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Title: Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models

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. Here we show that the hypoxia-inducible factor prolyl-hydroxylase (HIF- PHD) family of iron-dependent oxygen sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in mouse striatum improved functional recovery following ICH. A low molecular weight hydroxyquinoline inhibitor of the HIF-PHDs, adaptaquin, reduced neuronal death and behavioral deficits following ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of expression of the prodeath factor ATF4 rather than activation of a HIF-dependent prosurvival pathway. In conclusion, 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 following ICH in multiple rodent species.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [3] ;  [3] ;  [4] ;  [5] ;  [1] ;  [6] ;  [7] ;  [8] ;  [9] ;  [10] ;  [11] ;  [1] ;  [1] more »;  [5] ;  [12] ;  [4] ;  [13] ;  [14] ;  [14] ;  [14] ;  [1] ;  [3] ;  [2] ;  [15] ;  [1] « less
  1. Burke Medical Research Inst., White Plains, NY (United States). Sperling Center for Hemorrhagic Stroke Recovery; Weill Medical Collage of Cornell Univ., New York, NY (United States). Feil Family Brain and Mind Research Inst.
  2. Univ. of Alberta, Edmonton, AB (Canada)
  3. Univ. of Oxford (United Kingdom)
  4. Phillips-Univ. Marburg, Marburg (Germany). Inst. fuer Pharmakologie and Klinische Pharmazie
  5. Weill Medical Collage of Cornell Univ., New York, NY (United States). Dept. of Biochemistry
  6. Children’s Hospital of Oakland, Oakland, CA (United States)
  7. Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Neurology
  8. Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Neurosurgery
  9. Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Neurosurgery
  10. Univ. of Texas, Austin, TX (United States). Dept. of Psychology
  11. Brookhaven National Lab. (BNL), Upton, NY (United States). Photon Sciences Directorate
  12. Univ. of California, Santa Cruz, CA (United States). Dept. of Chemistry and Biochemistry
  13. Univ. of Connecticut Health Center, Farmington, CT (United States). Center for Vascular Biology
  14. Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States). Inst.for Cell Engineering
  15. Univ. of California, Los Angeles, CA (United States). Dept. of Psychiatry
Publication Date:
Report Number(s):
BNL-112574-2016-JA
Journal ID: ISSN 1946-6234
Grant/Contract Number:
SC0012704
Type:
Accepted Manuscript
Journal Name:
Science Translational Medicine
Additional Journal Information:
Journal Volume: 8; Journal Issue: 328; Journal ID: ISSN 1946-6234
Publisher:
AAAS
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1340386