title: The angiotensin type 2 receptor agonist Compound 21 elicits cerebroprotection in endothelin-1 induced ischemic stroke.
abstract: Evidence indicates that angiotensin II type 2 receptors (AT2R) exert cerebroprotective actions during stroke. A selective non-peptide AT2R agonist, Compound 21 (C21), has been shown to exert beneficial effects in models of cardiac and renal disease, as well as hemorrhagic stroke. Here, we hypothesize that C21 may exert beneficial effects against cerebral damage and neurological deficits produced by ischemic stroke. We determined the effects of central and peripheral administration of C21 on the cerebral damage and neurological deficits in rats elicited by endothelin-1 induced middle cerebral artery occlusion (MCAO), a model of cerebral ischemia. Rats infused centrally (intracerebroventricular) with C21 before endothelin-1 induced MCAO exhibited significant reductions in cerebral infarct size and the neurological deficits produced by cerebral ischemia. Similar cerebroprotection was obtained in rats injected systemically (intraperitoneal) with C21 either before or after endothelin-1 induced MCAO. The protective effects of C21 were reversed by central administration of an AT2R inhibitor, PD123319. While C21 did not alter cerebral blood flow at the doses used here, peripheral post-stroke administration of this agent significantly attenuated the MCAO-induced increases in inducible nitric oxide synthase, chemokine (C-C) motif ligand 2 and C-C chemokine receptor type 2 mRNAs in the cerebral cortex, indicating that the cerebroprotective action is associated with an anti-inflammatory effect. These results strengthen the view that AT2R agonists may have potential therapeutic value in ischemic stroke, and provide the first evidence of cerebroprotection induced by systemic post stroke administration of a selective AT2R agonist.
authors: Department of Physiology and Functional Genomics & McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors: Jason P
authors: JP
authors: Joseph
authors: Department of Physiology and Functional Genomics & McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors: Adam P
authors: AP
authors: Mecca
authors: Department of Physiology and Functional Genomics & McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors: Robert W
authors: RW
authors: Regenhardt
authors: Department of Physiology and Functional Genomics & McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors: Douglas M
authors: DM
authors: Bennion
authors: Department of Physiology and Functional Genomics & McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors: Vermali
authors: V
authors: Rodríguez
authors: Department of Physiology and Functional Genomics & McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors: Fiona
authors: F
authors: Desland
authors: Department of Physiology and Functional Genomics & McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors: Neal A
authors: NA
authors: Patel
authors: Department of Physiology and Functional Genomics & McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors: David J
authors: DJ
authors: Pioquinto
authors: School for Cardiovascular Diseases, Maastricht University, Netherlands.
authors: Thomas
authors: T
authors: Unger
authors: Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA.
authors: Michael J
authors: MJ
authors: Katovich
authors: Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark.
authors: U Muscha
authors: UM
authors: Steckelings
authors: Department of Physiology and Functional Genomics & McKnight Brain Institute, University of Florida, Gainesville, FL, USA. Electronic address: csumners@ufl.edu.
authors: Colin
authors: C
authors: Sumners
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D002545:Brain Ischemia / Q000139:chemically induced* / Q000150:complications*; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000633:toxicity*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D039481:CD11b Antigen; D016207:Cytokines; D019332:Endothelin-1; D005904:Glial Fibrillary Acidic Protein; D007093:Imidazoles; C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D011725:Pyridines; D013449:Sulfonamides; D013876:Thiophenes; C073402:PD 123319; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II
keywords: Angiotensin type 2 receptor; Chemokine; Compound 21; Endothelin-1; Ischemia; Stroke