title: Memantine improves safety of thrombolysis for stroke.
abstract: OBJECTIVE
  Despite side effects including N-methyl-d-aspartate-mediated neurotoxicity, recombinant tissue-type plasminogen activator (rtPA) remains the only approved acute treatment for ischemic stroke. Memantine, used for treatment of Alzheimer disease, is an antagonist for N-methyl-d-aspartate receptors. We investigated whether memantine could be used as a neuroprotective adjunct therapy for rtPA-induced thrombolysis after stroke.
  
  
  METHODS
  In vitro N-methyl-d-aspartate exposure, oxygen and glucose deprivation, and N-methyl-d-aspartate-mediated calcium videomicroscopy experiments were performed on murine cortical neurons in the presence of rtPA and memantine. The therapeutic safety of rtPA and memantine coadministration was evaluated in mouse models of thrombotic stroke and intracerebral hemorrhage. Ischemic and hemorrhagic volumes were assessed by MRI and neurological evaluation was performed by the string test and automated gait analysis.
  
  
  RESULTS
  Our in vitro observations showed that memantine was able to prevent the proneurotoxic effects of rtPA in cultured cortical neurons. Although memantine did not alter the fibrinolytic activity of rtPA, our in vivo observations revealed that it blunted the noxious effects of delayed thrombolysis on lesion volumes and neurological deficits after ischemic stroke. In addition, memantine rescued rtPA-induced decrease in survival rate after intracerebral hemorrhage.
  
  
  CONCLUSIONS
  Memantine could be used as an adjunct therapy to improve the safety of thrombolysis.
authors.affiliation: INSERM UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, GIP Cyceron, Bd H. Becquerel, BP 5229, Caen, F-14074 France.
authors.forename: Axel
authors.initials: A
authors.lastname: Montagne
authors.forename: Marie
authors.initials: M
authors.lastname: Hébert
authors.forename: Amandine
authors.initials: A
authors.lastname: Jullienne
authors.forename: Flavie
authors.initials: F
authors.lastname: Lesept
authors.forename: Audrey
authors.initials: A
authors.lastname: Le Béhot
authors.forename: Morgane
authors.initials: M
authors.lastname: Louessard
authors.forename: Maxime
authors.initials: M
authors.lastname: Gauberti
authors.forename: Cyrille
authors.initials: C
authors.lastname: Orset
authors.forename: Carine
authors.initials: C
authors.lastname: Ali
authors.forename: Véronique
authors.initials: V
authors.lastname: Agin
authors.forename: Eric
authors.initials: E
authors.lastname: Maubert
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D066298:In Vitro Techniques; D008279:Magnetic Resonance Imaging; D008297:Male; D008559:Memantine / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D023421:Models, Animal; D016202:N-Methylaspartate / Q000494:pharmacology; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018691:Excitatory Amino Acid Antagonists; D005343:Fibrinolytic Agents; D016202:N-Methylaspartate; D010959:Tissue Plasminogen Activator; D008559:Memantine