Neuroprotective effect of an angiotensin receptor type 2 agonist following cerebral ischemia in vitro and in vivo
- Seyoung LeeAffiliated withDepartment of Pharmacology, Monash University
- , Vanessa H BraitAffiliated withDepartment of Pharmacology, Monash University
- , Thiruma V ArumugamAffiliated withSchool of Biomedical Sciences, The University of Queensland
- , Megan A EvansAffiliated withDepartment of Pharmacology, Monash University
- , Hyun Ah KimAffiliated withDepartment of Pharmacology, Monash University
- , Robert E WiddopAffiliated withDepartment of Pharmacology, Monash University
- , Grant R DrummondAffiliated withDepartment of Pharmacology, Monash University
- , Christopher G SobeyAffiliated withDepartment of Pharmacology, Monash University Email author
- , Emma S JonesAffiliated withDepartment of Pharmacology, Monash University
Intracerebral administration of the angiotensin II type 2 receptor (AT2R) agonist, CGP42112, is neuroprotective in a rat model of ischemic stroke. To explore further its possible cellular target(s) and therapeutic utility, we firstly examined whether CGP42112 may exert direct protective effects on primary neurons following glucose deprivation in vitro. Secondly, we tested whether CGP42112 is effective when administered systemically in a mouse model of cerebral ischemia.
Primary cortical neurons were cultured from E17 C57Bl6 mouse embryos for 9 d, exposed to glucose deprivation for 24 h alone or with drug treatments, and percent cell survival assessed using trypan blue exclusion. Ischemic stroke was induced in adult male C57Bl6 mice by middle cerebral artery occlusion for 30 min, followed by reperfusion for 23.5 h. Neurological assessment was performed and then mice were euthanized and infarct and edema volume were analysed.
During glucose deprivation, CGP42112 (1x10-8 M and 1x10-7 M) reduced cell death by ~30%, an effect that was prevented by the AT2R antagonist, PD123319 (1x10-6 M). Neuroprotection by CGP42112 was lost at a higher concentration (1x10-6 M) but was unmasked by co-application with the AT1R antagonist, candesartan (1x10-7 M). By contrast, Compound 21 (1x10-8 M to 1x10-6 M), a second AT2R agonist, had no effect on neuronal survival. Mice treated with CGP42112 (1 mg/kg i.p.) after cerebral ischemia had improved functional outcomes over vehicle-treated mice as well as reduced total and cortical infarct volumes.
These results indicate that CGP42112 can directly protect neurons from ischemia-like injury in vitro via activation of AT2Rs, an effect opposed by AT1R activation at high concentrations. Furthermore, systemic administration of CGP42112 can reduce functional deficits and infarct volume following cerebral ischemia in vivo.
KeywordsApoptosis AT2 receptor Cerebral ischemia Glucose deprivation Mouse Neuronal death Neuroprotection Stroke
- Neuroprotective effect of an angiotensin receptor type 2 agonist following cerebral ischemia in vitro and in vivo
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Experimental & Translational Stroke Medicine
- Online Date
- August 2012
- Online ISSN
- BioMed Central
- Additional Links
- AT2 receptor
- Cerebral ischemia
- Glucose deprivation
- Neuronal death
- Author Affiliations
- 1. Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia
- 2. School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia