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 Blood–brain barrier disruption in CCL2 transgenic mice during pertussis toxin-induced brain inflammation

2012 ◽  
Vol 9 (1) ◽  
pp. 10 ◽  
Author(s):  
Angela E Schellenberg ◽  
Richard Buist ◽  
Marc R Del Bigio ◽  
Henrik Toft-Hansen ◽  
Reza Khorooshi ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Blood Brain Barrier ◽  
Pertussis Toxin ◽  
Brain Inflammation ◽  
Brain Barrier ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption

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 Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

Aging Cell ◽  
2015 ◽  
Vol 14 (6) ◽  
pp. 1003-1013 ◽  
Author(s):  
Divya D. A. Raj ◽  
Jill Moser ◽  
Susanne M. A. Pol ◽  
Ronald P. Os ◽  
Inge R. Holtman ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Mouse Model ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Telomere Shortening ◽  
Blood Brain

scholarly journals Pertussis toxin–induced inflammatory response exacerbates intracerebral haemorrhage and ischaemic stroke in mice

2021 ◽  
pp. svn-2021-000987
Author(s):  
Ming Zou ◽  
Yan Feng ◽  
Yuwhen Xiu ◽  
Yan Li ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Brain Injury ◽  
Inflammatory Response ◽  
Mouse Model ◽  
Ischaemic Stroke ◽  
Systemic Inflammation ◽  
Pertussis Toxin ◽  
Intracerebral Haemorrhage ◽  
Brain Inflammation ◽  
Neurological Deficits ◽  
Stroke Severity

BackgroundStroke is a devastating disease, including intracerebral haemorrhage (ICH) and ischaemic stroke. Emerging evidences indicate that systemic inflammatory cascades after stroke contribute to brain damage. However, the direct effects and features of systemic inflammation on brain injury, especially comparing between ischaemic and haemorrhagic stroke, are still obscure.MethodsPertussis toxin (PT) was used to build a pro-inflammatory milieu after ICH and ischaemic stroke in mouse model. The neurodeficits, stroke lesion, immune response and blood–brain barrier (BBB) destruction were assessed.ResultsIn ICH mouse model, PT-induced systemic inflammation exacerbated neurological deficits, and enlarged haemorrhage lesion and perihaematomal oedema. We also found promoted leucocyte infiltration and inflammatory cytokine release into the brain after PT treatment. Moreover, the integrity of the BBB was further disrupted after receiving PT. Furthermore, we demonstrated that PT enhanced brain inflammation and aggravated stroke severity in middle cerebral artery occlusion mouse model.ConclusionsOur results suggest that PT increases inflammatory response that exacerbates brain injury after ICH or ischaemic stroke in mouse model.

Increased blood-brain barrier permeability in contralateral hemisphere predicts worse outcome in acute ischemic stroke after reperfusion therapy

2018 ◽  
Vol 10 (10) ◽  
pp. 937-941 ◽  
Author(s):  
Chang Liu ◽  
Shenqiang Yan ◽  
Ruiting Zhang ◽  
Zhicai Chen ◽  
Feina Shi ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Multivariable Analysis ◽  
Reperfusion Therapy ◽  
Brain Barrier ◽  
Stroke Severity ◽  
Nihss Score ◽  
Blood Brain ◽  
Mirror Region

AimsWe sought to investigate the risk factors of blood-brain barrier (BBB) disruption, and its potential impact on 90-day clinical outcome in acute ischemic stroke (AIS) patients after reperfusion therapy.MethodsConsecutive acute anterior circulation AIS patients imaged with computed tomographic perfusion (CTP) before reperfusion therapy were included. Tmax >6 s was used for the volumetric measurement of the hypoperfusion area. BBB permeability (BBBP) was calculated as the average relative permeability-surface area product (rPS) within the hypoperfusion region (rPShypo-i) and its contralateral mirror region (rPShypo-c) on CTP-derived PS color maps. Modified Rankin Scale (mRS) score was obtained at 90-day post-stroke.ResultsA total of 187 patients were included, among whom the median age was 73 (61–80) years and 76 (40.6%) were women. Median baseline NIHSS score was 12 (7– 16). Ninety-eight (52.4%) patients had mRS score >2. Increased rPShypo-i and rPShypo-c were both independently associated with males and large infarct volume. The increased rPShypo-i was also independently associated with a history of atrial fibrillation and high NIHSS score. Multivariable analysis showed higher rPShypo-c was independently associated with higher mRS (OR: 1.064, 95% CI 1.011 to 1.121; P=0.018).ConclusionBBBP in both the hypoperfusion region and its contralateral mirror region are associated with stroke severity, but only increased BBBP in the contralateral mirror hypoperfusion region relates to worse outcome after reperfusion therapy.

scholarly journals Sustained Opening of the Blood-Brain Barrier with Progressive Accumulation of White Matter Hyperintensities Following Ischemic Stroke

2019 ◽  
Vol 9 (1) ◽  
pp. 16 ◽  
Author(s):  
Imama Naqvi ◽  
Emi Hitomi ◽  
Richard Leigh
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Stroke ◽  
Blood Brain Barrier ◽  
White Matter Hyperintensities ◽  
Brain Barrier ◽  
Common Finding ◽  
Blood Brain ◽  
History Of ◽  
Iv Tpa

Objective: To report a patient in whom an acute ischemic stroke precipitated chronic blood-brain barrier (BBB) disruption and expansion of vascular white matter hyperintensities (WMH) into regions of normal appearing white matter (NAWM) during the following year. Background: WMH are a common finding in patients with vascular risk factors such as a history of stroke. The pathophysiology of WMH is not fully understood; however, there is growing evidence to suggest that the development of WMH may be preceded by the BBB disruption in the NAWM. Methods: We studied a patient enrolled in the National Institutes of Health Natural History of Stroke Study who was scanned with magnetic resonance imaging (MRI) after presenting to the emergency room with an acute stroke. After a treatment with IV tPA, she underwent further MRI scanning at 2 h, 24 h, 5 days, 30 days, 90 days, 6 months, and 1-year post stroke. BBB permeability images were generated from the perfusion weighted imaging (PWI) source images. MRIs from each time point were co-registered to track changes in BBB disruption and WMH over time. Results: An 84-year-old woman presented after acute onset right hemiparesis, right-sided numbness and aphasia with an initial NIHSS of 13. MRI showed diffusion restriction in the left frontal lobe and decreased blood flow on perfusion imaging. Fluid attenuated inversion recovery (FLAIR) imaging showed bilateral confluent WMH involving the deep white matter and periventricular regions. She was treated with IV tPA without complication and her NIHSS improved initially to 3 and ultimately to 0. Permeability maps identified multiple regions of chronic BBB disruption remote from the acute stroke, predominantly spanning the junction of WMH and NAWM. The severity of BBB disruption was greatest at 24 h after the stroke but persisted on subsequent MRI scans. Progression of WMH into NAWM over the year of observation was detected bilaterally but was most dramatic in the regions adjacent to the initial stroke. Conclusions: WMH-associated BBB disruption may be exacerbated by an acute stroke, even in the contralateral hemisphere, and can persist for months after the initial event. Transformation of NAWM to WMH may be evident in areas of BBB disruption within a year after the stroke. Further studies are needed to investigate the relationship between chronic BBB disruption and progressive WMH in patients with a history of cerebrovascular disease and the potential for acute stroke to trigger or exacerbate the process leading to the development of WMH.

scholarly journals Blood-Brain Barrier Disruption Increases Amyloid-Related Pathology in TgSwDI Mice

2021 ◽  
Vol 22 (3) ◽  
pp. 1231
Author(s):  
Ihab M. Abdallah ◽  
Kamal M. Al-Shami ◽  
Euitaek Yang ◽  
Amal Kaddoumi
Keyword(s):  
Mouse Model ◽  
Blood Brain Barrier ◽  
High Throughput Screening ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Amyloid Angiopathy ◽  
Cancer Resistance ◽  
Screening Assay ◽  
Blood Brain ◽  
High Throughput Screening Assay

In Alzheimer’s disease (AD), several studies have reported blood-brain barrier (BBB) breakdown with compromised function. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are transport proteins localized at the BBB luminal membrane and play an important role in the clearance of amyloid-β (Aβ). The purpose of this study was to investigate the effect of pharmacological inhibition of Aβ efflux transporters on BBB function and Aβ accumulation and related pathology. Recently, we have developed an in vitro high-throughput screening assay to screen for compounds that modulate the integrity of a cell-based BBB model, which identified elacridar as a disruptor of the monolayer integrity. Elacridar, an investigational compound known for its P-gp and BCRP inhibitory effect and widely used in cancer research. Therefore, it was used as a model compound for further evaluation in a mouse model of AD, namely TgSwDI. TgSwDI mouse is also used as a model for cerebral amyloid angiopathy (CAA). Results showed that P-gp and BCRP inhibition by elacridar disrupted the BBB integrity as measured by increased IgG extravasation and reduced expression of tight junction proteins, increased amyloid deposition due to P-gp, and BCRP downregulation and receptor for advanced glycation end products (RAGE) upregulation, increased CAA and astrogliosis. Further studies revealed the effect was mediated by activation of NF-κB pathway. In conclusion, results suggest that BBB disruption by inhibiting P-gp and BCRP exacerbates AD pathology in a mouse model of AD, and indicate that therapeutic drugs that inhibit P-gp and BCRP could increase the risk for AD.

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