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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.

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

Science translational medicine (2016-03-05)
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 Cho, Frederick 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
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 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Z-Leu-Leu-Leu-al, ≥90% (HPLC)
Sigma-Aldrich
Anti-TRB3 (1-145) Rabbit pAb, liquid, Calbiochem®
Sigma-Aldrich
Anti-ATF4 Antibody, serum, from rabbit
Sigma-Aldrich
Anti-Histone H4 Antibody, pan, clone 62-10C-2, rabbit monoclonal, clone 62-10C-2, from rabbit
Sigma-Aldrich
Anti-acetyl-Histone H4 Antibody, serum, Upstate®