scholarly journals Treatment with Edoxaban Attenuates Acute Stroke Severity in Mice by Reducing Blood–Brain Barrier Damage and Inflammation

2021 ◽  
Vol 22 (18) ◽  
pp. 9893
Author(s):  
Michael Bieber ◽  
Kathrin I. Foerster ◽  
Walter E. Haefeli ◽  
Mirko Pham ◽  
Michael K. Schuhmann ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Blood Brain Barrier ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Brain Barrier ◽  
Protective Mechanism ◽  
Stroke Severity ◽  
Local Inflammatory Response ◽  
Blood Brain ◽  
Increased Risk

Patients with atrial fibrillation and previous ischemic stroke (IS) are at increased risk of cerebrovascular events despite anticoagulation. In these patients, treatment with non-vitamin K oral anticoagulants (NOAC) such as edoxaban reduced the probability and severity of further IS without increasing the risk of major bleeding. However, the detailed protective mechanism of edoxaban has not yet been investigated in a model of ischemia/reperfusion injury. Therefore, in the current study we aimed to assess in a clinically relevant setting whether treatment with edoxaban attenuates stroke severity, and whether edoxaban has an impact on the local cerebral inflammatory response and blood–brain barrier (BBB) function after experimental IS in mice. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in male mice receiving edoxaban, phenprocoumon or vehicle. Infarct volumes, functional outcome and the occurrence of intracerebral hemorrhage were assessed. BBB damage and the extent of local inflammatory response were determined. Treatment with edoxaban significantly reduced infarct volumes and improved neurological outcome and BBB function on day 1 and attenuated brain tissue inflammation. In summary, our study provides evidence that edoxaban might exert its protective effect in human IS by modulating different key steps of IS pathophysiology, but further studies are warranted.

scholarly journals Pertussis Toxin Induced Inflammatory Response Exacerbates Intracerebral Hemorrhage and Ischemic Stroke in Mice

2020 ◽  
Author(s):  
Ming Zou ◽  
Yan Li ◽  
Hui Zhao ◽  
Yan Feng ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Response ◽  
Mouse Model ◽  
Intracerebral Hemorrhage ◽  
Blood Brain Barrier ◽  
Pertussis Toxin ◽  
Brain Inflammation ◽  
Brain Barrier ◽  
Stroke Severity ◽  
Blood Brain

Abstract Background: Stroke is a devastating and debilitating disease and is a leading cause of death worldwide, including intracerebral hemorrhage (ICH) and ischemic stroke. Emerging evidence indicates that inflammatory cascades after hemorrhagic or ischemic stroke makes a great contribution to brain damage, mainly are involved in neuronal cell death, blood-brain-barrier (BBB) destruction and development of vasogenic edema. However, the features and direct effect of brain inflammation following stroke is still unknown. Methods: We adopted the ICH model by injection of collagenase and used a mouse model of transient cerebral ischemia and reperfusion. And pertussis toxin was used to create a pro-inflammatory milieu. Neurodeficits, lesion volume, production of reactive oxygen species (ROS) and inflammatory factors, brain-infiltrating leukocytes and blood-brain-barrier (BBB) destruction were assessed in mice model treated with pertussis toxin or vehicle.Results: Adopting collagenase induced intracerebral hemorrhage mouse model, we show that pertussis toxin-induced systemic inflammation exacerbated neurological deficits, enlarged lesion size and brain perihematomal edema after intracerebral hemorrhage. Pertussis toxin promoted leukocyte infiltration and inflammatory cytokine release in the brain. Moreover, the integrity of the BBB was further disrupted after receiving pertussis toxin in ICH mice. Furthermore, we demonstrated that pertussis toxin increased stroke severity and enhanced brain inflammation in middle cerebral artery occlusion (MCAO) mouse model. Conclusion: Our results suggest that pertussis toxin increases inflammatory response that exacerbates brain injury after intracerebral hemorrhage or ischemic stroke in mouse model.

scholarly journals Regulator of G‐Protein Signaling 5 Maintains Brain Endothelial Cell Function in Focal Cerebral Ischemia

2020 ◽  
Vol 9 (18) ◽  
Author(s):  
Nikola Sladojevic ◽  
Brian Yu ◽  
James K. Liao
Keyword(s):  
Endothelial Cells ◽  
Cerebral Ischemia ◽  
G Protein ◽  
Blood Brain Barrier ◽  
Focal Cerebral Ischemia ◽  
Brain Barrier ◽  
Stroke Severity ◽  
Protein Signaling ◽  
Blood Brain

Background Regulator of G‐protein signaling 5 (RGS5) is a negative modulator of G‐protein–coupled receptors. The role of RGS5 in brain endothelial cells is not known. We hypothesized that RGS5 in brain microvascular endothelial cells may be an important mediator of blood‐brain barrier function and stroke severity after focal cerebral ischemia. Methods and Results Using a transient middle cerebral artery occlusion model, we found that mice with global and endothelial‐specific deletion of Rgs5 exhibited larger cerebral infarct size, greater neurological motor deficits, and increased brain edema. In our in vitro models, we observed increased G q activity and elevated intracellular Ca 2+ levels in brain endothelial cells. Furthermore, the loss of endothelial RGS5 leads to decreased endothelial NO synthase expression and phosphorylation, relocalization of endothelial tight junction proteins, and increased cell permeability. Indeed, RGS5 deficiency leads to increased Rho‐associated kinase and myosin light chain kinase activity, which were partially reversed in our in vitro model by pharmacological inhibition of G q , metabotropic glutamate receptor 1, and ligand‐gated ionotropic glutamate receptor. Conclusions Our findings indicate that endothelial RGS5 plays a novel neuroprotective role in focal cerebral ischemia. Loss of endothelial RGS5 leads to hyperresponsiveness to glutamate signaling pathways, enhanced Rho‐associated kinase– and myosin light chain kinase–mediated actin‐cytoskeleton reorganization, endothelial dysfunction, tight junction protein relocalization, increased blood‐brain barrier permeability, and greater stroke severity. These findings suggest that preservation of endothelial RGS5 may be an important therapeutic strategy for maintaining blood‐brain barrier integrity and limiting the severity of ischemic stroke.

scholarly journals Modulation of α7nAchR by Melatonin Alleviates Ischemia and Reperfusion-Compromised Integrity of Blood Brain Barrier through Inhibiting HMGB1-Mediated Microglia Activation and CRTC1-Mediated Neuronal Loss

2021 ◽  
Author(s):  
Shuang Chen ◽  
Yanyun Sun ◽  
Fei Li ◽  
Xinyu Zhang ◽  
Xiaoyan Hu ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Ischemia Reperfusion ◽  
Neuronal Loss ◽  
Microglia Activation ◽  
Brain Barrier ◽  
Ischemia And Reperfusion ◽  
Therapeutic Benefits ◽  
Blood Brain ◽  
Increased Risk ◽  
Bbb Permeability

Abstract The only food and drug administration (FDA)-approved drug currently available for the treatment of acute ischemic stroke is tissue plasminogen activator (tPA), yet the therapeutic benefits of this drug are partially outweighed by the increased risk of hemorrhagic transformation (HT). Analysis of the NIH trial has shown that cigarette smoking protected tPA-treated patients from HT, however, the underlying mechanism is not clear. Nicotinic acetylcholine receptors (nAChR) has shown anti-inflammatory effect and modulation nAChR could be a strategy to reduce ischemia/reperfusion-induced blood brain barrier (BBB) damage. Since melatonin could regulate the expression of α7nAchR and melatonin’s neuroprotective effect against ischemic injury is mediated via α7nAChR modulation, here, we aim to test the hypothesis that melatonin reduces ischemia and reperfusion (I/R)-induced BBB damage through modulation of α7nACh receptor (α7nAChR). Mice were subjected to 1.5 h ischemia and 24 h reperfusion and at the onset of reperfusion, mice received intraperitoneal administration (i.p.) of either drug or saline. Mice were randomly assigned into five groups: Saline; α7nAChR agonist PNU282987; Melatonin; Melatonin + Methyllycaconitine (MLA, α7nAChR antagonist) and MLA group. BBB permeability was assessed by detecting the extravasation of Evan’s blue and IgG. Our results showed that I/R significantly increased BBB permeability accompanied by occludin degradation, microglia activation, and high mobility group box 1 (HMGB1) release from the neuron. In addition, I/R significantly induced neuronal loss accompanied by the decrease of CREB regulated transcriptional coactivator 1 (CRTC1) and p-CREB expression. Melatonin treatment significantly inhibited the above changes through modulating α7nAChR. Taken together, these results demonstrate that melatonin provides a protective effect on ischemia/reperfusion-induced BBB damage, at least in part, depending on modulation of α7nAChR.

scholarly journals Description of a Novel Phosphodiesterase (PDE)-3 Inhibitor Protecting Mice From Ischemic Stroke Independent From Platelet Function

Stroke ◽  
2019 ◽  
Vol 50 (2) ◽  
pp. 478-486 ◽  
Author(s):  
Michael Bieber ◽  
Michael K. Schuhmann ◽  
Julia Volz ◽  
Gangasani Jagadeesh Kumar ◽  
Jayathirtha Rao Vaidya ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Blood Brain Barrier ◽  
Platelet Function ◽  
Focal Cerebral Ischemia ◽  
Brain Barrier ◽  
Local Inflammatory Response ◽  
Blood Brain ◽  
Blood Brain Barrier Damage

Background and Purpose— Acetylsalicylic acid and clopidogrel are the 2 main antithrombotic drugs for secondary prevention in patients with ischemic stroke (IS) without indication for anticoagulation. Because of their limited efficacy and potential side effects, novel antiplatelet agents are urgently needed. Cilostazol, a specific phosphodiesterase (PDE)-3 inhibitor, protected from IS in clinical studies comprising mainly Asian populations. Nevertheless, the detailed mechanistic role of PDE-3 inhibitors in IS pathophysiology is hardly understood. In this project, we analyzed the efficacy and pathophysiologic mechanisms of a novel and only recently described PDE-3 inhibitor (substance V) in a mouse model of focal cerebral ischemia. Methods— Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in 6- to 8-week-old male C57Bl/6 wild-type mice receiving substance V or vehicle 1 hour after ischemia induction. Infarct volumes and functional outcomes were assessed between day 1 and day 7, and findings were validated by magnetic resonance imaging. Blood-brain barrier damage, as well as the extent of local inflammatory response and cell death, was determined. Results— Inhibition of PDE-3 by pharmacological blockade with substance V significantly reduced infarct volumes and improved neurological outcome on day 1 and 7 after experimental cerebral ischemia. Reduced blood-brain barrier damage, attenuated brain tissue inflammation, and decreased local cell death could be identified as potential mechanisms. PDE-3 inhibitor treatment did neither increase the number of intracerebral hemorrhages nor affect platelet function. Conclusions— The novel PDE-3 inhibitor substance V protected mice from IS independent from platelet function. Pharmaceutical inactivation of PDE-3 might become a promising therapeutic approach to combat IS via inhibition of thromboinflammatory mechanisms and stabilization of the blood-brain barrier.

scholarly journals Neuroprotective Effect of Activated Protein C on Blood–Brain Barrier Injury During Focal Cerebral Ischemia/Reperfusion

Dose-Response ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 155932582091728
Author(s):  
Jinqiao Wang ◽  
Gaofeng Rao ◽  
Yifan Ma ◽  
Jingjing Zhang ◽  
Jingjing Shen ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Blood Brain Barrier ◽  
Protein C ◽  
Focal Cerebral Ischemia ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Activated Protein C ◽  
Brain Barrier ◽  
Cerebral Ischemia Reperfusion ◽  
Blood Brain

Although the effect of activated protein C (APC) on neuronal injury and neuroinflammatory responses has been extensively studied, the detailed mechanism underlying APC-protective effect in the blood–brain barrier (BBB) injury during ischemia is still not clear. In this study, the APC effect against neuroinflammatory responses was evaluated in the model of right middle cerebral artery occlusion in male Sprague-Dawley rats with 2 hours of ischemia and 22 hours of reperfusion. The results showed that APC can significantly improve the neurological function scoring and reduce the infarct volume and BBB permeability. Moreover, the expression of protein nuclear factor-kappa B (NF-κB), both in cytoplasm and nuclei, was reduced. The downstream of NF-κB activation, including tumor necrosis factor-α and interleukin-1β secretion, was inhibited. In all, APC exerts a neuroprotective effect in focal cerebral ischemia–reperfusion in rats by inhibiting the activation and nuclear translocation of NF-κB. It may indicate a therapeutic approach for ischemic brain injury.

Pretreatment with rivaroxaban attenuates stroke severity in rats by a dual antithrombotic and anti-inflammatory mechanism

2016 ◽  
Vol 115 (04) ◽  
pp. 835-843 ◽  
Author(s):  
Peter Kraft ◽  
Michael K. Schuhmann ◽  
Melanie Dittmeier ◽  
Felix Fluri ◽  
Christoph Kleinschnitz
Keyword(s):  
Blood Brain Barrier ◽  
Therapeutic Potential ◽  
Thrombus Formation ◽  
Oral Anticoagulants ◽  
Brain Barrier ◽  
Stroke Severity ◽  
Ischaemia Reperfusion Injury ◽  
Blood Brain ◽  
Ischaemic Brain ◽  
Increased Risk

SummaryStroke outcome is more favourable in patients receiving oral anticoagulants compared with non-anticoagulated patients. The reasons for this “stroke-attenuating” property of oral anticoagulants are largely unknown. This study examined whether prestroke anticoagulation with rivaroxaban, a novel direct factor Xa inhibitor, influences stroke severity, thrombin-mediated intracerebral thrombus formation and pro-inflammatory processes in a rat model of brain ischaemia/reperfusion injury. Male Wistar rats were anticoagulated with rivaroxaban and subjected to 90 minutes of transient middle cerebral artery occlusion. Infarct size, functional outcome and the occurrence of intracranial haemorrhage (ICH) were assessed until day 7. Thrombin generation was determined by measuring the amount of thrombin/antithrombin complex. Intracerebral thrombus formation was evaluated by histology and Western blot. CD68-immunoreactivity and the expression of cytokines and adhesion molecules were investigated to assess postischaemic inflammation. The integrity of the blood–brain barrier was analysed using fluorescein isothiocyanate-dextran. Rats pretreated with rivaroxaban developed significantly smaller strokes and less severe functional deficits compared with controls. Although rivaroxaban strongly reduced thrombin-mediated thrombus formation, this was not accompanied by an increased risk of ICH. In addition, rivaroxaban dampened the inflammatory response in the ischaemic brain by downregulating ICAM-1 expression and the activation of CD68+-immune cells. In contrast, rivaroxaban had no effect on the integrity of the blood–brain barrier after stroke. Here, we identified reduced thrombo-inflammation as a major determinant of the stroke-protective property of rivaroxaban in rats. Further studies are needed to assess the therapeutic potential of novel oral anticoagulants in the acute phase after a stroke.

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