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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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 fromoxidativedeath invitroor fromICHinvivobyadaptaquinwasassociatedwithsuppression 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.

Original languageEnglish (US)
Article number328ra29
JournalScience Translational Medicine
Volume8
Issue number328
DOIs
StatePublished - Mar 2 2016

ASJC Scopus subject areas

  • Medicine(all)

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