Memantine Improves Safety of Thrombolysis for Stroke

Montagne, Axel; Hébert, Marie; Jullienne, A.; Lesept, Flavie; Béhot, Audrey Le; Louessard, Morgane; Gauberti, Maxime; Orset, Cyrille; Ali, Carine; Agin, Véronique; Maubert, Eric; Vivien, Denis

doi:10.1161/strokeaha.112.669374

Cited by 33 publications

(32 citation statements)

References 37 publications

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“…In the pooled analysis early rt-PA was associated with a significant reduction in the final infarct volume (absolute difference −6.63 mm 3 ; 95% CI, −9.08 to −4.17; P sig <0.0001; I 2 = 76%; figure 1) 19–28 whereas late r-tPA treatment showed a deleterious effect (+5.06 mm 3 ; 95% CI, +2.78 to +7.34; P sig <0.0001; I 2 = 42%; figure 1), with a statistically significant qualitative interaction ( P int <0.00001).…”

Section: Resultsmentioning

confidence: 92%

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Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke

Orset

Haelewyn

Allan

et al. 2016

Stroke

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Background and purpose The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation, has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large dataset from pre-clinical studies, in order to examine the effects of early versus late administration of intravenous recombinant tissue type plasminogen activator (rt-PA). Methods We collected data from 26 individual studies from 9 international centers (13 researchers, 716 animals) that compared rt-PA to controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (<3h) versus late (≥3h) drug administration. Final infarct volumes, assessed by histology or MRI, were compared in each study and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested. Results When compared to saline controls, early rt-PA administration was associated with a significant benefit (absolute difference = −6.63 mm3; 95%CI, −9.08 to −4.17; I2=76%) whereas late rt-PA treatment showed a deleterious effect (+5.06 mm3; 95%CI, +2.78 to +7.34; I2=42%, Pint<0.00001). Results remained unchanged following subgroup analyses. Conclusion Our results provide the basis needed for the design of future pre-clinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multi-center trial would require 123 animals per group instead of 40 for a single center trial.

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Section: Resultsmentioning

confidence: 92%

“…19–21 However, no large-scale validation of this model is available so far. Therefore, we evaluated the effects of early (< 3 h) and late (≥ 3 h) rt-PA administration in this stroke model in a retrospective pooled analysis of individual data from 9 international research centers.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke

Orset

Haelewyn

Allan

et al. 2016

Stroke

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“…In this regard, drugs such as MK801 or memantine have showed positive results in animal models of ICH when hematoma volume and brain edema are analyzed. 8,11,12 However, the continuous failure, as well as the adverse effects observed with these drugs in stroke clinical trials, has made other alternatives different from glutamate antagonists preferable for reducing the effect of glutamate excitotoxicity. 30 Figure 2.…”

Section: Discussionmentioning

confidence: 99%

Blood Glutamate Grabbing Does Not Reduce the Hematoma in an Intracerebral Hemorrhage Model but it is a Safe Excitotoxic Treatment Modality

Silva‐Candal

Vieites‐Prado

Gutiérrez-Fernández

et al. 2015

J Cereb Blood Flow Metab

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Recent studies have shown that blood glutamate grabbing is an effective strategy to reduce the excitotoxic effect of extracellular glutamate released during ischemic brain injury. The purpose of the study was to investigate the effect of two of the most efficient blood glutamate grabbers (oxaloacetate and recombinant glutamate oxaloacetate transaminase 1: rGOT1) in a rat model of intracerebral hemorrhage (ICH). Intracerebral hemorrhage was produced by injecting collagenase into the basal ganglia. Three treatment groups were developed: a control group treated with saline, a group treated with oxaloacetate, and a final group treated with human rGOT1. Treatments were given 1 hour after hemorrhage. Hematoma volume (analyzed by magnetic resonance imaging (MRI)), neurologic deficit, and blood glutamate and GOT levels were quantified over a period of 14 days after surgery. The results observed showed that the treatments used induced a significant reduction of blood glutamate levels; however, they did not reduce the hematoma, nor did they improve the neurologic deficit. In the present experimental study, we have shown that this novel therapeutic strategy is not effective in case of ICH pathology. More importantly, these findings suggest that blood glutamate grabbers are a safe treatment modality that can be given in cases of suspected ischemic stroke without previous neuroimaging. Keywords: blood glutamate grabbing; GOT; intracerebral hemorrhage; oxaloacetate; protection INTRODUCTION Intracerebral hemorrhage (ICH) represents approximately 15% of all strokes; moreover, the incidence of ICH is expected to grow, given the increase in the use of anticoagulants and aging of the population. Journal of Cerebral Blood1 It is a type of acute stroke characterized by extravasation of blood into the brain parenchyma and formation of hematoma. Hematoma produces primary damage because of the toxic effect of thrombin, a mass effect due to the extravasated blood that compresses the surrounding brain tissue; sometimes, this damage is also enhanced by rebleeding. Primary damage is followed by a secondary damage mainly characterized by edema formation, tissular ischemia, and glutamate excitotoxicity.

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“…First, we confirmed that tissuetype plasminogen activator induces early recanalization of the MCA and reduced ischemic lesion size ( Figure I and VIII in the online-only Data Supplement), as previously demonstrated. 15 However, early tissue-type plasminogen activator administration did not significantly influence poststroke cerebrovascular inflammation as assessed by MPIOs-αVCAM-1 enhanced imaging. The effect of late thrombolysis 16 on cerebrovascular inflammation deserves further investigation.…”

Section: Influence Of Tissue-type Plasminogen Activatorinduced Thrombmentioning

confidence: 90%

Ultra-Sensitive Molecular MRI of Vascular Cell Adhesion Molecule-1 Reveals a Dynamic Inflammatory Penumbra After Strokes

Gauberti

Montagne

Marcos‐Contreras

et al. 2013

Stroke

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100

110

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Background and Purpose-Our aim was to assess the spatiotemporal evolution of the cerebrovascular inflammation occurring after ischemic and hemorrhagic strokes using a recently developed, fast, and ultra-sensitive molecular MRI method. Methods-We first assessed longitudinally the cerebrovascular inflammation triggered by collagenase-induced hemorrhage and by permanent/transient middle cerebral artery occlusion in mice, using MRI after injection of microparticles of iron oxide targeted to vascular cell adhesion molecule-1 (MPIOs-αVCAM-1). Thereafter, we used this method to study the anti-inflammatory effects of celecoxib, atorvastatin, and dipyridamole after stroke. Results-Using multiparametric MRI, we demonstrated that the level and the kinetics of cerebrovascular VCAM-1 expression depend on several parameters, including stroke pathogenesis, the natural history of the disease, and the administration of inflammation-modulating drugs. Interestingly, in transient middle cerebral artery occlusion and intracranial hemorrhage models, VCAM-1 expression was maximal at 24 hours and almost returned to baseline 5 days after stroke onset. In contrast, after permanent middle cerebral artery occlusion, VCAM-1 overexpression was sustained between 24 hours and 5 days, and was particularly significant in the peri-infarct areas. Our results suggest that these perilesional areas expressing VCAM-1 constitute an inflammatory penumbra that is recruited by the ischemic core during the subacute phase. Using MPIOs-αVCAM-1-enhanced imaging, we also provided evidence that celecoxib and atorvastatin (but not dipyridamole) alleviate VCAM-1 overexpression after stroke and prevent formation of the inflammatory penumbra. Conclusions-MPIOs-αVCAM-1-enhanced imaging seems to be promising in the detection of individuals presenting with severe cerebrovascular responses after stroke, which could therefore benefit from anti-inflammatory treatments.

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Memantine Improves Safety of Thrombolysis for Stroke

Cited by 33 publications

References 37 publications

Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke

Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke

Blood Glutamate Grabbing Does Not Reduce the Hematoma in an Intracerebral Hemorrhage Model but it is a Safe Excitotoxic Treatment Modality

Ultra-Sensitive Molecular MRI of Vascular Cell Adhesion Molecule-1 Reveals a Dynamic Inflammatory Penumbra After Strokes

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