Protective Effects of the Angiotensin II AT2 Receptor Agonist Compound 21 in Ischemic Stroke: A Nose-to-Brain Delivery Approach

Significant neuroprotective effects of angiotensin II type 2 (AT2) receptor agonists in ischemic stroke have been previously demonstrated in multiple studies.  However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular and systemic administration, are unsuitable for translation to humans; in the latter case because AT2 receptor agonists are blood brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the blood brain barrier and deliver the selective AT2 receptor agonist Compound 21 (C21) to naïve rats or rats that had undergone endothelin 1-induced ischemic stroke.  The results obtained from this study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 mins in amounts that are therapeutically relevant (8.4 - 9nM), regardless of whether the BBB was intact or disintegrated. C21 first applied N2B at 1.5 hours after stroke indeed provided neuroprotection, as evidenced by a highly significant, 57% reduction in cerebral infarct size and significant improvements in Bederson and Garcia neurological scores.  N2B-administered C21 did not affect blood pressure or heart rate.  Thus, these data provide proof-of-principle for the idea that N2B application of an AT2 receptor agonist can exert neuroprotective actions when administered following ischemic stroke.  Since N2B delivery of ot...
Source: Clinical Science - Category: Biomedical Science Authors: Tags: PublishAheadOfPrint Source Type: research