title: Inhibition of neuronal ferroptosis protects hemorrhagic brain.
abstract: 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 ofPTGS2and 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.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Anesthesiology and Critical Care Medicine.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Anesthesiology and Critical Care Medicine.
authors.forename: Xi
authors.initials: X
authors.lastname: Lan
authors.affiliation: Department of Anesthesiology and Critical Care Medicine.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Anesthesiology and Critical Care Medicine.
authors.forename: Jieru
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Anesthesiology and Critical Care Medicine.
authors.forename: Frederick
authors.initials: F
authors.lastname: Durham
authors.affiliation: Department of Anesthesiology and Critical Care Medicine.
authors.forename: Tian
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Department of Anesthesiology and Critical Care Medicine.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine.
authors.forename: Chao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.|Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, USA.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Ying
authors.affiliation: Department of Anesthesiology and Critical Care Medicine.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Koehler
authors.affiliation: Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA.
authors.forename: Brent R
authors.initials: BR
authors.lastname: Stockwell
authors.affiliation: Department of Anesthesiology and Critical Care Medicine.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000517:prevention & control*; D003514:Cyclohexylamines / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006624:Hippocampus; D006801:Humans; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010655:Phenylenediamines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015415:Biomarkers; D003514:Cyclohexylamines; D018696:Neuroprotective Agents; D010655:Phenylenediamines; D017382:Reactive Oxygen Species; C573944:ferrostatin-1; D007501:Iron; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2