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

Inhibition of neuronal ferroptosis protects hemorrhagic brain.

Author information

1
Department of Anesthesiology and Critical Care Medicine.
2
Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
3
Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, USA.
4
Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA.

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 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.

PMID:
28405617
PMCID:
PMC5374066
DOI:
10.1172/jci.insight.90777
[Indexed for MEDLINE]
Free PMC Article

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