This Article Full Text Full Text (PDF) All Versions of this Article: 40/10/3349    most recent STROKEAHA.109.557314v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Leconte, C. Articles by Bernaudin, M. PubMed PubMed Citation Articles by Leconte, C. Articles by Bernaudin, M. Related Collections Animal models of human disease Behavioral Changes and Stroke Computerized tomography and Magnetic Resonance Imaging Neuroprotectors

(Stroke. 2009;40:3349.)
© 2009 American Heart Association, Inc.

Original Contributions

Delayed Hypoxic Postconditioning Protects Against Cerebral Ischemia in the Mouse

Claire Leconte, MSc; Emmanuelle Tixier, PhD; Thomas Freret, PhD; Jérôme Toutain, BSc; Romaric Saulnier; Michel Boulouard, PhD; Simon Roussel, PhD; Pascale Schumann-Bard, PhD Myriam Bernaudin, PhD

From the CERVOxy "Hypoxia and cerebrovascular pathophysiology" (C.L., E.T., J.T., R.S., S.R., M.B.), UMR 6232 CI-NAPS, Université de Caen Basse-Normandie; Université Paris-Descartes; CNRS; CEA; CYCERON, Caen, France; and GMPc "Groupe Mémoire et Plasticité comportementale" (C.L., T.F., M.B., P.S.-B.), UPRES EA4259, UFR Sciences Pharmaceutiques, Université de Caen Basse-Normandie, Caen, France.

Correspondence to Myriam Bernaudin, PhD, CI-NAPS UMR 6232, CERVOxy, CYCERON, Bd Henri Becquerel, BP5229, 14074 Caen Cedex, France. E-mail bernaudin{at}cyceron.fr

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 • erythropoietin • hypoxia • ischemia • postconditioning