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 Aug;42(8):2315-22. doi: 10.1161/STROKEAHA.110.606293. Epub 2011 Jun 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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