Journal article
Protective effects of the angiotensin II AT(2) receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach
Clinical science (1979), Vol.132(5), pp.581-593
03/15/2018
DOI: 10.1042/CS20180100
PMID: 29500223
Abstract
Significant neuroprotective effects of angiotensin II type 2 (AT(2)) receptor (AT(2) 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 AT(2) 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 AT(2) receptor agonist Compound 21 (C21) to naive 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 AT(2) 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 AT(2) receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients.
Details
- Title: Subtitle
- Protective effects of the angiotensin II AT(2) receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach
- Creators
- Douglas M. Bennion - University of FloridaChad H. Jones - University of FloridaAlex N. Dang - University of FloridaJacob Isenberg - University of FloridaJustin T. Graham - University of FloridaLena Lindblad - RISE Research Institutes of SwedenOliver Domenig - Attoquant Diagnost GmbH, Vienna, AustriaMichael F. Waters - Barrow Neurological InstituteMarko Poglitsch - Attoquant Diagnost GmbH, Vienna, AustriaColin Sumners - University of FloridaUlrike Muscha Steckelings - University of Southern Denmark
- Resource Type
- Journal article
- Publication Details
- Clinical science (1979), Vol.132(5), pp.581-593
- DOI
- 10.1042/CS20180100
- PMID
- 29500223
- NLM abbreviation
- Clin Sci (Lond)
- ISSN
- 0143-5221
- eISSN
- 1470-8736
- Publisher
- Portland Press Ltd
- Number of pages
- 13
- Grant note
- McKnight Brain Institute at the University of Florida Vicore Pharma; Dexcel Pharma T32HL083810 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) 2T32HL083810 / National Heart Lung and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Language
- English
- Date published
- 03/15/2018
- Academic Unit
- Otolaryngology
- Record Identifier
- 9984962627502771
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