scholarly journals Time-dependent dual effect of NLRP3 inflammasome in brain ischemia

2020 ◽  
Author(s):  
Alejandra Palomino-Antolin ◽  
Paloma Narros-Fernández ◽  
Victor Farré-Alins ◽  
Javier Sevilla-Montero ◽  
Celine Decouty-Pérez ◽  
...  
Keyword(s):  
Brain Injury ◽  
Blood Brain Barrier ◽  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Neurovascular Unit ◽  
Time Dependent ◽  
Brain Barrier ◽  
Dependent Manner ◽  
Dual Effect ◽  
Blood Brain

Background: Post-ischemic inflammation contributes to worsening of ischemic brain injury and in this process, the inflammasomes play a key role. Inflammasomes are cytosolic multiprotein complexes which upon assembly activate the maturation and secretion of the inflammatory cytokines IL-1β and IL-18. However, participation of the NLRP3 inflammasome in ischemic stroke remains controversial. Our aims were to determine the role of NLRP3 in ischemia and to explore the mechanism involved in the potential protective effect of the neurovascular unit. Methods: WT and NLRP3 knock-out mice were subjected to ischemia by middle cerebral artery occlusion (60 minutes) with or without treatment with MCC950 at different time points post-stroke. Brain injury was measured histologically with 2,3,5-triphenyltetrazolium chloride (TTC) staining. Results: We identified a time-dependent dual effect of NLRP3. While neither the pre-treatment with MCC950 nor the genetic approach (NLRP3 KO) proved to be neuroprotective, post-reperfusion treatment with MCC950 significantly reduced the infarct volume in a dose-dependent manner. Importantly, MCC950 improved the neuro-motor function and reduced the expression of different pro-inflammatory cytokines (IL-1β, TNF-α), NLRP3 inflammasome components (NLRP3, pro-caspase-1), protease expression (MMP9) and endothelial adhesion molecules (ICAM, VCAM). We observed a marked protection of the blood-brain barrier (BBB), which was also reflected in the recovery of the tight junctions proteins (ZO-1, Claudin-5). Additionally, MCC950 produced a reduction of the CCL2 chemokine in blood serum and in brain tissue, which lead to a reduction in the immune cell infiltration. Conclusions: These findings suggest that post-reperfusion NLRP3 inhibition may be an effective acute therapy for protecting the blood-brain barrier in cerebral ischemia with potential clinical translation.

scholarly journals Time-dependent dual effect of NLRP3 inflammasome in brain ischemia

2020 ◽  
Author(s):  
Alejandra Palomino-Antolin ◽  
Paloma Narros-Fernández ◽  
Víctor Farré-Alins ◽  
Javier Sevilla-Montero ◽  
Celine Decouty-Pérez ◽  
...  
Keyword(s):  
Brain Injury ◽  
Blood Brain Barrier ◽  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Neurovascular Unit ◽  
Time Dependent ◽  
Brain Barrier ◽  
Dependent Manner ◽  
Dual Effect ◽  
Blood Brain

AbstractBackground and purposePost-ischemic inflammation contributes to worsening of ischemic brain injury and in this process, the inflammasomes play a key role. Inflammasomes are cytosolic multiprotein complexes which upon assembly activate the maturation and secretion of the inflammatory cytokines IL-1β and IL-18. However, participation of the NLRP3 inflammasome in ischemic stroke remains controversial. Our aims were to determine the role of NLRP3 in ischemia and to explore the mechanism involved in the potential protective effect of the neurovascular unit.MethodsWT and NLRP3 knock-out mice were subjected to ischemia by middle cerebral artery occlusion (60 minutes) with or without treatment with MCC950 at different time points post-stroke. Brain injury was measured histologically with 2,3,5-triphenyltetrazolium chloride (TTC) staining.ResultsWe identified a time-dependent dual effect of NLRP3. While neither the pre-treatment with MCC950 nor the genetic approach (NLRP3 KO) proved to be neuroprotective, post-reperfusion treatment with MCC950 significantly reduced the infarct volume in a dose-dependent manner. Importantly, MCC950 improved the neuro-motor function and reduced the expression of different pro-inflammatory cytokines (IL-1β, TNF-α), NLRP3 inflammasome components (NLRP3, pro-caspase-1), protease expression (MMP9) and endothelial adhesion molecules (ICAM, VCAM). We observed a marked protection of the blood-brain barrier (BBB), which was also reflected in the recovery of the tight junctions proteins (ZO-1, Claudin-5). Additionally, MCC950 produced a reduction of the CCL2 chemokine in blood serum and in brain tissue, which lead to a reduction in the immune cell infiltration.ConclusionsThese findings suggest that post-reperfusion NLRP3 inhibition may be an effective acute therapy for protecting the blood-brain barrier in cerebral ischemia with potential clinical translation.

scholarly journals Ultrasound-mediated Blood-brain barrier opening increases cell-free DNA in a time dependent manner

2021 ◽  
Author(s):  
Daniel Y Zhang ◽  
Andrew Gould ◽  
Hannah C Happ ◽  
Mark W Youngblood ◽  
Crismita Dmello ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Time Dependent ◽  
Brain Barrier ◽  
Dependent Manner ◽  
Cell Free Dna ◽  
Free Dna ◽  
Blood Brain ◽  
Barrier Opening ◽  
Blood Brain Barrier Opening

scholarly journals Transient selective brain cooling confers neurovascular and functional protection from acute to chronic stages of ischemia/reperfusion brain injury

2018 ◽  
Vol 39 (7) ◽  
pp. 1215-1231 ◽  
Author(s):  
Jingyan Zhao ◽  
Hongfeng Mu ◽  
Liqiang Liu ◽  
Xiaoyan Jiang ◽  
Di Wu ◽  
...  
Keyword(s):  
Brain Injury ◽  
Blood Brain Barrier ◽  
Ischemia Reperfusion ◽  
Neurovascular Unit ◽  
Brain Barrier ◽  
Acute Injury ◽  
Experimental Stroke ◽  
Post Injury ◽  
Chronic Injury ◽  
Blood Brain

Ischemic injury can be alleviated by the judicious use of hypothermia. However, the optimal regimens and the temporal kinetics of post-stroke neurovascular responses to hypothermic intervention have not been systematically studied. These gaps slow the clinical translation of hypothermia as an anti-stroke therapy. Here, we characterized the effects of transient selective brain hypothermia (TSBH) from the hyperacute to chronic stages of focal ischemia/reperfusion brain injury induced by transient middle cerebral artery occlusion in mice. A simple cooling device was used to induce TSBH during cerebral ischemia. This treatment reduced mortality from 31.8% to 0% and improved neurological outcomes for at least 35 days post-injury. TSBH mitigated blood–brain barrier leakage during the hyperacute and acute injury stages (1–23 h post-reperfusion). This early protection of the blood–brain barrier was associated with anti-inflammatory phenotypic polarization of microglia/macrophages, reduced production of pro-inflammatory cytokines, and less brain infiltration of neutrophils and macrophages during the subacute injury stage (three days post-reperfusion). TSBH elicited enduring protective effects on both grey and white matter for at least 35 days post-injury and preserved the long-term electrophysiological function of fiber tracts. In conclusion, TSBH ameliorates ischemia/reperfusion injury in the neurovascular unit from hyperacute to chronic injury stages after experimental stroke.

scholarly journals Maf1 Ameliorates Sepsis-Associated Encephalopathy by Suppressing the NF-kB/NLRP3 Inflammasome Signaling Pathway

2020 ◽  
Vol 11 ◽  
Author(s):  
Shenglong Chen ◽  
Chaogang Tang ◽  
Hongguang Ding ◽  
Zhonghua Wang ◽  
Xinqiang Liu ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Brain Barrier ◽  
Blue Dye ◽  
Inflammasome Activation ◽  
Blood Brain ◽  
Pro Inflammatory Cytokines

BackgroundThe NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been identified as an important mediator of blood–brain-barrier disruption in sepsis-associated encephalopathy (SAE). However, no information is available concerning the critical upstream regulators of SAE.MethodsLipopolysaccharide (LPS) was used to establish an in vitro model of blood–brain barrier (BBB) disruption and an in vivo model of SAE. Disruption of BBB integrity was assessed by measuring the expression levels of tight-junction proteins. NLRP3 inflammasome activation, pro-inflammatory cytokines levels, and neuroapoptosis were measured using biochemical assays. Finally, the FITC-dextran Transwell assay and Evan’s blue dye assay were used to assess the effect of Maf1 on LPS-induced endothelial permeability in vitro and in vivo.ResultsWe found that Maf1 significantly suppressed the brain inflammatory response and neuroapoptosis induced by LPS in vivo and in vitro. Notably, Maf1 downregulated activation of the NF-κB/p65-induced NLRP3 inflammasome and the expression of pro-inflammatory cytokines. In addition, we found that Maf1 and p65 directly bound to the NLRP3 gene promoter region and competitively regulated the function of NLRP3 in inflammations. Moreover, overexpression of NLRP3 reversed the effects of p65 on BBB integrity, apoptosis, and inflammation in response to LPS. Our study revealed novel role for Maf1 in regulating NF-κB-mediated inflammasome formation, which plays a prominent role in SAE.ConclusionsRegulation of Maf1 might be a therapeutic strategy for SAE and other neurodegenerative diseases associated with inflammation.

scholarly journals Screening for Interacting Proteins with Peptide Biomarker of Blood–Brain Barrier Alteration under Inflammatory Conditions

2021 ◽  
Vol 22 (9) ◽  
pp. 4725
Author(s):  
Karina Vargas-Sanchez ◽  
Monica Losada-Barragán ◽  
Maria Mogilevskaya ◽  
Susana Novoa-Herrán ◽  
Yehidi Medina ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Specific Interaction ◽  
Brain Barrier ◽  
Mass Spectrometry Analysis ◽  
Peptide Ligand ◽  
Inflammatory Conditions ◽  
Blood Brain ◽  
Potential Biomarker

Neurodegenerative diseases are characterized by increased permeability of the blood–brain barrier (BBB) due to alterations in cellular and structural components of the neurovascular unit, particularly in association with neuroinflammation. A previous screening study of peptide ligands to identify molecular alterations of the BBB in neuroinflammation by phage-display, revealed that phage clone 88 presented specific binding affinity to endothelial cells under inflammatory conditions in vivo and in vitro. Here, we aimed to identify the possible target receptor of the peptide ligand 88 expressed under inflammatory conditions. A cross-link test between phage-peptide-88 with IL-1β-stimulated human hCMEC cells, followed by mass spectrometry analysis, was used to identify the target of peptide-88. We modeled the epitope–receptor molecular interaction between peptide-88 and its target by using docking simulations. Three proteins were selected as potential target candidates and tested in enzyme-linked immunosorbent assays with peptide-88: fibronectin, laminin subunit α5 and laminin subunit β-1. Among them, only laminin subunit β-1 presented measurable interaction with peptide-88. Peptide-88 showed specific interaction with laminin subunit β-1, highlighting its importance as a potential biomarker of the laminin changes that may occur at the BBB endothelial cells under pathological inflammation conditions.

scholarly journals Could Lipoxins Represent a New Standard in Ischemic Stroke Treatment?

2021 ◽  
Vol 22 (8) ◽  
pp. 4207
Author(s):  
Nikola Tułowiecka ◽  
Dariusz Kotlęga ◽  
Andrzej Bohatyrewicz ◽  
Małgorzata Szczuko
Keyword(s):  
Ischemic Stroke ◽  
Cardiovascular Diseases ◽  
Blood Brain Barrier ◽  
Inflammatory Cytokines ◽  
The Body ◽  
Brain Barrier ◽  
Lipoxin A4 ◽  
Stroke Treatment ◽  
Blood Brain ◽  
Anti Inflammatory

Introduction: Cardiovascular diseases including stroke are one of the most common causes of death. Their main cause is atherosclerosis and chronic inflammation in the body. An ischemic stroke may occur as a result of the rupture of unstable atherosclerotic plaque. Cardiovascular diseases are associated with uncontrolled inflammation. The inflammatory reaction produces chemical mediators that stimulate the resolution of inflammation. One of these mediators is lipoxins—pro-resolving mediators that are derived from the omega-6 fatty acid family, promoting inflammation relief and supporting tissue regeneration. Aim: The aim of the study was to review the available literature on the therapeutic potential of lipoxins in the context of ischemic stroke. Material and Methods: Articles published up to 31 January 2021 were included in the review. The literature was searched on the basis of PubMed and Embase in terms of the entries: ‘stroke and lipoxin’ and ‘stroke and atherosclerosis’, resulting in over 110 articles in total. Studies that were not in full-text English, letters to the editor, and conference abstracts were excluded. Results: In animal studies, the injection/administration of lipoxin A4 improved the integrity of the blood–brain barrier (BBB), decreased the volume of damage caused by ischemic stroke, and decreased brain edema. In addition, lipoxin A4 inhibited the infiltration of neutrophils and the production of cytokines and pro-inflammatory chemokines, such as interleukin (Il-1β, Il-6, Il-8) and tumor necrosis factor-α (TNF-α). The beneficial effects were also observed after introducing the administration of lipoxin A4 analog—BML-111. BML-111 significantly reduces the size of a stroke and protects the cerebral cortex, possibly by reducing the permeability of the blood–brain barrier. Moreover, more potent than lipoxin A4, it has an anti-inflammatory effect by inhibiting the production of pro-inflammatory cytokines and increasing the amount of anti-inflammatory cytokines. Conclusions: Lipoxins and their analogues may find application in reducing damage caused by stroke and improving the prognosis of patients after ischemic stroke.

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