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Introduction: Neuroprotective effects of normobaric oxygen (NBO) and ethanol (EtOH) has been shown. In a clinically relevant autologous embolus rat stroke model in which reperfusion was established by tissue-type plasminogen activator (rt-PA), the present study further evaluated whether low concentration NBO enhanced therapeutic effect of mild hypothermia (Hypo) or EtOH through a reduction in apoptosis and whether EtOH can substitute for hypothermia.Hypothesis: Hypo and EtOH has been shown to have neuroprotective effects through similar mechanisms. We assessed the hypothesis that low concentration NBO, whose neuroprotective effects are currently debated, has benefit in our stroke models, and we further assessed the hypothesis that EtOH can substitute for Hypo in the presence of tPA and NBO.Methods: At 1 hour of middle cerebral artery occlusion (MCAO) by an autologous embolus, rats (96 total, 12 in each treatment group) received rt-PA and other treatments of either EtOH (1.0 g/kg) or Hypo (33 °C for 3 hours) in combination with NBO (60% for 3 hours). Apoptotic cell death was measured by ELISA. Western immunoblotting was performed for pro- (AIF, Caspase-3, Bax) and anti-apoptotic (Bcl-2) protein expression at 3 and 24 hours of reperfusion.Results: Compared to ischemic rats treated only with rt-PA, animals with NBO, hypothermia or EtOH had significantly reduced apoptotic cell death by 32.5%, 43.1% and 36.0% respectively. However, combination therapy that included NBO+EtOH or NBO+Hypo with rt-PA exhibited a much larger decline (p<0.01) in the cell death by 71.1% and 73.6%, respectively. Similarly, NBO+EtOH or NBO+Hypo treatment in addition to rt-PA enhanced beneficial effects on both pro- and anti-apoptotic protein expressions as compared to other options.Conclusions: Neuroprotection after reperfusion with rt-PA in ischemic stroke induced by thromboembolism are enhanced by combination treatment with either EtOH or Hypo in the presence of 60% NBO through reduced apoptosis. Since the effects produced by EtOH and Hypo are comparable, their mechanism of action may not only be similar but also could be interchangeable. Since EtOH administration does not lead to temperature decrease, EtOH may a better alternative than Hypo.