期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 8, 期 328, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aac6008
关键词
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资金
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Burke Foundation
- New York State Department of Health Center for Research Excellence in Spinal Cord Injury [DOHC019772]
- NIH [P01 NIA AG014930]
- Welcome Trust
- British Heart Foundation
- National Institute of Neurological Disorders and Stroke Informatics Center for Neurogenetics and Neurogenomics [P30 NS062691]
- Sperling Center for Hemorrhagic Stroke Recovery at the Burke Medical Research Institute
- Biotechnology and Biological Sciences Research Council [BBS/B/07683] Funding Source: researchfish
- British Heart Foundation [PG/12/33/29546] Funding Source: researchfish
Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection fromo xidative death invitroor from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models.
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