Toll-Like Receptor 4 Mediates Hemorrhagic Transformation After Delayed Tissue Plasminogen Activator Administration in In Situ Thromboembolic Stroke

García‐Culebras, Alicia; Palma-Tortosa, Sara; Moraga, Ana; García-Yébenes, Isaac; Durán-Laforet, Violeta; Cuartero, María Isabel; Parra, Juana González; Barrios-Muñoz, Ana L.; Díaz-Guzmán, Jaime; Pradillo, Jesús M.; Moro, Marı́a A.

doi:10.1161/strokeaha.116.015956

Cited by 34 publications

(26 citation statements)

References 14 publications

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“…In line with pre-clinical reports by others [ 17 , 18 , 41 ], rt-PA caused substantial HTs in our study by 24 h post stroke, but only when given 4 h after stroke initiation. Rodent studies therefore mimic the basic clinical observation showing lower incidence of severe intracranial bleeding at onset to treatment (OTT) ≤ 90 min and a shift towards higher risk of dangerous bleeding outcome at later OTTs [ 2 ], which usually occurs within 24–36 h [ 6 ].…”

Section: Discussionsupporting

confidence: 93%

LDL receptor blockade reduces mortality in a mouse model of ischaemic stroke without improving tissue-type plasminogen activator-induced brain haemorrhage: towards pre-clinical simulation of symptomatic ICH

Niego

Broughton

et al. 2017

Fluids Barriers CNS

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BackgroundSymptomatic intracerebral haemorrhage (sICH) following tissue-type plasminogen activator (rt-PA) administration is the most feared and lethal complication of thrombolytic therapy for ischaemic stroke, creating a significant obstacle for a broader uptake of this beneficial treatment. rt-PA also undermines cerebral vasculature stability in a multimodal process which involves engagement with LDL receptor-related protein 1 (LRP-1), potentially underlying the development of sICH.Aims and methodsWe aimed to simulate rt-PA-induced haemorrhagic transformation (HT) in a mouse model of stroke and to assess if it drives symptomatic neurological deterioration and whether it is attenuated by LDL receptor blockade. rt-PA (10 mg/kg) or its vehicle, with or without the LDL receptor antagonist, receptor-associated protein (RAP; 2 mg/kg), were intravenously injected at reperfusion after 0.5 or 4 h of middle cerebral artery occlusion (MCAo). Albumin and haemoglobin content were measured in the perfused mouse brains 24 h post MCAo as indications of blood–brain barrier (BBB) compromise and HT, respectively.Resultsrt-PA did not elevate brain albumin and haemoglobin levels in sham mice or in mice subjected to 0.5 h MCAo. In contrast, administration of rt-PA after prolonged MCAo (4 h) caused a marked increase in HT (but similar changes in brain albumin) compared to vehicle, mimicking the clinical shift from a safe to detrimental intervention. Interestingly, this HT did not correlate with functional deficit severity at 24 h, suggesting that it does not play a symptomatic role in our mouse stroke model. Co-administration of RAP with or without rt-PA reduced mortality and neurological scores but did not effectively decrease brain albumin and haemoglobin levels.ConclusionDespite the proven causative relationship between severe HT and neurological deterioration in human stroke, rt-PA-triggered HT in mouse MCAo does not contribute to neurological deficit or simulate sICH. Model limitations, such as the long duration of occlusion required, the type of HT achieved and the timing of deficit assessment may account for this mismatch. Our results further suggest that blockade of LDL receptors improves stroke outcome irrespective of rt-PA, blood–brain barrier breakdown and HT.

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Section: Discussionsupporting

confidence: 93%

LDL receptor blockade reduces mortality in a mouse model of ischaemic stroke without improving tissue-type plasminogen activator-induced brain haemorrhage: towards pre-clinical simulation of symptomatic ICH

Niego

Broughton

et al. 2017

Fluids Barriers CNS

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“…Hemorrhagic transformation (HT) is a common and potentially catastrophic complication of acute ischemic stroke (AIS) in patients receiving mechanical thrombectomy (MT), 1 and it results in worse outcomes and delays the initiation of antiplatelet or anticoagulation therapy. 2 , 3 Therefore, to determine whether thrombolytic therapy is safe, it is essential to understand why HT can develop after AIS. 4 , 5 Accumulating studies indicate that old age, hypertension, thrombolytic treatment, large infarct, long reperfusion time, high baseline National Institutes of Health Stroke Scale (NIHSS) score, high systolic blood pressure, pretreatment involvement of the basal ganglia, and the extent of ischemic injury prior to administration of therapy 3 , 6 , 7 are risk factors for HT.…”

Section: Introductionmentioning

confidence: 99%

<p>Identification of Predictors for Hemorrhagic Transformation in Patients with Acute Ischemic Stroke After Endovascular Therapy Using the Decision Tree Model</p>

Feng¹,

Ye²,

Cao³

et al. 2020

CIA

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Purpose This study aimed to identify independent predictors for the risk of hemorrhagic transformation (HT) in arterial ischemic stroke (AIS) patients. Methods Consecutive patients with AIS due to large artery occlusion in the anterior circulation treated with mechanical thrombectomy (MT) were enrolled in a tertiary stroke center. Demographic and medical history data, admission lab results, and Circle of Willis (CoW) variations were collected from all patients. Results Altogether, 90 patients were included in this study; among them, 34 (37.8%) had HT after MT. The final pruned decision tree (DT) model consisted of collateral score and platelet to lymphocyte ratios (PLR) as predictors. Confusion matrix analysis showed that 82.2% (74/90) were correctly classified by the model (sensitivity, 79.4%; specificity, 83.9%). The area under the ROC curve (AUC) was 81.7%. The DT model demonstrated that participants with collateral scores of 2–4 had a 75.0% probability of HT. For participants with collateral scores of 0–1, if PLR at admission was <302, participants had a 13.0% probability of HT; otherwise, participants had an 75.0% probability of HT. The final adjusted multivariate logistic regression analysis indicated that collateral score 0–1 (OR, 10.186; 95% CI, 3.029–34.248; p < 0.001), PLR (OR, 1.005; 95% CI, 1.001–1.010; p = 0.040), and NIHSS at admission (OR, 1.106; 95% CI, 1.014–1.205; p = 0.022) could be used to predict HT. The AUC for the model was 0.855, with 83.3% (75/90) were correctly classified (sensitivity, 79.4%; specificity, 87.3%). Less patients with HT achieved independent outcomes (mRS, 0–2) in 90 days (20.6% vs. 64.3%, p < 0.001). Rate of poor outcomes (mRS, 4–6) was significantly higher in patients with HT (73.5% vs. 19.6%; p < 0.001). Conclusion Both the DT model and multivariate logistic regression model confirmed that the lower collateral status and the higher PLR were significantly associated with an increased risk for HT in AIS patients after MT. PLR may be one of the cost-effective and practical predictors for HT. Further prospective multicenter studies are needed to validate our findings.

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“…In our study, delayed tPA administration (5 h post ischaemia) caused a significant increase in brain infarct volume. Many previous studies have shown that brain infarct volume was not affected by delayed tPA treatment in both a thromboembolic and filament model (Kanazawa et al, 2011;Garcia-Culebras et al, 2017). However, delayed tPA treatment has also been found to tend to aggravate brain infarct volume (Zuo et al, 2014).…”

Section: Discussionmentioning

confidence: 94%

NAD replenishment with nicotinamide mononucleotide protects blood–brain barrier integrity and attenuates delayed tissue plasminogen activator‐induced haemorrhagic transformation after cerebral ischaemia

Wei

Kong

Xia

et al. 2017

British J Pharmacology

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Tissue plasminogen activator (tPA) is the only approved pharmacological therapy for acute brain ischaemia; however, a major limitation of tPA is the haemorrhagic transformation that follows tPA treatment. Here, we determined whether nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide biosynthesis, affects tPA-induced haemorrhagic transformation. EXPERIMENTAL APPROACHMiddle cerebral artery occlusion (MCAO) was achieved in CD1 mice by introducing a filament to the left MCA for 5 h. When the filament was removed for reperfusion, tPA was infused via the tail vein. A single dose of NMN was injected i.p. (300 mg·kg À1 ). Mice were killed at 24 h post ischaemia, and their brains were evaluated for brain infarction, oedema, haemoglobin content, apoptosis, neuroinflammation, blood-brain barrier (BBB) permeability, the expression of tight junction proteins (TJPs) and the activity/expression of MMPs. KEY RESULTSIn the mice infused with tPA at 5 h post ischaemia, there were significant increases in mortality, brain infarction, brain oedema, brain haemoglobin level, neural apoptosis, Iba-1 staining (microglia activation) and myeloperoxidase staining (neutrophil infiltration). All these tPA-induced alterations were significantly prevented by NMN administration. Mechanistically, the delayed tPA treatment increased BBB permeability by down-regulating TJPs, including claudin-1, occludin and zonula occludens-1, and enhancing the activities and protein expression of MMP9 and MMP2. Similarly, NMN administration partly blocked these tPA-induced molecular changes. CONCLUSIONS AND IMPLICATIONSOur results demonstrate that NMN ameliorates tPA-induced haemorrhagic transformation in brain ischaemia by maintaining the integrity of the BBB.

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Toll-Like Receptor 4 Mediates Hemorrhagic Transformation After Delayed Tissue Plasminogen Activator Administration in In Situ Thromboembolic Stroke

Abstract: Our results demonstrate TLR4 involvement in hemorrhagic transformation induced by delayed tPA administration, very likely by increasing matrix metalloproteinase 9 expression.

Cited by 34 publications

References 14 publications

LDL receptor blockade reduces mortality in a mouse model of ischaemic stroke without improving tissue-type plasminogen activator-induced brain haemorrhage: towards pre-clinical simulation of symptomatic ICH

LDL receptor blockade reduces mortality in a mouse model of ischaemic stroke without improving tissue-type plasminogen activator-induced brain haemorrhage: towards pre-clinical simulation of symptomatic ICH

<p>Identification of Predictors for Hemorrhagic Transformation in Patients with Acute Ischemic Stroke After Endovascular Therapy Using the Decision Tree Model</p>

NAD replenishment with nicotinamide mononucleotide protects blood–brain barrier integrity and attenuates delayed tissue plasminogen activator‐induced haemorrhagic transformation after cerebral ischaemia

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