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.

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.

Neutrophil affinity for PGP and HAIYPRH (T7) peptide dual-ligand functionalized nanoformulation enhances the brain delivery of tanshinone IIA and exerts neuroprotective effects against ischemic stroke by inhibiting proinflammatory signaling pathways

2018 ◽  
Vol 42 (23) ◽  
pp. 19043-19061
Author(s):  
Yutao Li ◽  
Chiying An ◽  
Danan Han ◽  
Yanxin Dang ◽  
Xin Liu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Physicochemical Properties ◽  
Signaling Pathways ◽  
Blood Brain Barrier ◽  
Tanshinone Iia ◽  
Brain Barrier ◽  
Brain Delivery ◽  
Neuroprotective Effects ◽  
The Poor ◽  
The Brain

A great challenge to the therapy of ischemic stroke is the poor physicochemical properties and inability of the drug to cross the blood–brain barrier (BBB).

scholarly journals BMS-986020, a Specific LPA1 Antagonist, Provides Neuroprotection against Ischemic Stroke in Mice

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1097
Author(s):  
Bhakta Prasad Gaire ◽  
Arjun Sapkota ◽  
Ji Woong Choi
Keyword(s):  
Ischemic Stroke ◽  
Survival Rate ◽  
Cell Apoptosis ◽  
Functional Disability ◽  
Brain Infarction ◽  
Tissue Loss ◽  
Neurological Deficits ◽  
Neuroprotective Effects ◽  
Acute Injuries

Stroke is a leading cause of death. Stroke survivors often suffer from long-term functional disability. This study demonstrated neuroprotective effects of BMS-986020 (BMS), a selective lysophosphatidic acid receptor 1 (LPA1) antagonist under clinical trials for lung fibrosis and psoriasis, against both acute and sub-acute injuries after ischemic stroke by employing a mouse model with transient middle cerebral artery occlusion (tMCAO). BMS administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, neurological deficits, and cell apoptosis at day 1 after tMCAO. Neuroprotective effects of BMS were preserved even when administered at 3 h after reperfusion. Neuroprotection by BMS against acute injuries was associated with attenuation of microglial activation and lipid peroxidation in post-ischemic brains. Notably, repeated BMS administration daily for 14 days after tMCAO exerted long-term neuroprotection in tMCAO-challenged mice, as evidenced by significantly attenuated neurological deficits and improved survival rate. It also attenuated brain tissue loss and cell apoptosis in post-ischemic brains. Mechanistically, it significantly enhanced neurogenesis and angiogenesis in injured brains. A single administration of BMS provided similar long-term neuroprotection except survival rate. Collectively, BMS provided neuroprotection against both acute and sub-acute injuries of ischemic stroke, indicating that BMS might be an appealing therapeutic agent to treat ischemic stroke.

scholarly journals AT2 Receptor-Interacting Proteins ATIPs in the Brain

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Sylvie Rodrigues-Ferreira ◽  
Erwann le Rouzic ◽  
Traci Pawlowski ◽  
Anand Srivastava ◽  
Florence Margottin-Goguet ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Intracellular Localization ◽  
Biologically Active ◽  
Receptor Subtypes ◽  
At2 Receptor ◽  
Interacting Proteins ◽  
Neuroprotective Effects ◽  
Brain Functions ◽  
Receptor Interacting Proteins ◽  
The Brain

A complete renin-angiotensin system (RAS) is locally expressed in the brain and fulfills important functions. Angiotensin II, the major biologically active peptide of the RAS, acts via binding to two main receptor subtypes designated AT1 and AT2. The present paper focuses on AT2 receptors, which have been reported to have neuroprotective effects on stroke, degenerative diseases, and cognitive functions. Our group has identified a family of AT2 receptor interacting proteins (ATIPs) comprising three major members (ATIP1, ATIP3, and ATIP4) with different intracellular localization. Of interest, all ATIP members are expressed in brain tissues and carry a conserved domain able to interact with the AT2 receptor intracellular tail, suggesting a role in AT2-mediated brain functions. We summarize here current knowledge on the ATIP family of proteins, and we present new experimental evidence showing interaction defects between ATIP1 and two mutant forms of the AT2 receptor identified in cases of mental retardation. These studies point to a functional role of the AT2/ATIP1 axis in cognition.

scholarly journals Inhibitory Effect of Gualou Guizhi Decoction on Microglial Inflammation and Neuron Injury by Promoting Anti-Inflammation via Targeting mmu-miR-155

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Haixia Hu ◽  
Xinghua Zhong ◽  
Xinjun Lin ◽  
Jinbo Yang ◽  
Xiaoqin Zhu
Keyword(s):  
Ischemic Stroke ◽  
Cell Line ◽  
Conditioned Medium ◽  
Neuronal Damage ◽  
Apoptotic Cell ◽  
Neuroprotective Effects ◽  
Ht22 Cells ◽  
Guizhi Decoction ◽  
Bv2 Cells ◽  
Microglial Inflammation

Gualou Guizhi decoction (GLGZD) treatment exerts neuroprotective effects and promotes spasticity following ischemic stroke. However, the molecular mechanism of GLGZD treatment on ischemic stroke remains unclear. Our previous study indicated that GLGZD ameliorates neuronal damage caused by secondary inflammatory injury induced by microglia. In the present study, we investigate the potential mechanism of GLGZD treatment on neuron damage induced by neuroinflammation via mmu-miR-155 in vitro. The HT22 cell line and the BV2 cell line were exposed to oxygen/glucose-deprive (OGD) conditions; the conditioned medium was prepared using the supernatants from OGD-stimulated BV2 cells after pretreating with GLGZD. Cell viability was determined by MTT assays; levels of released inflammatory cytokines were assessed using the BioPlex system. mmu-miR-155 and its targeting genes were detected using real-time reverse transcription polymerase chain reaction (RT-PCR). The expression of anti-inflammatory proteins was evaluated by Western blotting. DAPI staining was used to test the apoptotic cells. Our results showed that GLGZD pretreatment significantly induced IL10 release and decreased the production of TNF-α, IL6, and IFN-γ. In addition, GLGZD markedly attenuated mmu-miR-155 expression and its downstream SOCS1, SMAD2, SHIP1, and TAB2 expression levels. The DAPI-stained apoptotic cell death and caspase-3 activation in HT22 cells exposed to the conditioned medium were reversed by GLGZD treatment. Our findings suggested that GLGZD pretreatment downregulates the mmu-miR-155 signaling, which inhibits microglial inflammation, thereby resulting in the suppression of neuron apoptosis after OGD stress. The underlying mechanisms may provide the support for GLGZD treatment of cerebral ischemic injury.

409Cardiovascular risk profiles and outcomes in patients with type 2 diabetes - Implications for choice of new diabetes therapies

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M E Malik ◽  
C A Andersson ◽  
P B Blanche ◽  
C M R Rasmussen ◽  
B Z Zareini ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Ischemic Stroke ◽  
Sglt2 Inhibitors ◽  
Low Risk ◽  
Receptor Agonists ◽  
Risk Of Death ◽  
History Of ◽  
New Onset

Abstract Background Reflecting recent clinical trial findings, updated type 2 diabetes (T2D) guidelines recommend targeting SGLT2 inhibitors at patients at risk of heart failure (HF)-related events and GLP-1 receptor agonists at those at greater risk of atherosclerotic events. However, which cardiovascular disease phenotype in patients with T2D is more predictive of one or other type of these events is unclear. Purpose To estimate the risk of HF-related events and atherosclerotic events, according to background cardiovascular phenotype, in patients with T2D. Methods Patients with T2D and new-onset cardiovascular disease were identified using Danish health care registers (period 1995 to 2015). Patients were divided in four groups based on the primary type of cardiovascular disease: 1) HF, 2) ischemic heart disease (IHD), 3) ischemic stroke, and 4) peripheral artery disease (PAD). The absolute 5-year risks of the subsequent event, either a HF-related event or an atherosclerotic event (IHD, ischemic stroke and PAD), and the associated risk of death, were compared across the four groups. The Aalen-Johansen estimator was used to account for censoring, the competing risk of HF and atherosclerotic events, respectively, and death. Results We included 37,850 patients with T2D and new-onset cardiovascular disease. Median age was 70 years and 40% were female. Patients with HF were at higher risk of readmission for HF (18.1%; 95% confidence interval (CI): 17.2–19.0) than of an atherosclerotic event (14.2%; 13.4–15.0) (Figure). Patients with IHD were at higher risk of a new atherosclerotic event (23.5%; 22.8.-24.2) than of developing HF (9.3%; 8.9–9.8), although the risk of HF was still substantial. Conversely, patients with ischemic stroke were at low risk of HF (3.3%; 2.9–3.8) and higher risk of an atherosclerotic event (16.9%; 95% CI: 16.0–17.7). Patients with PAD had the lowest risk of HF (3.1%; 95% CI: 2.8–3.4) and the highest risk of an atherosclerotic event (35.0%; 95% CI: 33.4–36.7). Compared to a new atherosclerotic event, developing HF was associated with a higher 1-year risk of death (16.0%; 95% CI: 14.7–17.3 versus 33.0%; 95% CI: 31.8–34.2) amongst all patients. Cumulative incidence of first new event Conclusions In T2D, a patient's history of cardiovascular disease was predictive of type of subsequent cardiovascular event. While history of ischemic stroke and PAD were associated with a high risk of future atherosclerotic events, and low risk of HF, patients with IHD were at substantial risk of both types of event. Conversely, while history of HF was most predictive of future HF events, the risk of atherosclerotic events in patients with HF was also high. Our findings may help determine which type of therapy T2D patients with a particular cardiovascular disease history might benefit from – SGLT2 inhibitors, GLP-1 receptor agonists or potentially both. Acknowledgement/Funding Mariam Elmegaard Malik was funded by a research grant from Department of Cardiology, Herlev and Gentofte Hospital.

scholarly journals American Ginseng (Panax quinquefolium L.) as a Source of Bioactive Phytochemicals with Pro-Health Properties

Nutrients ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 1041 ◽  
Author(s):  
Daria Szczuka ◽  
Adriana Nowak ◽  
Małgorzata Zakłos-Szyda ◽  
Ewa Kochan ◽  
Grażyna Szymańska ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Contractile Function ◽  
Neuronal Damage ◽  
American Ginseng ◽  
Anxiolytic Activity ◽  
Panax Quinquefolium ◽  
Cardiac Contractile Function ◽  
Neuroprotective Effects ◽  
Beneficial Effects ◽  
Model Of Alzheimer’S Disease

Panax quinquefolium L. (American Ginseng, AG) is an herb characteristic for regions of North America and Asia. Due to its beneficial properties it has been extensively investigated for decades. Nowadays, it is one of the most commonly applied medical herbs worldwide. Active compounds of AG are ginsenosides, saponins of the glycosides group that are abundant in roots, leaves, stem, and fruits of the plant. Ginsenosides are suggested to be primarily responsible for health-beneficial effects of AG. AG acts on the nervous system; it was reported to improve the cognitive function in a mouse model of Alzheimer’s disease, display anxiolytic activity, and neuroprotective effects against neuronal damage resulting from ischemic stroke in animals, demonstrate anxiolytic activity, and induce neuroprotective effects against neuronal damage in ischemic stroke in animals. Administration of AG leads to inhibition of hypertrophy in heart failure by regulation of reactive oxygen species (ROS) in mice as well as depletion of cardiac contractile function in rats. It also has an anti-diabetic and anti-obesity potential as it increases insulin sensitivity and inhibits formation of adipose tissue. AG displays anti-cancer effect by induction of apoptosis of cancer cells and reducing local inflammation. It exerts antimicrobial effects against several pathogenic strains of bacteria. Therefore, AG presents a high potential to induce beneficial health effects in humans and should be further explored to formulate precise nutritional recommendations, as well as to assess its value in prevention and therapy of some disorders, including cancer.

An Angiopep-2 functionalized nanoformulation enhances brain accumulation of tanshinone IIA and exerts neuroprotective effects against ischemic stroke

2018 ◽  
Vol 42 (21) ◽  
pp. 17359-17370 ◽  
Author(s):  
Yutao Li ◽  
Yanxin Dang ◽  
Dandan Han ◽  
Yong Tan ◽  
Xin Liu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Tanshinone Iia ◽  
Effective Intervention ◽  
Neuroprotective Effects ◽  
Neuroprotective Drugs ◽  
The Brain

Effective intervention against ischemic stroke requires delivery of potent neuroprotective drugs to the brain.

Combination of Scutellaria baicalensis and Metformin Ameliorates Diet-Induced Metabolic Dysregulation in Mice via the Gut–Liver–Brain Axis

2020 ◽  
Vol 48 (06) ◽  
pp. 1409-1433
Author(s):  
AbuZar Ansari ◽  
Shambhunath Bose ◽  
Soo-Kyoung Lim ◽  
Jing-Hua Wang ◽  
Young-Hee Choi ◽  
...  
Keyword(s):  
Microbial Population ◽  
Metabolic Diseases ◽  
Neuronal Damage ◽  
The Body ◽  
Scutellaria Baicalensis ◽  
Metabolic Markers ◽  
Metabolic Dysregulation ◽  
High Fructose ◽  
The Brain

Scutellaria baicalensis (SB), a herbal medicine, is commonly used to treat metabolic diseases, while Metformin (MF) is a widely used drug for type 2 diabetes. The purpose of this study was to investigate whether co-treatment of SB with MF could produce a potential therapeutic effect on high-fat and high-fructose diet (HFFD)-induced metabolic dysregulation. First, we optimized the dose of SB (100, 200, 400, and 800[Formula: see text]mg/kg) with MF (200[Formula: see text]mg/kg) in HFFD-induced C57BL6J mice. Next, the optimized dose of SB (400[Formula: see text]mg/kg) was co-administered with MF (50, 100, and 200[Formula: see text]mg/kg) in a similar animal model to find the effective combinations of SB and MF. Metabolic markers were determined in serum and tissues using different assays, histology, gene expression, and gut microbial population. The SB and MF co-treatment significantly decreased the body, liver, and VAT weights. The outcome of OGTT was improved, and the fasting insulin, HbA1c, TG, TC, LDL-c, AST, and ALT were decreased, while HDL-c was significantly increased. Histological analyses revealed maintained the integrity of liver, adipose tissue, and intestine prevented lipid accumulation in the liver and intestine and combated neuronal damage in the brain. Importantly, controlled the expression of PPAR[Formula: see text], and IL-6 genes in the liver, and expression of BDNF, Glut1, Glut3, and Glut4 genes in the brain. Treatment-specific gut microbial segregation was observed in the PCA chart. Our findings indicate that SB and MF co-treatment is an effective therapeutic approach for HFFD-induced metabolic dysregulation which is operated through the gut–liver–brain axis.

scholarly journals Intravenous Thrombolysis in Ischemic Stroke Patients with Intracranial Neoplasms: Two Cases and a Literature Review

2011 ◽  
Vol 2011 ◽  
pp. 1-3 ◽  
Author(s):  
William Neil ◽  
Bruce Ovbiagele
Keyword(s):  
Ischemic Stroke ◽  
Intravenous Thrombolysis ◽  
Recombinant Tissue Plasminogen Activator ◽  
Brain Parenchyma ◽  
Intracranial Neoplasms ◽  
First Case ◽  
Tissue Plasminogen ◽  
Acoustic Schwannoma ◽  
Brain Parenchymal ◽  
The Brain

Based on exclusion criteria in the landmark NINDS-rtPA trial, current expert consensus guidelines preclude the use of intravenous recombinant tissue plasminogen activator (IV rtPA) in acute ischemic stroke (AIS) patients with intracranial neoplasm. There are only 3 published cases of administration of IV rtPA to AIS patients with intracranial neoplasms in the literature. Two of these published cases involved malignant brain parenchymal lesions discovered only after rtPA was inadvertently given, and one of these cases was associated with hemorrhage within the tumor. In this paper, we report two cases of administration of IV rtPA in AIS patients with intracranial neoplasms observed on neuroimaging prior to IV rtPA administration. In both cases, the tumor was outside of the brain parenchyma. The first case was an acoustic schwannoma and the second a falcine meningioma. Neither case was associated with intratumoral hemorrhage as of at least one week following IV rtPA treatment. More published cases are definitely warranted, but our experience with these two cases suggests that administration of IV rtPA to AIS patients in the presence of extraparenchymal brain tumors may not necessarily precipitate intra-tumoral bleeding and thereby worsen clinical outcomes.

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