Antibodies Preventing the Interaction of Tissue-Type Plasminogen Activator With N-Methyl-
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            -Aspartate Receptors Reduce Stroke Damages and Extend the Therapeutic Window of Thrombolysis

Macrez, Richard; Obiang, Pauline; Gauberti, Maxime; Roussel, Benoit D.; Baron, Amandine; Parcq, Jérôme; Cassé, Frédéric; Hommet, Yannick; Orset, Cyrille; Agin, Véronique; Bezin, Laurent; Berrocoso, Teresa Garcia; Petersen, Karl Uwe; Montaner, Joan; Maubert, Eric; Vivien, Denis; Ali, Carine

doi:10.1161/strokeaha.110.606293

Cited by 65 publications

(53 citation statements)

References 30 publications

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“…20 In addition, thrombolysis performed as for patients with stroke (10% bolus and 90% infusion >1 hour) also has a therapeutic window, with early recanalization being beneficial but not if performed too late. 21,22 Whether thrombin exerts specific effects on the neurovascular unit 23,24 beside clot formation in this model remains to be established.…”

Section: Alcohol Consumption Impairs the Beneficial Effect Of Tpa-indmentioning

confidence: 99%

Impact of Alcohol Consumption on the Outcome of Ischemic Stroke and Thrombolysis

Lemarchand

Gauberti

Lizarrondo

et al. 2015

Stroke

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Background and Purpose-Tissue-type plasminogen activator (tPA) is the only acute treatment for ischemic stroke.Unfortunately, the benefit of tPA-driven thrombolysis is not systematic, and understanding the reasons for this is mandatory. The balance between beneficial and detrimental effects of tPA might explain the limited overall efficiency of thrombolysis. Here, we investigated whether this balance could be influenced by excessive alcohol intake. Methods-We used a murine model of thromboembolic stroke, coupled to an array of biochemical assays, near-infrared or magnetic resonance imaging scans, 2-photon microscopy, hydrodynamic transfections, and immunohistological techniques. Results-We found that 6 weeks of alcohol consumption (10% in drinking water) worsens ischemic lesions and cancels the beneficial effects of tPA-induced thrombolysis. We accumulate in vivo and in vitro evidence showing that this aggravation is correlated with a decrease in lipoprotein receptor-related protein 1-mediated hepatic clearance of tPA in alcoholexposed mice. Conclusions-An efficient liver-driven clearance of tPA might influence the safety of thrombolysis after stroke.

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Section: Alcohol Consumption Impairs the Beneficial Effect Of Tpa-indmentioning

confidence: 99%

Impact of Alcohol Consumption on the Outcome of Ischemic Stroke and Thrombolysis

Lemarchand

Gauberti

Lizarrondo

et al. 2015

Stroke

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“…As previously described, 22 thrombotic stroke was induced by injecting thrombin (1.0 IU in 1 L) directly in the middle cerebral artery. To induce thrombolysis, rtPA was intravenously injected (tail vein, 200 L, 10 mg/kg, 10% bolus and 90% infusion over 40 minutes) either at 4 hours or 20 minutes postclot onset 15 with or without an intravenous bolus of memantine (200 L, 20 mg/kg) just before rtPA infusion. Control groups received the same volume of saline with or without memantine (nϭ7-8 per group).…”

Section: Thrombotic Stroke Model and Thrombolysismentioning

confidence: 99%

“…22 In this model, early thrombolysis by rtPA (20 minutes postonset) is beneficial, whereas late thrombolysis (4 hours postonset) is deleterious. 15 The effect of intravenous memantine (20 mg/kg, a dose chosen based on the literature 24 ) as an adjunct treatment to late thrombolysis by rtPA was thus tested. T2-weighted MR images at 6, 24, and 48 hours after stroke ( Figure 3A) revealed that although memantine did not alter the extent of the ischemic damage in the absence of rtPA ( Figure 3B Although the deleterious effects of delayed thrombolysis appeared at 6 hours postclot onset and continued to progress between 24 and 48 hours, the lesion volumes of control, memantine, and memantine/rtPA-treated groups reached their maximum at 24 hours ( Figure 3A-B).…”

Section: Memantine Reduces the Noxious Actions Of Delayed Thrombolysimentioning

confidence: 99%

“…14 Previously, in a model of thrombotic stroke in mice, we evidenced that an experimental strategy designed to block the interaction of tPA with NMDAR persistently reduced brain lesions, neurological deficits, and extended the therapeutic window of rtPA. 15 The uncompetitive NMDAR antagonist memantine (1-amino-3,5-dimethyladamantane) was approved for the symptomatic treatment of the moderate to severe forms of Alzheimer disease. Some preclinical studies in rodents have suggested the potential use of memantine as a neuroprotective agent for ischemic or hemorrhagic stroke.…”

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confidence: 99%

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Memantine Improves Safety of Thrombolysis for Stroke

Montagne

Hébert

Jullienne

et al. 2012

Stroke

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Background and Purpose-Despite side effects including N-methyl-D-aspartate-mediated neurotoxicity, recombinant tissue-type plasminogen activator (rtPA) remains the only approved acute treatment for ischemic stroke. Memantine, used for treatment of Alzheimer disease, is an antagonist for N-methyl-D-aspartate receptors. We investigated whether memantine could be used as a neuroprotective adjunct therapy for rtPA-induced thrombolysis after stroke. Methods-In vitro N-methyl-D-aspartate exposure, oxygen and glucose deprivation, and N-methyl-D-aspartate-mediated calcium videomicroscopy experiments were performed on murine cortical neurons in the presence of rtPA and memantine. The therapeutic safety of rtPA and memantine coadministration was evaluated in mouse models of thrombotic stroke and intracerebral hemorrhage. Ischemic and hemorrhagic volumes were assessed by MRI and neurological evaluation was performed by the string test and automated gait analysis. Results-Our in vitro observations showed that memantine was able to prevent the proneurotoxic effects of rtPA in cultured cortical neurons. Although memantine did not alter the fibrinolytic activity of rtPA, our in vivo observations revealed that it blunted the noxious effects of delayed thrombolysis on lesion volumes and neurological deficits after ischemic stroke. In addition, memantine rescued rtPA-induced decrease in survival rate after intracerebral hemorrhage. Conclusions-Memantine could be used as an adjunct therapy to improve the safety of thrombolysis.

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“…6 Activation of NMDAR has been suggested as a possible mechanism of tPA-dependent neuroprotection following OGD in cortical neurons, 20 but we did not confirm these results in our present model. This may be explained by the use of different strategies to block tPA-dependent NMDAR signaling, that is, MK-801 as a broad antagonist of NMDAR on one hand and an antibody previously characterized to specifically prevent the tPA-dependent potentiation of NMDAR signaling without affecting their basal activity 30 on the other hand. Although LRP was also reported to mediate some of the neuroprotective functions of tPA, 31 we excluded its implication in our models using RAP, a well-characterized antagonist of the interaction of tPA with LRP.…”

Section: Discussionmentioning

confidence: 99%

Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism

et al. 2015

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In the central nervous system, tissue-type plasminogen activator (tPA) has been associated with both pro-death and prosurvival actions on neurons. In most cases, this has been related to exogenous tPA. In the present study, we addressed the influence of endogenous tPA. We first observed an increased transcription of tPA following either in vivo global brain ischemia in rats or in vitro oxygen glucose deprivation (OGD) on mice and rats hippocampal slices. Hippocampal slices from tPA-deficient mice were more sensitive to OGD than wild-type slices. Pharmacological approaches targeting the known receptors of tPA revealed that only the inhibition of phosphorylation of epidermal growth factor receptors (EGFRs) prevented the neuroprotective effect of endogenous tPA. This study shows that ischemic hippocampal neurons overproduce endogenous tPA as an intend to protect themselves from ischemic death, by a mechanism involving an activation of EGFRs. Thus, strategies contributing to promote either endogenous production of tPA or its associated EGFR-linked signaling pathway may have beneficial effects following brain injuries such as stroke.

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Antibodies Preventing the Interaction of Tissue-Type Plasminogen Activator With N-Methyl- d -Aspartate Receptors Reduce Stroke Damages and Extend the Therapeutic Window of Thrombolysis

Abstract: Our strategy limits ischemic damages and extends the therapeutic window of tPA-driven thrombolysis. Thus, the prospect of this immunotherapy is an extension of the range of treatable patients.

Cited by 65 publications

References 30 publications

Impact of Alcohol Consumption on the Outcome of Ischemic Stroke and Thrombolysis

Impact of Alcohol Consumption on the Outcome of Ischemic Stroke and Thrombolysis

Memantine Improves Safety of Thrombolysis for Stroke

Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism

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