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 - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Stroke Année : 2011

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

Résumé

Background and Purpose— Tissue-type plasminogen activator (tPA) is the only drug approved for the acute treatment of ischemic stroke but with two faces in the disease: beneficial fibrinolysis in the vasculature and damaging effects on the neurovascular unit and brain parenchyma. To improve this profile, we developed a novel strategy, relying on antibodies targeting the proneurotoxic effects of tPA. Methods— After production and characterization of antibodies (αATD-NR1) that specifically prevent the interaction of tPA with the ATD-NR1 of N-methyl- d -aspartate receptors, we have evaluated their efficacy in a model of murine thromboembolic stroke with or without recombinant tPA-induced reperfusion, coupled to MRI, near-infrared fluorescence imaging, and behavior assessments. Results— In vitro, αATD-NR1 prevented the proexcitotoxic effect of tPA without altering N-methyl- d -aspartate-induced neurotransmission. In vivo, after a single administration alone or with late recombinant tPA-induced thrombolysis, antibodies dramatically reduced brain injuries and blood–brain barrier leakage, thus improving long-term neurological outcome. Conclusions— 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.

Dates et versions

hal-03895712 , version 1 (13-12-2022)

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Citer

Richard Macrez, Pauline Obiang, Maxime Gauberti, Benoit Roussel, Amandine Baron, et al.. 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. Stroke, 2011, 42 (8), pp.2315-2322. ⟨10.1161/STROKEAHA.110.606293⟩. ⟨hal-03895712⟩
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