Background and Purpose-Inspired from preconditioning studies, ischemic postconditioning, consisting of the application of intermittent interruptions of blood flow shortly after reperfusion, has been described in cardiac ischemia and recently in stroke. It is well known that ischemic tolerance can be achieved in the brain not only by ischemic preconditioning, but also by hypoxic preconditioning. However, the existence of hypoxic postconditioning has never been reported in cerebral ischemia. Methods-Adult mice subjected to transient middle cerebral artery occlusion underwent chronic intermittent hypoxia starting either 1 or 5 days after ischemia and brain damage was assessed by T2-weighted MRI at 43 days. In addition, we investigated the potential neuroprotective effect of hypoxia applied after oxygen glucose deprivation in primary neuronal cultures. Results-The present study shows for the first time that a late application of hypoxia (5 days) after ischemia reduced delayed thalamic atrophy. Furthermore, hypoxia performed 14 hours after oxygen glucose deprivation induced neuroprotection in primary neuronal cultures. We found that hypoxia-inducible factor-1␣ expression as well as those of its target genes erythropoietin and adrenomedullin is increased by hypoxic postconditioning. Further studies with pharmacological inhibitors or recombinant proteins for erythropoietin and adrenomedullin revealed that these molecules participate in this hypoxia postconditioning-induced neuroprotection. Conclusions-Altogether, this study demonstrates for the first time the existence of a delayed hypoxic postconditioning in cerebral ischemia and in vitro studies highlight hypoxia-inducible factor-1␣ and its target genes, erythropoietin and adrenomedullin, as potential effectors of postconditioning. Key Words: adrenomedullin Ⅲ erythropoietin Ⅲ hypoxia Ⅲ ischemia Ⅲ postconditioning I schemic or hypoxic preconditioning is a sublethal stress able to reduce ischemia-induced injury when applied before ischemia, 1 a phenomenon called ischemic tolerance. Understanding the mechanisms underlying this preconditioning-induced tolerance might allow identification of new therapeutic targets. However, its application is not clinically feasible because the occurrence of stroke is hardly predictable. By analogy with preconditioning, postconditioning represents another promising strategy to modulate brain ischemic damage. Based on studies in the heart, 2 ischemic postconditioning was defined as a repetitive series of brief interruptions of reperfusion applied after ischemia that confers neuroprotection, probably by attenuating reperfusion injury. Inspired from these studies, the neuroprotective effect of ischemic postconditioning applied immediately after the ischemic insult has been reported in models of focal cerebral ischemia in the rat. [3][4][5] More delayed ischemic postconditioning, starting 6 hours and 24 hours after focal and global cerebral ischemia, respectively, has been also recently described. 6,7 Whereas the molecular mechanisms of cer...

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