The effect of angiopoietin-1 upregulation on the outcome of acute ischaemic stroke in rodent models: A meta-analysis

Moxon, Joseph V.; Trollope, Alexandra F.; Dewdney, Brittany; Hollander, Catherine de; Nastasi, Domenico R.; Maguire, Jane; Golledge, Jonathan

doi:10.1177/0271678x19876876

Cited by 14 publications

(18 citation statements)

References 54 publications

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“…The reduction in lesion volume may contribute to improved neurological function in VT‐treated rats compared to control T1DM stroke rats. The neuroprotective effects of Ang1 treatment in non‐DM rodents have been previously demonstrated 7,8,14,48–50 . In non‐DM rats subject to 2 h of transient MCAo stroke, intravascular administration of recombinant Ang1 (1 μg/kg) once every 12 h starting immediately after reperfusion significantly decreases neurological severity score, decreases infarct volume, attenuates BBB leakage, and increases the expression of tight junction proteins in the ischemic brain 49,50 .…”

Section: Discussionmentioning

confidence: 85%

“…Ang1 has previously been shown to reduce infarct volume in mice subjected to focal cerebral embolic ischemia 7 . A meta‐analysis study of 11 pre‐clinical stroke studies reported that Ang1 upregulation significantly decreases lesion volume and improves BBB integrity following transient ischemic stroke in rodents 14 . Treatment with Ang1 has also been shown to reduce neuronal cell death by inhibiting the upregulation of pro‐apoptotic factors in vitro 47 .…”

Section: Discussionmentioning

confidence: 99%

“…In our previous study, we found that VT pre‐treatment of stroke in rats with type 1 diabetes mellitus (T1DM) exerts neuroprotective effects by decreasing the expression of pro‐inflammatory factors in the ischemic brain 13 . While the neuroprotective effects of Ang1 treatment in non‐diabetic stroke are well documented, 7,8,14,15 there are few studies investigating the therapeutic effects of Ang‐1 in diabetic stroke 13,14 . The therapeutic efficacy and long‐term effects of delayed treatment with VT in T1DM rats subjected to stroke remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Treatment with an Angiopoietin‐1 mimetic peptide promotes neurological recovery after stroke in diabetic rats

et al. 2020

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Aim Vasculotide (VT), an angiopoietin‐1 mimetic peptide, exerts neuroprotective effects in type one diabetic (T1DM) rats subjected to ischemic stroke. In this study, we investigated whether delayed VT treatment improves long‐term neurological outcome after stroke in T1DM rats. Methods Male Wistar rats were induced with T1DM, subjected to middle cerebral artery occlusion (MCAo) model of stroke, and treated with PBS (control), 2 µg/kg VT, 3 µg/kg VT, or 5.5 µg/kg VT. VT treatment was initiated at 24 h after stroke and administered daily (i.p) for 14 days. We evaluated neurological function, lesion volume, vascular and white matter remodeling, and inflammation in the ischemic brain. In vitro, we evaluated the effects of VT on endothelial cell capillary tube formation and inflammatory responses of primary cortical neurons (PCN) and macrophages. Results Treatment of T1DM‐stroke with 3 µg/kg VT but not 2 µg/kg or 5.5 µg/kg significantly improves neurological function and decreases infarct volume and cell death compared to control T1DM‐stroke rats. Thus, 3 µg/kg VT dose was employed in all subsequent in vivo analysis. VT treatment significantly increases axon and myelin density, decreases demyelination, decreases white matter injury, increases number of oligodendrocytes, and increases vascular density in the ischemic border zone of T1DM stroke rats. VT treatment significantly decreases MMP9 expression and decreases the number of M1 macrophages in the ischemic brain of T1DM‐stroke rats. In vitro, VT treatment significantly decreases endothelial cell death and decreases MCP‐1, endothelin‐1, and VEGF expression under high glucose (HG) and ischemic conditions and significantly increases capillary tube formation under HG conditions when compared to non‐treated control group. VT treatment significantly decreases inflammatory factor expression such as MMP9 and MCP‐1 in macrophages subjected to LPS activation and significantly decreases IL‐1β and MMP9 expression in PCN subjected to ischemia under HG conditions. Conclusion Delayed VT treatment (24 h after stroke) significantly improves neurological function, promotes vascular and white matter remodeling, and decreases inflammation in the ischemic brain after stroke in T1DM rats.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Treatment with an Angiopoietin‐1 mimetic peptide promotes neurological recovery after stroke in diabetic rats

et al. 2020

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“…In the remodeling phase after myocardial infarction, endothelial-and macrophage-derived ANGPT2 promotes abnormal vascular remodeling and exacerbates inflammation. In contrast, ANGPT1 plays a protective role in preclinical models of vascular injury [37,38] and exerts anti-inflammatory effects [20].…”

Section: Discussionmentioning

confidence: 99%

“…ANGPT2 has been proposed as a prognostic biomarker of adverse cardiovascular events in myocardial infarction [34] and after percutaneous coronary intervention (PCI) [35,36]. In contrast, ANGPT1 plays a protective role in rodent models of vascular injuries [37,38].…”

Section: Introductionmentioning

confidence: 99%

Angiopoietins, Vascular Endothelial Growth Factors and Secretory Phospholipase A2 in Ischemic and Non-Ischemic Heart Failure

Varricchi

Loffredo

Bencivenga

et al. 2020

JCM

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Heart failure (HF) is a growing public health burden, with high prevalence and mortality rates. In contrast to ischemic heart failure (IHF), the diagnosis of non-ischemic heart failure (NIHF) is established in the absence of coronary artery disease. Angiopoietins (ANGPTs), vascular endothelial growth factors (VEGFs) and secretory phospholipases A2 (sPLA2s) are proinflammatory mediators and key regulators of endothelial cells. In the present manuscript, we analyze the plasma concentrations of angiogenic (ANGPT1, ANGPT2, VEGF-A) and lymphangiogenic (VEGF-C, VEGF-D) factors and the plasma activity of sPLA2 in patients with IHF and NIHF compared to healthy controls. The concentrations of ANGPT1, ANGPT2 and their ratio significantly differed between HF patients and healthy controls. Similarly, plasma levels of VEGF-D and sPLA2 activity were higher in HF as compared to controls. Concentrations of ANGPT2 and the ANGPT2/ANGPT1 ratio (an index of vascular permeability) were increased in NIHF patients. VEGF-A and VEGF-C concentrations did not differ among the three examined groups. Interestingly, VEGF-D was selectively increased in IFH patients compared to controls. Plasma activity of sPLA2 was increased in IHF and NIHF patients compared to controls. Our results indicate that several regulators of vascular permeability and smoldering inflammation are specifically altered in IHF and NIHF patients. Studies involving larger cohorts of these patients will be necessary to demonstrate the clinical implications of our findings.

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Ceruletide and Alpha-1 Antitrypsin as a Novel Combination Therapy for Ischemic Stroke

et al. 2022

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Ischemic stroke is a primary cause of morbidity and mortality worldwide. Beyond the approved thrombolytic therapies, there is no effective treatment to mitigate its progression. Drug repositioning combinational therapies are becoming promising approaches to identify new uses of existing drugs to synergically target multiple disease-response mechanisms underlying complex pathologies. Here, we used a systems biology-based approach based on artificial intelligence and pattern recognition tools to generate in silico mathematical models mimicking the ischemic stroke pathology. Combinational treatments were acquired by screening these models with more than 5 million two-by-two combinations of drugs. A drug combination (CA) formed by ceruletide and alpha-1 antitrypsin showing a predicted value of neuroprotection of 92% was evaluated for their synergic neuroprotective effects in a mouse pre-clinical stroke model. The administration of both drugs in combination was safe and effective in reducing by 39.42% the infarct volume 24 h after cerebral ischemia. This neuroprotection was not observed when drugs were given individually. Importantly, potential incompatibilities of the drug combination with tPA thrombolysis were discarded in vitro and in vivo by using a mouse thromboembolic stroke model with t-PA-induced reperfusion, revealing an improvement in the forepaw strength 72 h after stroke in CA-treated mice. Finally, we identified the predicted mechanisms of action of ceruletide and alpha-1 antitrypsin and we demonstrated that CA modulates EGFR and ANGPT-1 levels in circulation within the acute phase after stroke. In conclusion, we have identified a promising combinational treatment with neuroprotective effects for the treatment of ischemic stroke.

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The effect of angiopoietin-1 upregulation on the outcome of acute ischaemic stroke in rodent models: A meta-analysis

Cited by 14 publications

References 54 publications

Treatment with an Angiopoietin‐1 mimetic peptide promotes neurological recovery after stroke in diabetic rats

Treatment with an Angiopoietin‐1 mimetic peptide promotes neurological recovery after stroke in diabetic rats

Angiopoietins, Vascular Endothelial Growth Factors and Secretory Phospholipase A2 in Ischemic and Non-Ischemic Heart Failure

Ceruletide and Alpha-1 Antitrypsin as a Novel Combination Therapy for Ischemic Stroke

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