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Background: A hemoglobin-albumin cluster designated as “HemoAct” was developed as a red blood cell substitute. It is composed of one core hemoglobin center wrapped covalently by three albumin shells. Since its particle size with a diameter of 10 nm is far smaller than red blood cell, it is expected to maintain good perfusion in the cerebral microvessels, leading to neuroprotective effects on ischemia-reperfusion (I/R) injury.Purpose: We aim to examine whether HemoAct have neuroprotective effects in rat transient middle cerebral artery occlusion (tMCAO) model, without toxic effects of hemoglobin, by administering it though the recanalized artery just before the onset of reperfusion.Subjects and Methods: Male Sprague-Dawley rats were subjected to 2-hour tMCAO by suture occlusion and then divided into four groups with respective treatments: (1) control group; no infusion, (2) vehicle group; infusion of PBS as the solvent (3) 0.5х HemoAct group; infusion of one-half diluted HemoAct (4) HemoAct group; infusion of undiluted HemoAct. Physical and neurological states, infarct and edema volumes, reactive oxygen species (ROS) and protease immunoblot levels were compared between the four groups after 24 hours of reperfusion. Microvascular hemoglobin perfusion and morphological states were compared between the control and HemoAct groups with immunohistochemical technique.Results: No significant changes were observed in blood pressure, pH, and blood gas after HemoAct infusion. Neurological symptoms were significantly less severe in the HemoAct group than in the other groups. Infarct and edema volumes were significantly smaller in the 0.5х HemoAct group (27.1%/15.2%) and the HemoAct group (20.2%/14.1%) than in the control group (55.2%/26.4%) and the vehicle group (53.2%/27.1%). ROS (4-HNE) and protease (MMP-9) immunoblot levels were significantly reduced in HemoAct group compared with the control and vehicle groups. Microvascular hemoglobin perfusion was more and microvascular narrowing changes was less in the HemoAct group than in the control group.Conclusion: HemoAct exhibited strong neuroprotective effects on I/R injury without toxic effects of hemoglobin. Superior microvascular perfusion of HemoAct may be a possible neuroprotective mechanism.