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Introduction: Apolipoprotein E (apoE) is an endogenous brain protein synthesized in response to brain injury and modifies neuroinflammatory responses by downregulating glial activation and release of inflammatory mediators. Due to its size, however, the intact apoE holoprotein does not cross the blood brain barrier, and thus has limited therapeutic potential. We have demonstrated that a small 5 amino acid apoE-mimetic peptide (CN-105) derived from the receptor-binding region of apoE retains the neuroprotective effects of the intact holoprotein, is well tolerated, and effectively crosses the blood brain barrier. This study investigates whether CN105 improves functional and histological outcomes in a murine model of transient focal ischemia and reperfusion.Methods: We used the transient middle cerebral artery occlusion murine model of ischemic stroke for all our experiments. Thirty-minutes ischemic occlusion time was used for infarct volume and survival analysis at 72 hours while 15 minutes ischemic occlusion time was used for functional outcome analysis performed 7 days post stroke. A dose of CN-105 (0.1mg/kg) in 100 μl volume was administered as a single dose 30 minutes post-perfusion via tail vein injection. Motor-sensory functional outcomes were evaluated using daily rotarod assessment for 7 days and 4-limb wire hanging test on days 2 and 7 days post injury. Infarct volume was evaluated using 2,3,5-Triphenyltetrazolium chloride staining method. Independent t-test was used for infarct volume analysis, repeated measures ANOVA was used for functional outcomes evaluation and log-rank test was used for survival evaluation. Experiments were performed in a randomized and blinded fashion.Results: Administration of CN-105 improved motor and sensory functional outcomes at 7 days in rotarod (p = 0.035) and 4-limb wire hanging test (p=0.013) when compared to vehicle. There was also a survival benefit (n = 8 (66.7%) vs n = 3 (25%), p=0.037) and a significant reduction of infarct volumes (79 ± 43 mm3) compared to vehicle (127 ± 31 mm3) (p = 0.039) at 72 hours.Conclusion: Intravenous administration of CN-105 is associated with functional, survival, and histological benefits in a murine ischemic stroke model when given at 30 minutes post-reperfusion.