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

Karuppagounder, Saravanan S.; Alim, Ishraq; Khim, Soah J.; Bourassa, Megan W.; Sleiman, Sama F.; John, Roseleen; Thinnes, Cyrille C.; Yeh, Tzu-Lan; Demetriades, Marina; Neitemeier, Sandra; Cruz, Dana; Gazaryan, Irina; Killilea, David W.; Morgenstern, Lewis; Xi, Guohu; Keep, Richard F.; Schallert, Timothy; Tappero, Ryan V.; Zhong, Jian; Cho, Sunghee; Maxfield, Frederick R.; Holman, T. R.; Culmsee, Carsten; Fong, Guo-Hua -H.; Su, Yijing; Ming, Guo-li; Song, Hongjun; Cave, John W.; Schofield, Christopher J.; Colbourne, Frederick; Coppola, Giovanni; Ratan, Rajiv R.

doi:10.1126/scitranslmed.aac6008

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

Journal Article · Wed Mar 02 00:00:00 EST 2016 · Science Translational Medicine

DOI:https://doi.org/10.1126/scitranslmed.aac6008· OSTI ID:1340386

Karuppagounder, Saravanan S. ^[1]; Alim, Ishraq ^[1]; Khim, Soah J. ^[1]; Bourassa, Megan W. ^[1]; Sleiman, Sama F. ^[1]; John, Roseleen ^[2]; Thinnes, Cyrille C. ^[3]; Yeh, Tzu-Lan ^[3]; Demetriades, Marina ^[3]; Neitemeier, Sandra ^[4]; Cruz, Dana ^[5]; Gazaryan, Irina ^[1]; Killilea, David W. ^[6]; Morgenstern, Lewis ^[7]; Xi, Guohu ^[8]; Keep, Richard F. ^[9]; Schallert, Timothy ^[10]; Tappero, Ryan V. ^[11]; Zhong, Jian ^[1]; Cho, Sunghee ^[1] more »

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.
Univ. of Alberta, Edmonton, AB (Canada)
Univ. of Oxford (United Kingdom)
Phillips-Univ. Marburg, Marburg (Germany). Inst. fuer Pharmakologie and Klinische Pharmazie
Weill Medical Collage of Cornell Univ., New York, NY (United States). Dept. of Biochemistry
Childrenâs Hospital of Oakland, Oakland, CA (United States)
Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Neurology
Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Neurosurgery
Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Neurosurgery
Univ. of Texas, Austin, TX (United States). Dept. of Psychology
Brookhaven National Lab. (BNL), Upton, NY (United States). Photon Sciences Directorate
Univ. of California, Santa Cruz, CA (United States). Dept. of Chemistry and Biochemistry
Univ. of Connecticut Health Center, Farmington, CT (United States). Center for Vascular Biology
Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States). Inst.for Cell Engineering
Univ. of California, Los Angeles, CA (United States). Dept. of Psychiatry

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.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: SC0012704

OSTI ID:: 1340386

Alternate ID(s):: OSTI ID: 1354595

Report Number(s):: BNL--112574-2016-JA

Journal Information:: Science Translational Medicine, Journal Name: Science Translational Medicine Journal Issue: 328 Vol. 8; ISSN 1946-6234

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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Journal Article · Sat Jul 08 00:00:00 EDT 2017 · Biochemical and Biophysical Research Communications · OSTI ID:22719012

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59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES

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

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