title: 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: OBJECTIVE
  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.affiliation: INSERM U919, Serine Proteases and Pathophysiology of the Neurovascular Unit; UMR-CNRS 6232 Ci-NAPs, Cyceron, Bd Becquerel, 14074 Caen, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Macrez
authors.forename: Pauline
authors.initials: P
authors.lastname: Obiang
authors.forename: Maxime
authors.initials: M
authors.lastname: Gauberti
authors.forename: Benoit
authors.initials: B
authors.lastname: Roussel
authors.forename: Amandine
authors.initials: A
authors.lastname: Baron
authors.forename: Jérôme
authors.initials: J
authors.lastname: Parcq
authors.forename: Frédéric
authors.initials: F
authors.lastname: Cassé
authors.forename: Yannick
authors.initials: Y
authors.lastname: Hommet
authors.forename: Cyrille
authors.initials: C
authors.lastname: Orset
authors.forename: Véronique
authors.initials: V
authors.lastname: Agin
authors.forename: Laurent
authors.initials: L
authors.lastname: Bezin
authors.forename: Teresa Garcia
authors.initials: TG
authors.lastname: Berrocoso
authors.forename: Karl Uwe
authors.initials: KU
authors.lastname: Petersen
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.forename: Eric
authors.initials: E
authors.lastname: Maubert
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.forename: Carine
authors.initials: C
authors.lastname: Ali
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000276:immunology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000276:immunology; D005343:Fibrinolytic Agents / Q000276:immunology / Q000627:therapeutic use*; D051379:Mice; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology*; D020521:Stroke / Q000188:drug therapy* / Q000276:immunology; D010959:Tissue Plasminogen Activator / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D000906:Antibodies; D005343:Fibrinolytic Agents; D016194:Receptors, N-Methyl-D-Aspartate; D010959:Tissue Plasminogen Activator