Neuroprotection by post-stroke administration of an oral formulation of angiotensin-(1–7) in ischaemic stroke

Abstract

New Findings: What is the central question of this study? Angiotensin-(1–7) decreases cerebral infarct volume and improves neurological function when delivered centrally before and during ischaemic stroke. Here, we assessed the neuroprotective effects of angiotensin-(1–7) when delivered orally post-stroke. What is the main finding and its importance? We show that oral delivery of angiotensin-(1–7) attenuates cerebral damage induced by middle cerebral artery occlusion in rats, without affecting blood pressure or cerebral blood flow. Importantly, these treatments begin post-stroke at times coincident with the treatment window for tissue plasminogen activator, providing supporting evidence for clinical translation of this new therapeutic strategy. Abstract: As a target for stroke therapies, the angiotensin-converting enzyme 2–angiotensin-(1–7)–Mas [ACE2/Ang-(1–7)/Mas] axis of the renin–angiotensin system can be activated chronically to induce neuroprotective effects, in opposition to the deleterious effects of angiotensin II via its type 1 receptor. However, more clinically relevant treatment protocols with Ang-(1–7) that involve its systemic administration beginning after the onset of ischaemia have not been tested. In this study, we tested systemic post-stroke treatments using a molecule where Ang-(1–7) is included within hydroxypropyl-β-cyclodextrin [HPβCD–Ang-(1–7)] as an orally bioavailable treatment. In three separate protocols, HPβCD–Ang-(1–7) was administered orally to Sprague–Dawley rats after induction of ischaemic stroke by endothelin-1-induced middle cerebral artery occlusion: (i) to assess its effects on cerebral damage and behavioural deficits; (ii) to determine its effects on cardiovascular parameters; and (iii) to determine whether it altered cerebral blood flow. The results indicate that post-stroke oral administration of HPβCD–Ang-(1–7) resulted in 25% reductions in cerebral infarct volumes and improvement in neurological functions (P < 0.05), without inducing any alterations in blood pressure, heart rate or cerebral blood flow. In conclusion, Ang-(1–7) treatment using an oral formulation after the onset of ischaemia induces significant neuroprotection in stroke and might represent a viable approach for taking advantage of the protective ACE2/Ang-(1–7)/Mas axis in this disease.