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Despite displaying efficacy in experimental stroke studies, neuroprotection has failed in clinical trials. The translational difficulties include a limited methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to standardized strokes in animal models. Promising neuroprotective approaches based on a deeper understanding of the complex pathophysiology of ischemic stroke, such as blocking pro-inflammatory pathways plus pro-survival mediators, are now evaluated in preclinical studies. Combinatorial therapy has become increasingly attractive in recent years as recognizing the complexity of stroke progression becomes evident. The paper aimed to test the hypothesis that blocking pro-inflammatory platelet-activating factor receptor (PAF-R) with LAU-0901 plus administering a selected docosanoid, aspirin-triggered neuroprotectin D1 (AT-NPD1), which activates cell-survival pathways after middle cerebral artery occlusion (MCAo), would lead to neurological recovery.  We have demonstrated that LAU-0901 plus AT-NPD1 treatment affords high-grade neuroprotection in MCAo, equaling or exceeding that afforded by LAU-0901 or AT-NPD1 alone at considerably moderate doses, and it has a broad therapeutic window extending to 6 hours after stroke onset.