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

See allHide authors and affiliations

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

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.

View Full Text

Stay Connected to Science Translational Medicine