Delayed Hypoxic Postconditioning Protects Against Cerebral Ischemia in the Mouse

Abstract

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...

Hypoxic conditioning and the central nervous system: A new therapeutic opportunity for brain and spinal cord injuries?

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Hypoxic postconditioning reduces microglial activation, astrocyte and caspase activity, and inflammatory markers after hypoxia–ischemia in the neonatal rat brain

“…While animal studies have shown robust protective effects of hypoxic preconditioning, the bench to bedside application remains limited due to the unpredictable nature of HI brain injury in human newborns. Recent studies have shown neuroprotective effects after exposure to hypoxic postconditioning (PostC) following a brain injury in rodents (20,21). The current study investigates the potential mechanism of neuroprotection by hypoxic PostC after a neonatal HI brain injury in rats.…”

Enhanced Retinal Ganglion Cell Survival in Glaucoma by Hypoxic Postconditioning After Disease Onset

“…Given that the progressive RGC injury occurring in glaucoma is characterized by a multifactorial pathology putatively involving a host of excitotoxic, inflammatory, immune, vascular, biomechanical, and other factors [58][59][60], and that the mechanisms dictating RGC soma and RGC axon loss may be quite distinct [61][62][63], the epigenetic changes induced by RH-Post will likely be extensive in order to account for the magnitude of the protection achieved. It is also worth noting that, although exposures to intermittent systemic hypoxia may not ultimately be adopted as a clinical treatment for glaucoma patients, this very stimulus has established a strong record for protection against a variety of acute and chronic diseases in the CNS [27][28][29][30][64][65][66][67], and other tissues [68][69][70], and may not be easily mimicked by a pharmacologic, monotherapy approach.…”