Stroke is a devastating disease that afflicts millions of people each year worldwide. Ischemic stroke, which accounts for ~88% of cases, occurs when blood supply to the brain is decreased, often because of thromboembolism or atherosclerotic occlusion. This deprives the brain of oxygen and nutrients, causing immediate, irreversible necrosis within the core of the ischemic area, but more delayed and potentially reversible neuronal damage in the surrounding brain tissue, the penumbra. The only currently approved therapies for ischemic stroke, the thrombolytic agent recombinant tissue plasminogen activator (rtPA) and the endovascular clot retrieval/destruction processes, are aimed at restoring blood flow to the infarcted area, but are only available for a minority of patients and are not able in most cases to completely restore neurological deficits. Consequently, there remains a need for agents that will protect neurones against death following ischemic stroke. Here, we evaluate angiotensin II (Ang II) type 2 (AT2) receptor agonists as a possible therapeutic target for this disease. We first provide an overview of stroke epidemiology, pathophysiology, and currently approved therapies. We next review the large amount of preclinical evidence, accumulated over the past decade and a half, which indicates that AT2 receptor agonists exert significant neuroprotective effects in various animal models, and discuss the potential mechanisms involved. Finally, after discussing the challenges of delivering blood–brain barrier (BBB) impermeable AT2 receptor agonists to the infarcted areas of the brain, we summarize the evidence for and against the development of these agents as a promising therapeutic strategy for ischemic stroke.
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May 2018
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Depiction of a macrophage. In issue 9 of Clinical science, Liu et al. discuss the role of miRNAs in alveolar macrophage activation; for details see pages 943–958.
Review Article|
May 25 2018
Neuroprotection via AT2 receptor agonists in ischemic stroke
Douglas M. Bennion;
Douglas M. Bennion
1Department of Physiology and Functional Genomics, McKnight Brain Institute, University of Florida, Gainesville, FL, U.S.A.
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U. Muscha Steckelings;
U. Muscha Steckelings
2IMM – Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
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Colin Sumners
1Department of Physiology and Functional Genomics, McKnight Brain Institute, University of Florida, Gainesville, FL, U.S.A.
Correspondence: Colin Sumners ([email protected])
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Publisher: Portland Press Ltd
Received:
March 26 2018
Revision Received:
April 30 2018
Accepted:
May 01 2018
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Clin Sci (Lond) (2018) 132 (10): 1055–1067.
Article history
Received:
March 26 2018
Revision Received:
April 30 2018
Accepted:
May 01 2018
Citation
Douglas M. Bennion, U. Muscha Steckelings, Colin Sumners; Neuroprotection via AT2 receptor agonists in ischemic stroke. Clin Sci (Lond) 31 May 2018; 132 (10): 1055–1067. doi: https://doi.org/10.1042/CS20171549
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