Research ArticleBRAIN HEMORRHAGE

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  02 Mar 2016:
Vol. 8, Issue 328, pp. 328ra29
DOI: 10.1126/scitranslmed.aac6008

You are currently viewing the abstract.

View Full Text

Via your Institution

Log in through your institution

Log in through your institution


Beating back damage from brain bleeding

Brain bleeding is associated with stroke, anticoagulant use, amyloid angiopathy, and brain trauma. Blood in the brain leads to the deposition of toxic iron, and as expected, chelators of iron can enhance functional recovery after stroke. Here, Karuppagounder et al. show that iron chelators protect from a bleeding stroke not by binding all iron but rather by targeting a small family of iron-containing enzymes, the hypoxia-inducible factor prolyl hydroxylases. The target enzymes are oxygen sensors that, when inhibited, engage a broad homeostatic response to low oxygen and oxidative stress. The authors characterize and validate a selective, brain-penetrant inhibitor of brain oxygen sensors, which they call adaptaquin, as a new candidate treatment for brain bleeding in several rodent models. Protective doses of adaptaquin were used in combination with unbiased RNA profiling to identify an unexpected hypoxia-inducible factor–independent pathway mediated by the prodeath transcription factor ATF4.

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.

View Full Text