• Axel Montagne, Marie Hébert, Amandine Jullienne, Flavie Lesept, Audrey Le Béhot, Morgane Louessard, Maxime Gauberti, Cyrille Orset, Carine Ali, Véronique Agin, Eric Maubert, and Denis Vivien.
• INSERM UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, GIP Cyceron, Bd H. Becquerel, BP 5229, Caen, F-14074 France.
• Stroke. 2012 Oct 1; 43 (10): 2774-81.

Background And PurposeDespite 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.MethodsIn 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.ResultsOur 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.ConclusionsMemantine could be used as an adjunct therapy to improve the safety of thrombolysis.

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