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

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.

• Authors: Richard Macrez, Pauline Obiang, Maxime Gauberti, Benoit Roussel, Amandine Baron, Jérôme Parcq, Frédéric Cassé, Yannick Hommet, Cyrille Orset, Véronique Agin, Laurent Bezin, Teresa Garcia Berrocoso, Karl Uwe Petersen, Joan Montaner, Eric Maubert, Denis Vivien, Carine Ali
• Journal: Stroke (Stroke) Vol. 42 Issue 8 Pg. 2315-22 (Aug 2011) ISSN: 1524-4628 [Electronic] United States
• PMID: 21680906 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Fibrinolytic Agents
• Receptors, N-Methyl-D-Aspartate
• Tissue Plasminogen Activator

Topics

• Animals
• Antibodies (immunology, therapeutic use)
• Brain (drug effects, immunology)
• Brain Ischemia (drug therapy, immunology)
• Fibrinolytic Agents (immunology, therapeutic use)
• Mice
• Receptors, N-Methyl-D-Aspartate (immunology)
• Stroke (drug therapy, immunology)
• Tissue Plasminogen Activator (immunology, therapeutic use)