title: Effect of a Selective Mas Receptor Agonist in Cerebral Ischemia In Vitro and In Vivo.
abstract: Functional modulation of the non-AT1R arm of the renin-angiotensin system, such as via AT2R activation, is known to improve stroke outcome. However, the relevance of the Mas receptor, which along with the AT2R forms the protective arm of the renin-angiotensin system, as a target in stroke is unclear. Here we tested the efficacy of a selective MasR agonist, AVE0991, in in vitro and in vivo models of ischemic stroke. Primary cortical neurons were cultured from E15-17 mouse embryos for 7-9 d, subjected to glucose deprivation for 24 h alone or with test drugs, and percentage cell death was determined using trypan blue exclusion assay. Additionally, adult male mice were subjected to 1 h middle cerebral artery occlusion and were administered either vehicle or AVE0991 (20 mg/kg i.p.) at the commencement of 23 h reperfusion. Some animals were also treated with the MasR antagonist, A779 (80 mg/kg i.p.) 1 h prior to surgery. Twenty-four h after MCAo, neurological deficits, locomotor activity and motor coordination were assessed in vivo, and infarct and edema volumes estimated from brain sections. Following glucose deprivation, application of AVE0991 (10-8 M to 10-6 M) reduced neuronal cell death by ~60% (P<0.05), an effect prevented by the MasR antagonist. By contrast, AVE0991 administration in vivo had no effect on functional or histological outcomes at 24 h following stroke. These findings indicate that the classical MasR agonist, AVE0991, can directly protect neurons from injury following glucose-deprivation. However, this effect does not translate into an improved outcome in vivo when administered systemically following stroke.
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, 3800, Australia.|Cardiovascular Disease Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Seyoung
authors.initials: S
authors.lastname: Lee
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, 3800, Australia.|Cardiovascular Disease Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Evans
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, 3800, Australia.|Cardiovascular Disease Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Hannah X
authors.initials: HX
authors.lastname: Chu
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, 3800, Australia.|Cardiovascular Disease Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Kim
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, 3800, Australia.|Cardiovascular Disease Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Widdop
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, 3800, Australia.|Cardiovascular Disease Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.|Department of Surgery, Southern Clinical School, Monash University, Clayton, Victoria, Australia.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, 3800, Australia.|Cardiovascular Disease Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.|Department of Surgery, Southern Clinical School, Monash University, Clayton, Victoria, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005947:Glucose / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000819:agonists*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D012084:Renin-Angiotensin System / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D005947:Glucose