Protective effects of the angiotensin II AT2 receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach

2018 ◽  
Vol 132 (5) ◽  
pp. 581-593 ◽  
Author(s):  
Douglas M. Bennion ◽  
Chad H. Jones ◽  
Alex N. Dang ◽  
Jacob Isenberg ◽  
Justin T. Graham ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Angiotensin Ii ◽  
Receptor Agonist ◽  
At2 Receptor ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Receptor Agonists ◽  
Compound 21 ◽  
Neuroprotective Actions

Significant neuroprotective effects of angiotensin II type 2 (AT2) receptor (AT2 receptor) agonists in ischemic stroke have been previously demonstrated in multiple studies. However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular (ICV) and systemic administration, are unsuitable for translation into humans; in the latter case because AT2 receptor agonists are blood–brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver the selective AT2 receptor agonist Compound 21 (C21) to naïve rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke. The results obtained from the present study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 min in amounts that are therapeutically relevant (8.4–9 nM), regardless of whether BBB was intact or disintegrated. C21 was first applied N2B at 1.5 h after stroke indeed provided neuroprotection, as evidenced by a highly significant, 57% reduction in cerebral infarct size and significant improvements in Bederson and Garcia neurological scores. N2B-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT2 receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective in certain human central nervous system diseases, the N2B application of AT2 receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients.

Neuroprotection via AT2 receptor agonists in ischemic stroke

2018 ◽  
Vol 132 (10) ◽  
pp. 1055-1067 ◽  
Author(s):  
Douglas M. Bennion ◽  
U. Muscha Steckelings ◽  
Colin Sumners
Keyword(s):  
Ischemic Stroke ◽  
Neuronal Damage ◽  
Recombinant Tissue Plasminogen Activator ◽  
Neurological Deficits ◽  
At2 Receptor ◽  
Neuroprotective Effects ◽  
Receptor Agonists ◽  
Stroke Epidemiology ◽  
The Brain

Stroke is a devastating disease that afflicts millions of people each year worldwide. Ischemic stroke, which accounts for ~88% of cases, occurs when blood supply to the brain is decreased, often because of thromboembolism or atherosclerotic occlusion. This deprives the brain of oxygen and nutrients, causing immediate, irreversible necrosis within the core of the ischemic area, but more delayed and potentially reversible neuronal damage in the surrounding brain tissue, the penumbra. The only currently approved therapies for ischemic stroke, the thrombolytic agent recombinant tissue plasminogen activator (rtPA) and the endovascular clot retrieval/destruction processes, are aimed at restoring blood flow to the infarcted area, but are only available for a minority of patients and are not able in most cases to completely restore neurological deficits. Consequently, there remains a need for agents that will protect neurones against death following ischemic stroke. Here, we evaluate angiotensin II (Ang II) type 2 (AT2) receptor agonists as a possible therapeutic target for this disease. We first provide an overview of stroke epidemiology, pathophysiology, and currently approved therapies. We next review the large amount of preclinical evidence, accumulated over the past decade and a half, which indicates that AT2 receptor agonists exert significant neuroprotective effects in various animal models, and discuss the potential mechanisms involved. Finally, after discussing the challenges of delivering blood–brain barrier (BBB) impermeable AT2 receptor agonists to the infarcted areas of the brain, we summarize the evidence for and against the development of these agents as a promising therapeutic strategy for ischemic stroke.

scholarly journals Angiotensin II type 2 receptor stimulation with compound 21 improves neurological function after stroke in female rats: a pilot study

2019 ◽  
Vol 316 (5) ◽  
pp. H1192-H1201 ◽  
Author(s):  
Wael Eldahshan ◽  
Tauheed Ishrat ◽  
Bindu Pillai ◽  
Mohammed A. Sayed ◽  
Abdulrahman Alwhaibi ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Angiotensin Ii ◽  
Female Rats ◽  
Male Rats ◽  
Size Analysis ◽  
Neuroprotective Effects ◽  
Compound 21 ◽  
The Impact

The angiotensin II type 2 receptor (AT2R) agonist, compound 21 (C21), has been shown to be neurovascularly protective after ischemic stroke in male rats. In the current study, we aim to study the impact of C21 treatment on female rats. Young female Wistar rats were subjected to different durations of middle cerebral artery occlusion (MCAO) (3 h, 2 h, and 1 h) using a silicone-coated monofilament, treated at reperfusion with 0.03 mg/kg ip of C21 and followed up for different times (1, 3, and 14 days) after stroke. Behavioral tests were performed (Bederson, paw grasp, beam walk, and rotarod), and animals were euthanized for infarct size analysis and Western blot analysis. In vitro, primary male and female brain microvascular endothelial cells (ECs) were grown in culture, and the expression of the AT2R was compared between males and females. At 1 day, C21 treatment resulted in an improvement in Bederson scores. However, at 3 days and 14 days, the impact of C21 on stroke outcomes was less robust. In vitro, the expression of the AT2R was significantly higher in female ECs compared with male ECs. In conclusion, C21 improves Bederson scores after stroke in female rats when administered early at reperfusion. The ability of C21 to exert its neuroprotective effects might be affected by fluctuating levels of female hormones. NEW & NOTEWORTHY The present study shows the neuroprotective impact of C21 on ischemic stroke in female rats and how the protective effects of C21 can be influenced by the hormonal status of female rodents.

scholarly journals Angiotensin II type 2 receptor agonist Compound 21 attenuates pulmonary inflammation in a model of acute lung injury

2018 ◽  
Vol Volume 11 ◽  
pp. 169-178 ◽  
Author(s):  
Mario Menk ◽  
Jan Adriaan Graw ◽  
Clarissa von Haefen ◽  
Henrik Kurt Alexander Steinkraus ◽  
Burkhard Lachmann ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Angiotensin Ii ◽  
Lung Injury ◽  
Receptor Agonist ◽  
Pulmonary Inflammation ◽  
Compound 21

Effect of Compound 21, a Selective Angiotensin II Type 2 Receptor Agonist, in a Murine Xenograft Model of Dupuytren Disease

2017 ◽  
Vol 140 (5) ◽  
pp. 686e-696e ◽  
Author(s):  
Jessica Chisholm ◽  
Alison J. Gareau ◽  
Stephanie Byun ◽  
Justin L. Paletz ◽  
David Tang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Receptor Agonist ◽  
Xenograft Model ◽  
Murine Xenograft Model ◽  
Compound 21 ◽  
Dupuytren Disease

Angiotensin ii type 2 receptor agonist, compound 21, prevents tubular epithelial cell damage caused by renal ischemia

2021 ◽  
pp. 114804
Author(s):  
Fussi María Fernanda ◽  
Hidalgo Florencia ◽  
Buono Gabriel ◽  
Marquez Susana Beatriz ◽  
Pariani Alejandro ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Epithelial Cell ◽  
Receptor Agonist ◽  
Cell Damage ◽  
Tubular Epithelial Cell ◽  
Renal Ischemia ◽  
Compound 21

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: ]]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.

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

scholarly journals The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury

2018 ◽  
Vol 9 ◽  
Author(s):  
Anandharajan Rathinasabapathy ◽  
Alana Horowitz ◽  
Kelsey Horton ◽  
Ashok Kumar ◽  
Santhi Gladson ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Angiotensin Ii ◽  
Lung Injury ◽  
Experimental Model ◽  
Lung Fibrosis ◽  
Receptor Agonist ◽  
Compound 21

Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells

2015 ◽  
Vol 128 (9) ◽  
pp. 567-578 ◽  
Author(s):  
Yi Zhao ◽  
Ulf Lützen ◽  
Jürgen Fritsch ◽  
Maaz Zuhayra ◽  
Stefan Schütze ◽  
...  
Keyword(s):  
Cell Death ◽  
Receptor Agonist ◽  
Uterine Leiomyosarcoma ◽  
At2 Receptor ◽  
Cytotoxic Effects ◽  
High Affinity ◽  
Compound 21 ◽  
Angiotensin Type ◽  
At2 Receptors

The angiotensin type 2 (AT2) receptor is substantially over-expressed in quiescent human uterine leiomyosarcoma cells and displays high densities in mitochondria. The high-affinity, non-peptide AT2 receptor agonist, Compound 21 exerts profound cytotoxic effects in these cells.

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