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Based upon our previous findings that microRNA-122 (miR-122) was decreased in peripheral blood of both humans and rats after ischemic stroke, we hypothesized that elevating miR-122 in blood might improve outcomes after ischemic stroke.Using the in vivo polyethylene glycol 2000 (PEG)-liposome based miRNA transfection system and the rat middle cerebral artery occlusion (MCAO) model, we recently demonstrated that intravenous (i.v.) miR-122 mimic, given immediately after MCAO, elevated miR-122 in peripheral blood, prevented neurological impairments, and reduced brain infarction volume up to 93% after MCAO in rats. Using Taqman PCR based assays, we demonstrate fourteen direct miR-122 target genes (e.g. Nos2, Vcam1, Clic4, Ucp2, Dlg2, and others) were decreased in blood leukocytes following miR-122 mimic treatment after MCAO in rats. Focusing on ONE miR-122 target gene (Nos2), we demonstrated that miR-122 binds to the complementary sequence within three prime untranslated regions (3’UTRs) of Nos2 using luciferase reporter assay, and that miR-122 mimic decreases Nos2 expression in brain microvascular endothelial cells (BMVECs) after MCAO in rats.These results show that Nos2 is decreased in leukocytes and BMVECs following miR-122 mimic treatment after MCAO, which likely contributes to miR-122 induced protection after MCAO in rats.Acknowledgements: This study was supported by NIH grants R01NS089901 (DZL) and NS054652 (FRS). There were no conflicts of interest.