inferred at p<0.05.
Results: Mean infarct sizes (%) were significantly decreased by post-stroke oral gavage of HPβCD/Ang-(1-7) (32.57±2.74) vs. dH2O (43.65±5.27, Fig 1). As compared to deficits at 4h post-stroke, 72h neurologic deficits (Bederson Scale) were significantly improved in HPβCD/Ang-(1-7)-treated rats (4h: 1.67±0.22; 72h: 0.83±0.21) and not in dH2O-treated rats (4h: 1.25±0.22; 72h: 1.17±0.24).
Conclusions: Our results suggest that activating the ACE2/Ang-(1-7)/Mas axis by post-stroke administration of an oral formulation of Ang-(1-7) is neuroprotective.
Author Disclosures: D.M. Bennion: None. E. Haltigan: None. A. Irwin: None. F.B. De Sousa: None. R.D. Sinisterra: None. R.A.S. Santos: None. C. Sumners: None.
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate – Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico, Tennessee, U.S. Virgin Islands.
- © 2014 by American Heart Association, Inc.