Abstract W P196: Post-Stroke Activation of Angiotensin Converting Enzyme 2 is Neuroprotective

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Douglas M Bennion ◽  
Emily Haltigan ◽  
Alexander Irwin ◽  
Donnangelo Lauren ◽  
David Pioquinto ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Infarct Size ◽  
Brain Homogenate ◽  
Artery Occlusion ◽  
Converting Enzyme ◽  
Diminazene Aceturate ◽  
Angiotensin Converting Enzyme 2 ◽  
Post Stroke ◽  
Relevant Evidence ◽  
Cerebral Artery Occlusion

Background: Recent discoveries point to the angiotensin converting enzyme 2/angiotensin-(1-7)/mas (ACE2-Ang-(1-7)-Mas) axis as a potential target for neuroprotective stroke therapies. Central pre-stroke activation of this axis by infusion of diminazene aceturate (DIZE), an activator of ACE2, improves stroke outcomes in rats. This led us to hypothesize that intraperitoneal (IP) post-stroke injections of DIZE may exert similar Mas-mediated neuroprotection and thus offer additional clinically-relevant evidence to support this approach. We also assessed the direct effects of DIZE on ACE2 activity in brain tissue. Methods: Male SD rats underwent ischemic stroke by endothelin-1-induced middle cerebral artery occlusion and were randomly divided into groups (n=~12/group) that received IP injections of dH2O or DIZE (0.75, 2.5, or 7.5 mg/kg) at 4, 24, and 48 h after stroke, as well as blinded neurological assessments at 4, 24, and 72 h after stroke. Additional groups received pre- and post-stroke intracerebroventricular (ICV) infusion of sterile 0.9% saline or Mas receptor antagonist A-779 in addition to post-stroke control or drug therapy. Immediately after the 72 h tests, animals were euthanized, cerebral infarct size assessed by TTC staining, and tissue harvested for ACE2 activity assay. Data are expressed as mean ± SEM with significance inferred at p<0.05. Results: Mean infarct sizes (%) were significantly decreased by post-stroke IP injections of all doses of DIZE (0.75 mg/kg: 29.9±5.0; 2.5 mg/kg: 27.9±4.2; 7.5 mg/kg: 31.36±4.1) vs. dH2O (41.9±3.8). At 24 h post-stroke, neurologic deficits (Garcia and Bederson scales) were significantly improved in DIZE-treated rats (7.5 mg/kg: 16.7±0.2 and 0.5±0.1) vs. controls (15.5±0.4 and 1.1±0.2). ICV infusion of A-779 in DIZE-treated rats abolished the improvement in infarct size observed in saline infused DIZE-treated rats (A-779: 43.8%±7.5; saline: 25.8±6.7). Addition of DIZE (4 nmol/μg protein) to brain homogenate increased ACE2 activity by more than 3-fold. Conclusions: This suggests that targeting the ACE2/Ang-(1-7)/Mas axis by post-stroke DIZE injections exerts neuroprotection in a Mas-dependent fashion.

Anti-hypertensive Effects of Diminazene Aceturate: An Angiotensin- Converting Enzyme 2 Activator in Rats

2015 ◽  
Vol 23 (1) ◽  
pp. 9-16 ◽  
Author(s):  
Marilda L.A. De Maria ◽  
Liliane D. Araújo ◽  
Rodrigo A. Fraga-Silva ◽  
Letícia A.S. Pereira ◽  
Heder J. Ribeiro ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Converting Enzyme ◽  
Diminazene Aceturate ◽  
Angiotensin Converting Enzyme 2

Abstract T P228: Ischemic Stroke Results in Increased Activity of the Neuroprotective Angiotensin Converting Enzyme 2 in Rat Brain and Serum

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Douglas M Bennion ◽  
Emily Haltigan ◽  
Alexander J Irwin ◽  
Daniel L Purich ◽  
Colin Sumners
Keyword(s):  
Cerebral Cortex ◽  
Ischemic Stroke ◽  
Angiotensin Converting Enzyme ◽  
Rat Cerebral Cortex ◽  
Mrna Levels ◽  
Converting Enzyme ◽  
Stroke Treatment ◽  
Angiotensin Converting Enzyme 2 ◽  
Post Stroke ◽  
Rebound Increase

Background: Recent studies show that pharmacological induction of the angiotensin converting enzyme 2/angiotensin-(1-7)/mas [ACE2-Ang-(1-7)-Mas] axis, a protective pathway of the renin angiotensin system, elicits neuroprotection in ischemic stroke. However, endogenous levels and activity of the components of this axis in the brain and serum following stroke are not well established. Here, we assessed the post-stroke activity and expression of ACE2 in rat cerebral cortex and serum after ischemic stroke in rats, in the absence or presence of an ACE2 activator. Methods: Sprague Dawley rats underwent sham surgery or endothelin-1-induced middle cerebral artery occlusion (ET-1 MCAO). Activity of ACE2 was analyzed within serum and cerebral cortical tissue samples using a fluorometric assay, and mRNA levels were assessed by qRT-PCR. In an additional experiment, rats received daily intraperitoneal administration of diminazene aceturate (DIZE), a putative ACE2 activator, or vehicle after ET-1 MCAO. Data are normalized to corresponding control values and expressed as means ± SEM with a significance of p<0.05. Results: ACE2 activity levels were significantly increased in ischemic brain cortex at 4, 12, and 24 h after a stroke (4h: 237.1±46.1%; 12h: 212.4±12.8%; 24h: 191.6±19.1%) versus rats with sham strokes. Paradoxically, there was a significant decrease in ACE2 mRNA levels in the ischemic cortex at 24h (0.71±0.1) compared to shams (1.0±0.08). After decreasing in activity at 4h after stroke, serum ACE2 activity was increased at 24h in stroked rats (96.08±9.4%) versus shams (70.80±7.1%). Post-stroke treatment with DIZE (7.5 mg/kg) resulted in significantly increased ACE2 activity in serum (213.7±49.8%) versus controls, two days following stroke. Conclusions: Activity of the protective enzyme ACE2 is increased in rat cerebral cortex following stroke, with a rebound increase in serum activity. Post-stroke treatment with an ACE2 activator resulted in significantly increased ACE2 activity in serum. These results suggest that stroke therapeutics designed to target the ACE2/Ang-(1-7)/Mas axis may act in synergy with endogenous changes in the acute post-stroke setting, lending promise to their further study as potential neuroprotective agents.

scholarly journals Ocular Inserts for Sustained Release of the Angiotensin-Converting Enzyme 2 Activator, Diminazene Aceturate, to Treat Glaucoma in Rats

PLoS ONE ◽  
2015 ◽  
Vol 10 (7) ◽  
pp. e0133149 ◽  
Author(s):  
Giselle Foureaux ◽  
Juçara Ribeiro Franca ◽  
José Carlos Nogueira ◽  
Gustavo de Oliveira Fulgêncio ◽  
Tatiana Gomes Ribeiro ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Sustained Release ◽  
Converting Enzyme ◽  
Diminazene Aceturate ◽  
Angiotensin Converting Enzyme 2

scholarly journals Diminazene Aceturate Enhances Angiotensin-Converting Enzyme 2 Activity and Attenuates Ischemia-Induced Cardiac Pathophysiology

Hypertension ◽  
2013 ◽  
Vol 62 (4) ◽  
pp. 746-752 ◽  
Author(s):  
YanFei Qi ◽  
Juan Zhang ◽  
Colleen T. Cole-Jeffrey ◽  
Vinayak Shenoy ◽  
Andrew Espejo ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Converting Enzyme ◽  
Diminazene Aceturate ◽  
Angiotensin Converting Enzyme 2 ◽  
Cardiac Pathophysiology

scholarly journals Evaluation of the Effectiveness of Post-Stroke Metformin Treatment Using Permanent Middle Cerebral Artery Occlusion in Rats

2021 ◽  
Vol 14 (4) ◽  
pp. 312
Author(s):  
Gintare Zemgulyte ◽  
Shigeru Tanaka ◽  
Izumi Hide ◽  
Norio Sakai ◽  
Katryna Pampuscenko ◽  
...  
Keyword(s):  
Infarct Size ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Neuroprotective Effect ◽  
Artery Occlusion ◽  
Metformin Treatment ◽  
Stroke Treatment ◽  
Post Stroke ◽  
Anti Inflammatory ◽  
Cerebral Artery Occlusion

Stroke is the second leading cause of death worldwide. Treatment options for ischemic stroke are limited, and the development of new therapeutic agents or combined therapies is imperative. Growing evidence suggests that metformin treatment, due to its anti-inflammatory action, exerts a neuroprotective effect against ischemia/reperfusion-induced brain damage. Experimental assessment has typically been performed in models of cerebral transient ischemia followed by long-term reperfusion. The aim of this study was to evaluate the neuroprotective effect of metformin treatment after permanent middle cerebral artery occlusion (pMCAO) without reperfusion in rats. Neurological deficits were assessed using the Longa scale, which offers a graded scale on body movement following pMCAO. Both infarct size and brain oedema area were measured by staining with 2,3,5-triphenyltetrazolium chloride. The number of neurons and total and activated microglia, as well as interleukin 10 (IL-10) production, in brain sections were evaluated by immunohistochemical staining. Our results show that metformin treatment improves the neurological state and reduces infarct size after 120 h of pMCAO. Metformin also prevents neuronal loss in the ischemic cortex but not in the striatum after 48 h of pMCAO. Moreover, post-stroke treatment with metformin significantly decreases the number of total and activated microglia at 48 h. The anti-inflammatory effect of metformin is associated with increased IL-10 production at 48 h after pMCAO. The results of the present study suggest that post-stroke treatment with metformin exerts anti-inflammatory and neuroprotective effects in a pMCAO model.

Abstract 12650: Activity of Serum Angiotensin Converting Enzyme 2 is Decreased During Acute Ischemic Stroke in Humans

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Douglas M Bennion ◽  
Christian A Rosado ◽  
Emily H Haltigan ◽  
Colin Sumners ◽  
Michael F Waters
Keyword(s):  
Enzyme Activity ◽  
Ischemic Stroke ◽  
Angiotensin Converting Enzyme ◽  
Acute Ischemic Stroke ◽  
Converting Enzyme ◽  
Serum Samples ◽  
Necrosis Factor Alpha ◽  
Angiotensin Converting Enzyme 2 ◽  
Post Stroke ◽  
Rebound Increase

Introduction: The expression and activity of angiotensin converting enzyme 2 (ACE2), a cardio and neuro-protective carboxypeptidase, has recently been shown to be dynamically altered during and after stroke in animal models. Hypothesis: The aim of this study was to characterize the previously unexplored changes in activity of ACE2 in the serum of patients experiencing acute ischemic stroke. Methods: Serum samples were obtained from patients presenting with acute ischemic stroke (n=20) and again at three days post-stroke and enzyme activity levels were analyzed by fluorometric assay and compared to levels from non-stroke control patients (n=20). Results: Ischemic stroke resulted in a significant decrease in serum ACE2 at an average of 3.5 hours after stroke, which was followed by a rebound increase by three days later (Fig 1). ACE activity was also significantly decreased following stroke, but without rebound increases. Tumor necrosis factor-alpha converting enzyme activity was not significantly different from control. ACE2 activity was negatively correlated with systolic blood pressure (SBP) among stroke patients (Fig 2), while activity was positively correlated with SBP among a cohort of healthy young adults (n=16). Conclusions: The characterization of the dynamic and novel changes in serum ACE2 activity in human stroke, which follow observations from preclinical studies, along with the demonstration of a negative association with SBP, provides new insight for the development of therapies that target this protective system in the context of ischemic stroke. Data are mean ± SEM. RFU: relative fluorescence units; *p<0.001 vs. control; †p<0.05 vs. 4h post stroke.

Diminazene aceturate, an angiotensin converting enzyme 2 (ACE2) activator, promotes cardioprotection in ischemia/reperfusion-induced cardiac injury

Peptides ◽  
2022 ◽  
pp. 170746
Author(s):  
Danielle C.O. Coutinho ◽  
Artur Santos-Miranda ◽  
Julliane V. Joviano-Santos ◽  
Giselle Foureaux ◽  
Anderson Santos ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Converting Enzyme ◽  
Diminazene Aceturate ◽  
Angiotensin Converting Enzyme 2
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