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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. et al.
2016In Science Translational Medicine, 8 (328), p. 328ra29
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Abstract :
[en] 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 from oxidative death in vitro or 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.
Disciplines :
Human health sciences: Multidisciplinary, general & others
Author, co-author :
Karuppagounder, Saravanan S.
Alim, Ishraq
Khim, Soah J.
Bourassa, Megan W.
Sleiman, Sama F.
John, Roseleen
THINNES, Cyrille ;  University of Oxford > Department of Chemistry
Yeh, Tzu-Lan
Demetriades, Marina
Neitemeier, Sandra
Cruz, Dana
Gazaryan, Irina
Killilea, David W.
Morgenstern, Lewis
Xi, Guohua
Keep, Richard F.
Schallert, Timothy
Tappero, Ryan V.
Zhong, Jian
Cho, Sunghee
Maxfield, Frederick R.
Holman, Theodore R.
Culmsee, Carsten
Fong, Guo-Hua
Su, Yijing
Ming, Guo-Li
Song, Hongjun
Cave, John W.
Schofield, Christopher J.
Colbourne, Frederick
Coppola, Giovanni
Ratan, Rajiv R.
More authors (22 more) Less
External co-authors :
yes
Language :
English
Title :
Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models.
Publication date :
2016
Journal title :
Science Translational Medicine
ISSN :
1946-6242
Publisher :
American Association for the Advancement of Science, United States
Volume :
8
Issue :
328
Pages :
328ra29
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2016, American Association for the Advancement of Science.
Available on ORBilu :
since 29 March 2016

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