Delayed hypoxic postconditioning protects against cerebral ischemia in the mouse.
OBJECTIVE
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-1alpha 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-1alpha and its target genes, erythropoietin and adrenomedullin, as potential effectors of postconditioning.
Leconte
Claire
C
CERVOxy Hypoxia and cerebrovascular pathophysiology, UMR 6232 CI-NAPS, Université de Caen Basse-Normandie, CNRS, CEA, CYCERON, Caen, France.
Tixier
Emmanuelle
E
Freret
Thomas
T
Toutain
Jérôme
J
Saulnier
Romaric
R
Boulouard
Michel
M
Roussel
Simon
S
Schumann-Bard
Pascale
P
Bernaudin
Myriam
M
D053607:Adrenomedullin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001284:Atrophy / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000502:physiology; D004921:Erythropoietin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000503:physiopathology / Q000517:prevention & control* / Q000628:therapy*; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy; D018384:Oxidative Stress / Q000502:physiology; D013997:Time Factors
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004921:Erythropoietin; D053607:Adrenomedullin