Stroke is still the second cause of death and the first cause of acquired adult disability worldwide. Due to strict inclusion criteria, thrombolysis with tissue plasminogen activator (tPA), the only approved stroke treatment, is given to few patients. Therefore, new treatments are urgently needed. Excitotoxicity, relevant to secondary neuronal death in ischemic penumbra, has become a popular stroke target. Recently, administration of a peptide -Tat-NR2B9c, or NA-1- that prevents the interaction of the ionotropic glutamate receptor subunit GluN2B (formerly NR2B) with the postsynaptic density protein 95 (PSD-95) scaffold protein showed promising results. A systematic analysis of all identified preclinical studies using NA-1 in stroke models was conducted, and translational strategies to use the agent in human stroke were described and discussed. Seven studies involving 359 animals (260 rats, 33 mice and 66 macaques; corresponding, respectively, to 189 control- and 170 NA-1-treated animals) showed a significant 42.8% reduction in infarct size in the NA-1-treated group. However, funnel plot analysis demonstrated a publication bias which decreased protection to 17.6% after correction. Overall, the quality score of those studies was acceptable (6; interquartile range = 5-9), although no study used comorbid animals. Interestingly, successful translation to human iatrogenic stroke during aneurysm repair make NA-1 a strong candidate. NA-1 has successfully advanced from preclinical to human brain ischemia trials but still needs to fulfill some important STAIR requirements to become an ideal neuroprotectant.

MC has received a predoctoral fellowship from the Instituto de Salud Carlos III and DG is a statistical fellow funded by the Spanish stroke network (INVICTUS). MD-G is supported by grant BFU2010-18380/BFI from the Ministerio de Economía y Competitividad.

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