Abdelrahman Y Fouda1, Bindu Pillai1, Krishnan M Dhandapani2, Adviye Ergul3, Susan C Fagan4. 1. Charlie Norwood VA Medical Center, Center for Pharmacy and Experimental Therapeutics, University of Georgia, College of Pharmacy, Augusta, GA, USA. 2. Department of Neurosurgery, Augusta University, Augusta, GA, USA. 3. Charlie Norwood VA Medical Center, Center for Pharmacy and Experimental Therapeutics, University of Georgia, College of Pharmacy, Augusta, GA, USA; Department of Physiology, Augusta University, Augusta, GA, USA. 4. Charlie Norwood VA Medical Center, Center for Pharmacy and Experimental Therapeutics, University of Georgia, College of Pharmacy, Augusta, GA, USA. Electronic address: sfagan@uga.edu.
Abstract
INTRODUCTION: We and others have shown that the angiotensin type 2 (AT2) receptor agonist, compound 21 (C21), provides neuroprotection and enhances recovery in rodent stroke models yet the mechanism involved is not known. Moreover, C21 treatment is associated with an anti-inflammatory response. Here we tested the hypothesis that C21 mediates neuroprotection by upregulating the neuroprotective and anti-inflammatory cytokine, interleukin (IL)-10. METHODS: Wistar rats were subjected to 3h-middle cerebral artery suture occlusion and treated at reperfusion with C21 (0.03mg/kg)±IL-10 neutralizing antibody (0.1mg/kg) both given i.p. Infarct size, behavioral outcomes, and molecular analysis were performed at 24h post-injury. Primary rat neurons were used to test the direct neuroprotective effect of C21 in vitro. RESULTS: C21 treatment reduced infarct size, improved functional outcome and decreased the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) in the ischemic hemisphere compared to saline. Anti-IL-10 co-treatment blocked the C21-induced reduction in infarct size and inflammation, and the improvement in behavioral outcome. In vitro, C21 treatment increased neuron survival and reduced cell apoptosis after oxygen glucose deprivation (OGD) and OGD/reoxygenation. These effects were mediated through AT2R stimulation. CONCLUSION: C21 provides direct neuroprotection as well as indirect protection through IL-10.
INTRODUCTION: We and others have shown that the angiotensin type 2 (AT2) receptor agonist, compound 21 (C21), provides neuroprotection and enhances recovery in rodent stroke models yet the mechanism involved is not known. Moreover, C21 treatment is associated with an anti-inflammatory response. Here we tested the hypothesis that C21 mediates neuroprotection by upregulating the neuroprotective and anti-inflammatory cytokine, interleukin (IL)-10. METHODS:Wistar rats were subjected to 3h-middle cerebral artery suture occlusion and treated at reperfusion with C21 (0.03mg/kg)±IL-10 neutralizing antibody (0.1mg/kg) both given i.p. Infarct size, behavioral outcomes, and molecular analysis were performed at 24h post-injury. Primary rat neurons were used to test the direct neuroprotective effect of C21 in vitro. RESULTS: C21 treatment reduced infarct size, improved functional outcome and decreased the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) in the ischemic hemisphere compared to saline. Anti-IL-10 co-treatment blocked the C21-induced reduction in infarct size and inflammation, and the improvement in behavioral outcome. In vitro, C21 treatment increased neuron survival and reduced cell apoptosis after oxygenglucose deprivation (OGD) and OGD/reoxygenation. These effects were mediated through AT2R stimulation. CONCLUSION: C21 provides direct neuroprotection as well as indirect protection through IL-10.
Authors: Caterina Curato; Svetlana Slavic; Jun Dong; Anna Skorska; Wassim Altarche-Xifró; Kapka Miteva; Elena Kaschina; Andreas Thiel; Hans Imboden; Jianan Wang; Ulrike Steckelings; Gustav Steinhoff; Thomas Unger; Jun Li Journal: J Immunol Date: 2010-10-08 Impact factor: 5.422
Authors: Claudia A McCarthy; Antony Vinh; Alyson A Miller; Anders Hallberg; Mathias Alterman; Jennifer K Callaway; Robert E Widdop Journal: PLoS One Date: 2014-04-21 Impact factor: 3.240
Authors: Weihua Guan; Payaningal R Somanath; Anna Kozak; Anna Goc; Azza B El-Remessy; Adviye Ergul; Maribeth H Johnson; Ahmed Alhusban; Sahar Soliman; Susan C Fagan Journal: PLoS One Date: 2011-09-01 Impact factor: 3.240
Authors: Bryna S M Chow; Martina Kocan; Matthew Shen; Yan Wang; Lei Han; Jacqueline Y Chew; Chao Wang; Sanja Bosnyak; Katrina M Mirabito-Colafella; Giannie Barsha; Belinda Wigg; Elizabeth K M Johnstone; Mohammed A Hossain; Kevin D G Pfleger; Kate M Denton; Robert E Widdop; Roger J Summers; Ross A D Bathgate; Tim D Hewitson; Chrishan S Samuel Journal: J Am Soc Nephrol Date: 2019-09-11 Impact factor: 10.121
Authors: U Muscha Steckelings; Robert E Widdop; Edward D Sturrock; Lizelle Lubbe; Tahir Hussain; Elena Kaschina; Thomas Unger; Anders Hallberg; Robert M Carey; Colin Sumners Journal: Pharmacol Rev Date: 2022-10 Impact factor: 18.923
Authors: João Vian; Círia Pereira; Victor Chavarria; Cristiano Köhler; Brendon Stubbs; João Quevedo; Sung-Wan Kim; André F Carvalho; Michael Berk; Brisa S Fernandes Journal: BMC Med Date: 2017-08-01 Impact factor: 8.775