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Clin Sci (Lond). 2018 Mar 15;132(5):581-593. doi: 10.1042/CS20180100. Print 2018 Mar 15.

Protective effects of the angiotensin II AT2 receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach.

Author information

1
Department of Physiology and Functional Genomics and McKnight Brain Institute, University of Florida, Gainesville, FL, U.S.A.
2
RISE Research Institutes of Sweden AB, Department of Certification, Boras, Sweden.
3
Attoquant Diagnostics GmbH, Vienna, Austria.
4
Barrow Neurological Institute, Department of Neurology, Phoenix, AZ, U.S.A.
5
Department of Physiology and Functional Genomics and McKnight Brain Institute, University of Florida, Gainesville, FL, U.S.A. csumners@ufl.edu usteckelings@health.sdu.dk.
6
IMM - Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark csumners@ufl.edu usteckelings@health.sdu.dk.

Abstract

Significant neuroprotective effects of angiotensin II type 2 (AT2) receptor (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 (ICV) and systemic administration, are unsuitable for translation into 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 BBB and deliver the selective AT2 receptor agonist Compound 21 (C21) to naïve rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke. The results obtained from the present study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 min in amounts that are therapeutically relevant (8.4-9 nM), regardless of whether BBB was intact or disintegrated. C21 was first applied N2B at 1.5 h 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 other agents has been shown to be effective in certain human central nervous system diseases, the N2B application of AT2 receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients.

KEYWORDS:

AT2 receptor; Angiotensin; Ischemic Stroke

PMID:
29500223
DOI:
10.1042/CS20180100

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