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Neuroprotection by hypoxic preconditioning involves upregulation of hypoxia‐inducible factor‐1 in a prenatal model of acute hypoxia
Author(s) -
Giusti Sebastián,
Fiszer de Plazas Sara
Publication year - 2012
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22766
Subject(s) - neuroprotection , hypoxia (environmental) , hypoxia inducible factors , in vivo , pharmacology , downregulation and upregulation , hypoxia inducible factor 1 , neuroscience , chemistry , medicine , biology , biochemistry , oxygen , microbiology and biotechnology , organic chemistry , gene
The molecular pathways underlying the neuroprotective effects of preconditioning are promising, potentially drugable targets to promote cell survival. However, these pathways are complex and are not yet fully understood. In this study we have established a paradigm of hypoxic preconditioning based on a chick embryo model of normobaric acute hypoxia previously developed by our group. With this model, we analyzed the role of hypoxia‐inducible factor‐1α (HIF‐1α) stabilization during preconditioning in HIF‐1 signaling after the hypoxic injury and in the development of a neuroprotective effect against the insult. To this end, we used a pharmacological approach, based on the in vivo administration of positive (Fe 2+ , ascorbate) and negative (CoCl 2 ) modulators of the activity of HIF‐prolyl hydroxylases (PHDs), the main regulators of HIF‐1. We have found that preconditioning has a reinforcing effect on HIF‐1 accumulation during the subsequent hypoxic injury. In addition, we have also demonstrated that HIF‐1 induction during hypoxic preconditioning is necessary to obtain an enhancement in HIF‐1 accumulation and to develop a tolerance against a subsequent hypoxic injury. We provide in vivo evidence that administration of Fe 2+ and ascorbate modulates HIF accumulation, suggesting that PHDs might be targets for neuroprotection in the CNS. © 2011 Wiley Periodicals, Inc.