Inhibition of neuronal ferroptosis protects hemorrhagic brain

JCI Insight. 2017 Apr 6;2(7):e90777. doi: 10.1172/jci.insight.90777.


Intracerebral hemorrhage (ICH) causes high mortality and morbidity, but our knowledge of post-ICH neuronal death and related mechanisms is limited. In this study, we first demonstrated that ferroptosis, a newly identified form of cell death, occurs in the collagenase-induced ICH model in mice. We found that administration of ferrostatin-1, a specific inhibitor of ferroptosis, prevented neuronal death and reduced iron deposition induced by hemoglobin in organotypic hippocampal slice cultures (OHSCs). Mice treated with ferrostatin-1 after ICH exhibited marked brain protection and improved neurologic function. Additionally, we found that ferrostatin-1 reduced lipid reactive oxygen species production and attenuated the increased expression level of PTGS2 and its gene product cyclooxygenase-2 ex vivo and in vivo. Moreover, ferrostatin-1 in combination with other inhibitors that target different forms of cell death prevented hemoglobin-induced cell death in OHSCs and human induced pluripotent stem cell-derived neurons better than any inhibitor alone. These results indicate that ferroptosis contributes to neuronal death after ICH, that administration of ferrostatin-1 protects hemorrhagic brain, and that cyclooxygenase-2 could be a biomarker of ferroptosis. The insights gained from this study will advance our knowledge of the post-ICH cell death cascade and be essential for future preclinical studies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Biomarkers / metabolism
  • Brain / metabolism*
  • Cells, Cultured
  • Cerebral Hemorrhage / prevention & control*
  • Cyclohexylamines / pharmacology*
  • Cyclooxygenase 2 / metabolism
  • Hippocampus
  • Humans
  • In Vitro Techniques
  • Iron / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / cytology
  • Neurons / drug effects*
  • Neuroprotective Agents / pharmacology*
  • Phenylenediamines / pharmacology*
  • Reactive Oxygen Species / metabolism


  • Biomarkers
  • Cyclohexylamines
  • Neuroprotective Agents
  • Phenylenediamines
  • Reactive Oxygen Species
  • ferrostatin-1
  • Iron
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2