Immunotherapy blocking the tissue plasminogen activator-dependent activation of N-methyl-d-aspartate glutamate receptors improves hemorrhagic stroke outcome

Ischemic and hemorrhagic strokes have different etiologies, but share some pathogenic mechanisms, including a pro-neurotoxic effect of endogenous tissue plasminogen activator (tPA) via N-methyl-d-Aspartate (NMDA) receptors. Thus, in a model of intracerebral hemorrhage in rats, we investigated the th...

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Bibliographic Details
Published in:Neuropharmacology 2013-04, Vol.67, p.267-271
Main Authors: Gaberel, Thomas, Macrez, Richard, Gauberti, Maxime, Montagne, Axel, Hebert, Marie, Petersen, Karl-Uwe, Touze, Emmanuel, Agin, Véronique, Emery, Evelyne, Ali, Carine, Vivien, Denis
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal, Murine-Derived - administration & dosage
Cerebral hemorrhage
Immunotherapy
Immunotherapy - methods
Intracranial Hemorrhages - immunology
Intracranial Hemorrhages - metabolism
Intracranial Hemorrhages - therapy
Male
Mice
Neurotoxicity
Random Allocation
Rats
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate - metabolism
Stroke - immunology
Stroke - metabolism
Stroke - therapy
Tissue plasminogen activator
Tissue Plasminogen Activator - antagonists & inhibitors
Tissue Plasminogen Activator - physiology
Treatment Outcome
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Summary:Ischemic and hemorrhagic strokes have different etiologies, but share some pathogenic mechanisms, including a pro-neurotoxic effect of endogenous tissue plasminogen activator (tPA) via N-methyl-d-Aspartate (NMDA) receptors. Thus, in a model of intracerebral hemorrhage in rats, we investigated the therapeutic value of a strategy of immunotherapy (αATD-GluN1 antibody) preventing the interaction of tPA with NMDA receptors. We found that a single intravenous injection of αATD-GluN1 reduced brain edema, neuronal death, microglial activation and functional deficits following intracerebral hemorrhage, without affecting the hematoma volume. ► An antibody targeting NMDA receptors (αATD-GluN1) prevents the neurotoxicity of tPA. ► We evaluate the impact of αATD-GluN1 in a rat model of intracerebral hemorrhage (ICH). ► αATD-GluN1 decreases neuronal death as well as microglial activation after ICH. ► αATD-GluN1 decreases brain edema after ICH. ► αATD-GluN1 improves neurological outcome after ICH.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2012.11.023