scholarly journals Blocking PSD-93-CX3CL1 Interaction Promotes the Phenotypic Transformation of Microglia During Acute Ischemic Stroke

2021 ◽  
Author(s):  
qingxiu zhang ◽  
xiaowei cao ◽  
hui yang ◽  
xiaomei Liu ◽  
shiying Lou ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Neuroprotective Effect ◽  
Underlying Mechanism ◽  
White Matter Injury ◽  
Tetrazolium Chloride ◽  
Stroke Treatment ◽  
Microglial Polarization ◽  
M1 Type

Abstract BackgroundPostsynaptic density 93 (PSD-93) plays an important role in ischemic brain injury by mediating neurotoxicity and neuroinflammation. Different photypes of microglia perform an important role in ischemic crerbral injury and repair. Blocking the combination of PSD-93 and CX3C chemokine ligand 1 (CX3CL1) is beneficial in acute ischemic stroke, but the underlying mechanism remains unclear. MethodsMiddle cerebral artery occlusion (MCAO) model was established in male C57BL/6 mice. The peptide Tat-CX3CL1 (357-395aa) which disturbing the interaction of PSD-93 and CX3CL1 was used in this study to explore the mechanism of its neuroprotective effect. The production and secretion of cytokines associated with M1 and M2 type of microglia was detected by PCR and ELISA, respectively. Neurologic damage was evaluated by behavior, triphenyl tetrazolium chloride staining, and brain water content. MBP and SMI32 double immunostaining were used to detect white matter injury and double staining for Iba1 and CD68 to assess M1 type microglia polarization. ResultsThe cytokines level of M1 phenotype cytokines was increased at 6 h after stroke and peaked at 24 h after perfusion. However, the cytokines level of M2 phenotype was decreased at 6 h and 24 h following reperfusion. The Tat-CX3CL1 (357-395aa) facilitated microglial polarization from M1 type to M2 type by reducing the production of soluble CX3CL1. Furthermore, ADAM17 inhibitor GW280264x could restrain the polarization of microglia from M1 to M2 via reducing soluble CX3CL1 formation. Moreover, Tat-CX3CL1 (357-395aa) attenuated long-term cognitive deficits and improved white matter integrity. ConclusionsBlocking the binding between CX3CL1 and PSD-93 by Tat-CX3CL1 (357-395aa) could facilitate the functional recovery after ischemic stroke by promoting M1 to M2 microglial polarization transformation. Tat-CX3CL1 (357-395aa) may be a potent agent for ischemic stroke treatment.

scholarly journals Blocking PSD-93-CX3CL1 Interaction Promotes Phenotypic Polarization Transformation of Microglia During Acute Ischemic Stroke Injury

2021 ◽  
Author(s):  
Qingxiu Zhang ◽  
Xiaowei Cao ◽  
Hui Yang ◽  
Xiaomei Liu ◽  
Shiying Lou ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Underlying Mechanism ◽  
Artery Occlusion ◽  
White Matter Injury ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tetrazolium Chloride ◽  
Time Points ◽  
Microglia Polarization

Abstract Background：Postsynaptic density 93 (PSD-93) plays an important role in ischemic brain injury through mediating neurotoxicity and neuroinflammation. Blocked the combination of PSD-93 and Fractalkine (CX3Cchemokineligand1, CX3CL1) play beneficial roles in acute ischemic stroke. However, the underlying mechanism still need further exploration. Methods：In this study, male C57BL/6 mice aged 8-12 weeks and weighted 22-26g were applied with Middle Cerebral Artery Occlusion (MCAO) model and randomly divided into different groups. Firstly, real-time quantitative PCR was to detect some cytokines associated with M1 and M2 type of microglia at different time points in transient MCAO model. Secondly, triphenyl tetrazolium chloride (TTC) staining, brain water content and behavioral assessments were used to evaluate the neurologic damage. Immunofluorescence staining was performed to measure the white matter injury, and microglia polarization. Moreover, enzyme-linked immunosorbent assay (ELISA) was used to investigate the expression of soluble CX3CL1. Results：M1 phenotype cytokines were detected at different time points and found that their expression increased from beginning at 6 hours after reperfusion and most peaked at 24 h after reperfusion. However, the expression of M2 phenotype cytokines decreased or still keep invariant at 6 hours and 24 h after reperfusion. Interestingly, Tat-CX3CL1 (357-395aa) can facilitate microglia polarization from M1 type to M2 type through inhibiting expression of the soluble CX3CL1. Furthermore, CX3CL1 specific cleavase inhibitor ADAM17 could restrain the microglia polarization transformation via reducing the soluble CX3CL1 formation. Moreover, Tat-CX3CL1 (357-395aa) also attenuate long-term cognitive deficits and improved white matter integrity. Conclusions: In conclusion, we demonstrated that specific blockage the binding of PSD-93 and CX3CL1 by Tat-CX3CL1 (357-395aa) could perform functional recovery after ischemic stroke by promoting type microglia polarization transformation from M1 to M2. And the peptide Tat-CX3CL1 (357-395aa) is a promising strategy for treatment of ischemic stroke.

Association of white matter lesions and outcome after endovascular stroke treatment

Neurology ◽  
2020 ◽  
pp. 10.1212/WNL.0000000000010994
Author(s):  
Sven P.R. Luijten ◽  
Daniel Bos ◽  
Kars C.J. Compagne ◽  
Lennard Wolff ◽  
Charles B.L.M. Majoie ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Endovascular Treatment ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Treatment Effect ◽  
White Matter Lesions ◽  
Effect Modification ◽  
Stroke Treatment ◽  
Logistic Regression Models

ObjectiveTo investigate the association between white matter lesions (WML) and functional outcome in patients with acute ischemic stroke (AIS) and the modification of the effect of endovascular treatment (EVT) by WML.MethodsWe used data from the Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN) trial and assessed severity of WML on baseline non-contrast CT imaging (NCCT; n = 473) according to the Van Swieten Scale. Post-stroke functional outcome was assessed with the modified Rankin Scale (mRS). We investigated the association of WML with functional outcome using ordinal logistic regression models adjusted for age, sex, and other relevant cardiovascular and prognostic risk factors. In addition, an interaction term between treatment allocation and WML severity was used to assess treatment effect modification by WML.ResultsWe found an independent negative association between more severe WML and functional outcome (acOR 0.77 [95% CI 0.66–0.90]). Patients with absent to moderate WML had similar benefit of EVT on functional outcome (acOR 1.93 [95% CI 1.31–2.84]) as patients with severe WML (acOR 1.95 [95% CI 0.90–4.20]). No treatment effect modification of WML was found (p for interaction = 0.85).ConclusionsWe found that more severe WML predict poor functional outcome after acute ischemic stroke, but do not modify effect of EVT.Classification of evidencePrognostic accuracy. This study provides Class II evidence that for patients with AIS, the presence of WML on baseline NCCT is associated with worse functional outcomes.

scholarly journals Cerebral endothelial cell-derived small extracellular vesicles enhance neurovascular function and neurological recovery in rat acute ischemic stroke models of mechanical thrombectomy and embolic stroke treatment with tPA

2021 ◽  
pp. 0271678X2199298
Author(s):  
Chao Li ◽  
Chunyang Wang ◽  
Yi Zhang ◽  
Owais K Alsrouji ◽  
Alex B Chebl ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Extracellular Vesicles ◽  
Mechanical Thrombectomy ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Therapeutic Effects ◽  
Vessel Occlusion ◽  
Healthy Human ◽  
Stroke Treatment

Treatment of patients with cerebral large vessel occlusion with thrombectomy and tissue plasminogen activator (tPA) leads to incomplete reperfusion. Using rat models of embolic and transient middle cerebral artery occlusion (eMCAO and tMCAO), we investigated the effect on stroke outcomes of small extracellular vesicles (sEVs) derived from rat cerebral endothelial cells (CEC-sEVs) in combination with tPA (CEC-sEVs/tPA) as a treatment of eMCAO and tMCAO in rat. The effect of sEVs derived from clots acquired from patients who had undergone mechanical thrombectomy on healthy human CEC permeability was also evaluated. CEC-sEVs/tPA administered 4 h after eMCAO reduced infarct volume by ∼36%, increased recanalization of the occluded MCA, enhanced cerebral blood flow (CBF), and reduced blood-brain barrier (BBB) leakage. Treatment with CEC-sEVs given upon reperfusion after 2 h tMCAO significantly reduced infarct volume by ∼43%, and neurological outcomes were improved in both CEC-sEVs treated models. CEC-sEVs/tPA reduced a network of microRNAs (miRs) and proteins that mediate thrombosis, coagulation, and inflammation. Patient-clot derived sEVs increased CEC permeability, which was reduced by CEC-sEVs. CEC-sEV mediated suppression of a network of pro-thrombotic, -coagulant, and -inflammatory miRs and proteins likely contribute to therapeutic effects. Thus, CEC-sEVs have a therapeutic effect on acute ischemic stroke by reducing neurovascular damage.

Abstract TP476: White Matter Hyperintensity Burden is Associated With Poor Collateral Flow and Worse Outcomes in an Acute Ischemic Stroke Cohort

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Rami-James Assadi ◽  
Hongyu An ◽  
Yasheng Chen ◽  
Andria Ford ◽  
Jin-Moo Lee
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Pearson Correlation ◽  
Stroke Onset ◽  
White Matter Hyperintensity ◽  
Flow Index ◽  
Acute Ischemia ◽  
Collateral Flow ◽  
Core Volume

Introduction: White matter hyperintensity volume (WMHv), a quantitative neuroimaging biomarker of cerebral small vessel disease (CSVD), is associated worse outcomes after ischemic stroke. In this study, we hypothesized that worse outcomes in CSVD patients were due to poor collateral flow during acute ischemia. Methods: 47 patients with acute ischemic stroke (AIS) were prospectively enrolled in this study. Serial MRIs were performed at 3 hours and 30 days after stroke onset. 3-hour FLAIR images were used to determine WMHv, after manually delineating lesions with MIPAV. An index of collateral flow (delayed perfusion to the penumbra) was determined by subtracting core volume (volume of tissue with ADC<600) from the volume of brain tissue with Tmax>2. Patient’s NIHSS was scored at 3 hours and 30 days after stroke onset and the difference was calculated (ΔNIHSS). Log-transformed WMHv was correlated to ΔNIHSS and the collateral flow index, using Pearson correlation. Results: Mean age = 63.9 years (SD 13.5); 37% female; median 3-hour NIHSS = 13 (IQR 6.5-20); median change in NIHSS between 3h and 30d = 4 (IQR: 0-7); median core volume = 13cm3 (IQR 4.3-35.6); median WMHv = 1.257cm3 (IQR 641-3595). WMHv was associated with reduced improvement in ΔNIHSS (R=-0.42, ρ=0.005). Furthermore, WMHv demonstrated a trend for association with poor collateral flow (R=-0.28, ρ=0.062). In this dataset, we will explore the relationship between WMHv and other tissue-based metrics of collateral flow, including the hypoperfusion intensity ratio (HIR) and the cerebral blood volume ratio (rCBV). Conclusions: Our study confirms that patients with CSVD have worse outcomes after AIS. The data also raise the possibility that these worse outcomes in CSVD patients may be mediated by compromised collateral flow in the setting of acute ischemia.

Abstract MP16: Excessive White Matter Hyperintensity Burden and Functional Outcomes After Acute Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Sungmin Hong ◽  
Anne-katrin Giese ◽  
Markus D Schirmer ◽  
Adrian V Dalca ◽  
Anna Bonkhoff ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Functional Outcomes ◽  
Life Time ◽  
Stroke Recovery ◽  
White Matter Hyperintensity ◽  
Brain Health ◽  
Stroke Outcomes ◽  
The Brain

Objective: Ability of the brain to recover after an acute ischemic stroke (AIS) is linked to the pre-stroke burden of white matter hyperintensity (WMH), a radiographic marker of brain health. We sought to determine the excessive WMH burden in an AIS population and investigate its association with 3-month stroke outcomes. Data: We used 2,435 subjects from the MRI-GENIE study. Three-month functional outcomes of 872 subjects among those subjects were measured by 90-day modified Ranking Scale (mRS). Methods: We automatically quantified WMH volume (WMHv) on FLAIR images and adjusted for a brain volume. We modeled a trend using the factor analysis (FA) log-linear regression using age, sex, atrial fibrillation, diabetes, hypertension, coronary artery disease and smoking as input variables. We categorized three WMH burden groups based on the conditional probability given by the model (LOW: lower 33%, MED: middle 34%, and HIGH: upper 33%). The subgroups were compared with respect to mRS (median and dichotomized odds ratio (OR) (good/poor: mRS 0-2/3-6)). Results: Five FA components out of seven with significant relationship to WMHv (p<0.001) were used for the regression modeling (R 2 =0.359). The HIGH group showed higher median (median=2, IQR=2) mRS score than LOW (median=1, IQR=1) and MED (median=1, IQR=1). The odds (OR) of good AIS outcome for LOW and MED were 1.8 (p=0.0001) and 1.6 (p=0.006) times higher than HIGH, respectively. Conclusion: Once accounted for clinical covariates, the excessive WMHv was associated with worse 3-month stroke outcomes. These data suggest that a life-time of injury to the white matter reflected in WMH is an important factor for stroke recovery and an indicator of the brain health.

Abstract WP62: Enhanced Neuroprotection of Normobaric Oxygenation with Ethanol Conferred by Apoptosis Reduction in Acute Ischemic Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Sweena Parmar ◽  
Xiaokun Geng ◽  
Changya Peng ◽  
Murali Guthikonda ◽  
Yuchuan Ding
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Neuroprotective Effect ◽  
Apoptotic Cell Death ◽  
Ethanol Administration ◽  
Sprague Dawley ◽  
Apoptotic Proteins

Objectives: Normobaric oxygenation (NBO) has been shown to provide neuroprotection in vivo and in vitro . Yet, a recent Phase 2 clinical trial investigating NBO therapy in acute ischemic stroke was terminated due to questionable therapeutic benefit. NBO therapy alone may be insufficient to produce improved outcomes. In our recent study, we demonstrated a strong neuroprotective effect of ethanol at a dose of 1.5 g/kg (equivalent to the human legal driving limit). In this study, we sought to identify whether low-dose ethanol administration enhances the neuroprotection offered by NBO and whether combined administration of NBO with ethanol is associated with reduced apoptosis. Methods: Sprague-Dawley rats were subjected to right middle cerebral artery occlusion (MCAO) for 2 h, followed by reperfusion. Ischemic animals received either an intraperitoneal injection of 1.0 g/kg ethanol, 2 h of 100% NBO, or both ethanol and NBO. The Cell Death Detection ELISA Assay (Roche) was performed to determine apoptotic cell death at 24 h after reperfusion. Levels of pro-apoptotic (Caspase-3, Bcl-2-associated X-BAX, and Apoptosis-Inducing Factor-AIF) and anti-apoptotic proteins (Bcl-2 and Bcl-xL) were determined by Western blot analysis at 3 and 24 h after reperfusion. Results: As expected, untreated ischemic rats had the highest apoptotic cell death. Combined NBO/ethanol therapy decreased cell death by 48%, as compared to 29% with ethanol and 22% with NBO. Similarly, combined NBO/ethanol therapy promoted the greatest expression of anti-apoptotic factors and the lowest expression of pro-apoptotic proteins at 3 h after reperfusion. This effect was maintained at 24 h and even more pronounced for AIF and Caspase-3. Conclusions: Given singularly, NBO and ethanol improved the degree of cell death, decreased the expression of pro-apoptotic proteins, and increased the expression of anti-apoptotic proteins. Yet, when administered together, their effects largely compounded. These results suggest a synergistic neuroprotection offered by NBO with ethanol, which may be attributed at least in part to their shared role in modulating neuronal apoptosis.

Abstract TP201: The Relationship Between Chronic Kidney Diseases and the Presence of Cerebral Small Vessel Disease in Patients With Acute Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Kana Ueki ◽  
Asako Nakamura ◽  
Masahiro Yasaka ◽  
Takahiro Kuwashiro ◽  
Seiji Gotoh ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
White Matter Lesion ◽  
Kidney Diseases ◽  
Univariate Analysis ◽  
Small Vessel ◽  
Chronic Kidney Diseases ◽  
History Of ◽  
The Relationship

Introduction: Cerebral small vessel diseases (SVDs) i.e. white matter lesion and cerebral microbleeds (CMBs) are related to the patients with stroke more deeply than those without. In general population, in addition to age, hypertension, diabetes chronic kidney diseases (CKD) is well known to be related to SVDs, but it remains unclear in patients with stroke. We investigated the relationship between CKD and the presence of SVDs in patients with acute ischemic stroke. Methods: We enrolled 493 patients with acute ischemic stroke patients or transient ischemic attack patients (mean age 71; 60% male) who had undergone 1.5T MR imaging within a week of the index events from April 2013 to march 2015. We evaluated kidney function by estimated glomerular filtration rate (eGFR) with the modification of diet in Renal Disease. CKD was defined as an eGFR less than 60mil/min/1.73m 2 . CMBs were defined as focal areas of very low signal intensity smaller than 10mm. White matter lesion as Periventricular hyper intensity (PVH)>grade 2 and Deep and Subcortical White Matter Hyper intensity (DSWMH)> grade 2 were defied as advanced PVH and advanced DSWMH, respectively. We investigated relationship between CKD and CMBs, advanced PVH and advanced DSWMH using a logistic regression analysis. Results: We noted CMBs in 173 patients (35%), PVH in 81 (16%), and DSWMH in 151 (31%). An univariate analysis revealed that the age, CKD, history of stroke, and antiplatelet agents were associated with presence of CMBs, advanced PVH and severe DSWMH . The multivariate analysis revealed that CMBs, advanced PVH and advanced DSWMH were associated with age (CMBs: odds ratio(OR) ; 1.32 ; 95% confidence interval(CI), 1.10-1.60, p=0.004, advanced PVH : OR ; 3.00 ; 95% CI, 2.17-4.26, p<0.01, advanced DSWMH: OR ; 1.94; 95% CI, 1.56-2.45, p<0.01 ), history of stroke(CMBs : OR ; 2.01 ; 95% CI, 1.21-3.34, p=0.007, advanced PVH : OR ; 2.25 ; 95% CI, 1.18-4.27, p=0.01, advanced DSWMH: OR ; 1.78 ; 95% CI, 1.03-3.06, p=0.038). CKD was associated with CMBs (OR ; 1.62 ; 95% CI, 1.04-2.52, p=0.03), but PVH and DSWMH were not. Conclusions: It seems that age and history of stroke are related to CMBs, advanced PVH and advanced DSWMH, and that CKD is associates with CMBs but not with either advanced PVH or advanced DSWMH.

Inflammation as a Therapeutic Target in Acute Ischemic Stroke Treatment

2009 ◽  
Vol 9 (14) ◽  
pp. 1240-1260 ◽  
Author(s):  
Antonino Tuttolomondo ◽  
Riccardo Di Sciacca ◽  
Domenico Di Raimondo ◽  
Chiara Renda ◽  
Antonio Pinto ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Therapeutic Target ◽  
Stroke Treatment

scholarly journals Neuroimaging risk factors for participation restriction after acute ischemic stroke: 1-year follow-up study

2021 ◽  
pp. jim-2020-001675
Author(s):  
Jian-Feng Qu ◽  
Huo-Hua Zhong ◽  
Wen-Cong Liang ◽  
Yang-Kun Chen ◽  
Yong-Lin Liu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Activities Of Daily Living ◽  
Acute Ischemic Stroke ◽  
Daily Living ◽  
Male Gender ◽  
Perivascular Spaces ◽  
Participation Restriction ◽  
Nihss Score

The aim of the present study was to determine the neuroimaging predictors of poor participation after acute ischemic stroke. A total of 443 patients who had acute ischemic stroke were assessed. At 1-year recovery, the Reintegration to Normal Living Index was used to assess participation restriction. We also assessed the Activities of Daily Living Scale and modified Rankin Scale (mRS) score. Brain MRI measurement included acute infarcts and pre-existing abnormalities such as enlarged perivascular spaces, white matter lesions, ventricular-brain ratio, and medial temporal lobe atrophy (MTLA). The study included 324 men (73.1%) and 119 women (26.9%). In the univariate analysis, patients with poor participation after 1 year were older, more likely to be men, had higher National Institutes of Health Stroke Scale (NIHSS) score on admission, with more histories of hypertension and atrial fibrillation, larger infarct volume, more severely enlarged perivascular spaces and MTLA, and more severe periventricular hyperintensities and deep white matter hyperintensities. Patients with participation restriction also had poor activities of daily living (ADL) and mRS score. Multiple logistic regression showed that, in model 1, age, male gender, NIHSS score on admission, and ADL on follow-up were significant predictors of poor participation, accounting for 60.2% of the variance. In model 2, which included both clinical and MRI variables, male gender, NIHSS score on admission, ADL on follow-up, and MTLA were significant predictors of poor participation, accounting for 61.2% of the variance. Participation restriction was common after acute ischemic stroke despite good mRS score. Male gender, stroke severity, severity of ADL on follow-up, and MTLA may be predictors of poor participation.Trial registration number ChiCTR1800016665.

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