Abstract WP137: Angiotensin Type 2 Receptor Stimulation With Compound 21 Prevents Delayed Cognitive Impairment in Hypertensive, Ovariectomized Female Rats After Ischemic Stroke: A Randomized, Blinded, Preclinical Study

Stroke ◽  
2019 ◽  
Vol 50 (Suppl_1) ◽  
Author(s):  
Wael Eldahshan ◽  
Mohammed A Sayed ◽  
Heba A Ahmed ◽  
Bindu Pillai ◽  
Guangkuo Dong ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cognitive Impairment ◽  
Preclinical Study ◽  
Female Rats ◽  
Receptor Stimulation ◽  
Angiotensin Type 2 Receptor ◽  
Compound 21 ◽  
Angiotensin Type

scholarly journals The angiotensin type 2 receptor agonist Compound 21 elicits cerebroprotection in endothelin-1 induced ischemic stroke

2014 ◽  
Vol 81 ◽  
pp. 134-141 ◽  
Author(s):  
Jason P. Joseph ◽  
Adam P. Mecca ◽  
Robert W. Regenhardt ◽  
Douglas M. Bennion ◽  
Vermali Rodríguez ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Receptor Agonist ◽  
Endothelin 1 ◽  
Angiotensin Type 2 Receptor ◽  
Compound 21 ◽  
Angiotensin Type

Abstract WMP84: Intranasal Trans-olfactory Delivery of the Angiotensin Type 2 Receptor Agonist Compound 21 is Neuroprotective in Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Douglas M Bennion ◽  
Jacob D Isenberg ◽  
Alex N Dang ◽  
Chad H Jones ◽  
Justin T Graham ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Ischemic Stroke ◽  
Locomotor Activity ◽  
Post Stroke ◽  
Sd Rats ◽  
Angiotensin Type 2 Receptor ◽  
Compound 21 ◽  
Angiotensin Type

Background: Compound 21 (C21), a selective small-molecule angiotensin type 2 receptor (AT2R) agonist, has been proven in multiple preclinical studies to reduce infarct size and ameliorate neurological deficits, when administered after ischemic stroke via intracerebroventricular or intraperitoneal routes. However, C21 poorly penetrates the blood brain barrier (BBB). In this study, we used the novel and non-invasive approach of intranasal trans-olfactory (INTO) application, in order to bypass the BBB and deliver C21 directly into the brain. The therapeutic efficacy of INTO application of C21 was assessed in a model of transient middle cerebral artery occlusion (MCAO). Methods: (i) Male SD rats (12 weeks old) underwent ischemic stroke by endothelin-1-induced MCAO. They were randomly divided into two treatment groups, either receiving 0.9% saline or C21 (1.5 ug/kg) at 1.5, 4, 24 and 48 h post-stroke, using a rat intranasal catheter device (Impel Neuropharma, Seattle, WA) for INTO application. All rats underwent blinded neurological assessments at 4, 24 and 72 h after stroke, and immediately after the 72 h tests, were euthanized and cerebral infarct volumes were assessed by TTC staining. (ii) Male SD rats (12 weeks old) underwent implantation of a telemetry transducer (DSI, St. Paul, MN) into the abdominal aorta for measurement of blood pressure, heart rate and locomotor activity after INTO C21 (1.5 ug/kg) vs. 0.9% saline at baseline and post-ischemic stroke. Results: (i) Post-stroke INTO delivery of C21 (1.5 ug/kg) elicited a significant lowering of % cerebral infarct volume (25.4 ± 4.7; n=9) compared with saline-treated rats (48.4 ± 4.4; n=21) [p<0.05; two-way Mann-Whitney test]. The C21 (1.5 ug/kg)-treated rats also displayed highly significant improvements in Garcia and Bederson neurological scores (p<0.01; two-way Mann-Whitney test]. (ii) INTO delivery of C21 (1.5 ug/kg) either in naïve rats (n=7), or in rats post-stroke (n=4), did not significantly alter baseline blood pressure, heart rate and locomotor activity. Conclusions: Our results demonstrate, that INTO delivery of C21 exerts protective effects after ischemic stroke. These studies suggest INTO administration as potential future route of application of C21 to stroke patients.

scholarly journals Mas mediated cerebroprotective action of the angiotensin type 2 receptor agonist Compound 21 in ischemic stroke.

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Neal Anil Patel ◽  
Jason Joseph ◽  
David Pioquinto ◽  
Jacob Ludin ◽  
David Greenstein ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Receptor Agonist ◽  
Angiotensin Type 2 Receptor ◽  
Compound 21 ◽  
Angiotensin Type

Abstract WP101: Involvement of the Contralesional Angiotensin Type 2 Receptor in Compound 21 Mediated Functional Recovery After Stroke

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Abdelrahman Y Fouda ◽  
Tauheed Ishrat ◽  
Heba Ahmed ◽  
Bindu Pillai ◽  
Sandeep Artham ◽  
...  
Keyword(s):  
Western Blotting ◽  
Functional Recovery ◽  
Artery Occlusion ◽  
Behavioral Outcome ◽  
Brain Hemisphere ◽  
Angiotensin Type 2 Receptor ◽  
Male Wistar Rats ◽  
Compound 21 ◽  
Angiotensin Type

Introduction: We have recently shown that the angiotensin type 2 receptor (AT2R) agonist, compound 21 (C21), provides sustained functional recovery after ischemic stroke. This was associated with upregulation of the AT2R and the neurotrophin, brain derived neurotrophic factor (BDNF), in the contralesional brain hemisphere. Here, we aimed to study the contribution of this hemisphere in C21 mediated functional recovery after stroke through localized knockdown of the AT2R. Methods: male wistar rats (34) received two intrastriatal injections of short hairpin RNA (shRNA) lentiviral particles against AT2R, or non-targeting control vector (NTC) into the left brain hemisphere to achieve localized AT2R knockdown. After 14 days, rats were subjected to 90 minutes right middle cerebral artery occlusion (MCAO) and received either C21 (0.03 mg/kg) or saline at reperfusion (IV) then daily (IP) for 7 days. Rats were blindly assessed for behavioral outcome up to 10 days as well as molecular analysis. Results (table): PCR and Western blotting confirmed successful knockdown of the AT2R in the left (contralesional) hemisphere by about 50%. All groups showed worsened outcome on days 1 to 3 then recovered on days 7 to 10. The C21/NTC group showed better behavioral outcome compared to other groups at days 7 and 10, while the saline/shRNA group was associated with the least recovery. Using Western blotting, C21/NTC group showed higher BDNF and lower proBDNF (pro-form) levels in the ischemic and contralesional hemispheres respectively. Expression of the pro-apoptotic P75NTR receptor of proBDNF was decreased with C21 treatment irrespective of AT2R knockdown. Conclusion: Contralesional AT2R could be involved in C21 mediated functional recovery after stroke.

scholarly journals Relaxin attenuates organ fibrosis via an angiotensin-type 2 receptor mechanism in aged hypertensive female rats

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0002722021
Author(s):  
Giannie Barsha ◽  
Sarah L Walton ◽  
Edmund Kwok ◽  
Katrina M Mirabito Colafella ◽  
Anita P Pinar ◽  
...  
Keyword(s):  
Vascular Function ◽  
Cardiac Fibrosis ◽  
Female Rats ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Spontaneously Hypertensive ◽  
Angiotensin Type 2 Receptor ◽  
Models Of Disease ◽  
Angiotensin Type

Background: The anti-fibrotic effects of recombinant human relaxin (RLX) in the kidney are dependent on an interaction between its cognate receptor (RXFP1) and the angiotensin type 2 receptor (AT2R) in male models of disease. Whether RLX has therapeutic effects, which are also mediated via the AT2R, in hypertensive adult and aged/reproductively senescent females is unknown. Thus, we determined whether treatment with RLX provides cardiorenal protection, via an AT2R-dependent mechanism, in adult and aged female stroke prone-spontaneously hypertensive rats (SHRSP). Methods: In 6- (6MO) and 15-month-old (15MO; reproductively senescent) female SHRSP, systolic blood pressure (SBP), glomerular filtration rate (GFR) and proteinuria were measured before and after 4 weeks treatment with vehicle (Veh), RLX (0.5 mg/kg/day s.c.) or RLX+PD123319 (AT2R antagonist; 3 mg/kg/day s.c.). Aortic endothelium-dependent relaxation and fibrosis of the kidney, heart and aorta were assessed. Results: In 6MO SHRSP, RLX significantly enhanced GFR by ~25% (P=0.001) and reduced cardiac fibrosis (P=0.01) as compared to vehicle-treated counterparts. These effects were abolished or blunted by PD123319 co-administration. In 15MO females, RLX reduced interstitial renal (P=0.02) and aortic (P=0.003) fibrosis, and lowered SBP (13±3 mmHg; P=0.04) relative to controls. These effects were also blocked by PD123319 co-treatment (all p<0.05 versus RLX treatment alone). RLX also markedly improved vascular function by ~40% (P<0.0001) in 15MO SHRSP, but this was not modulated by PD123319 co-treatment. Conclusion: The anti-fibrotic and organ-protective effects of RLX, when administered to a severe model of hypertension, conferred cardiorenal protection in adult and reproductively senescent female rats, to a great extent via an AT2R-mediated mechanism.

Abstract 32: Direct Angiotensin II Type 2 Receptor Stimulation by Compound 21 Prevents Vascular Dementia

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Jun Iwanami ◽  
Masaki Mogi ◽  
Kana Tsukuda ◽  
Xiao-Li Wang ◽  
Masanori Kukida ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Angiotensin Ii ◽  
Cognitive Decline ◽  
Vascular Dementia ◽  
Laser Speckle ◽  
At2 Receptor ◽  
Receptor Stimulation ◽  
Morris Water Maze Task ◽  
Compound 21

Objectives: Recent clinical evidence demonstrated that angiotensin II type 1 receptor blockers (ARBs) were associated with a significant reduction in the incidence and progression of dementia compared with angiotensin converting enzyme inhibitor. Therefore, we examined the possibility that direct angiotensin II type 2 (AT2) receptor stimulation by AT2 receptor agonist, compound 21 (C21), could prevent cognitive decline associated with hypoperfusion in the brain. Methods: We employed a bilateral common carotid artery stenosis (BCAS) model in mice as a model of vascular dementia. The Morris water maze task was performed 6 weeks after BCAS operation. ARB, azilsartan (0.1 mg/kg/day) or C21 (10 μg/kg/day) was administered from 1 week before BCAS. Cerebral blood flow (CBF) was measured by laser speckle flowmetry and inflammatory cytokine levels were determined by real-time RT-PCR. Results: Wild-type (WT) mice showed the significant prolongation of escape latency after BCAS and this cognitive impairment was attenuated by the pretreatment of azilsartan. Cognitive impairment was more marked in AT2 receptor knockout (AT2KO) mice, and preventive effect of azilsartan on cognitive decline was weaker in AT2KO mice than in WT mice, suggesting that improvement of cognitive decline by azilsartan may involve the stimulation of AT2 receptor. The significant impairment of spatial learning after BCAS in WT mice was attenuated by C21 treatment. CBF in the whole brain in the BCAS-treated group was significantly decreased compared with that in the sham group at 6 weeks after BCAS operation. This decrease was increased by treatment with C21. We assessed expression of inflammatory cytokines such as TNF-[[Unable to Display Character: &#61472;]]α and MCP-1 in the cerebral cortex. TNF-α and MCP-1 mRNA expression were significantly increased after BCAS operation, but significantly attenuated by treatment with C21. Azilsartan or C21 at these doses did not affect systolic blood pressure. Conclusions: These findings indicate that direct AT2 stimulation prevents ischemic vascular dementia induced by hypoperfusion at least in part through an increase in CBF, and reduction of inflammation. We expect that direct AT2 receptor stimulation could be a new therapeutic strategy for preventing and treating vascular dementia.

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