Inhibition of neuronal ferroptosis protects hemorrhagic brain.

By Qian Li, Xiaoning Han, Xi Lan, Yufeng Gao, Jie-ru Wan, Frederick Durham, Tian Cheng, Jie Yang, Zhong-yu Wang, Chao Jiang and 4 more. JCI Insight, 2017

631 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Neurology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/54f9a38ef033be0b6878cbd1c32aa2d8f8ec1706

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Citations in the corpus

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. (2017, positive): “Indeed, inhibition of glutaminolysis has been shown to attenuate ischemia/reperfusion-induced heart and kidney damage and brain hemorrhage in experimental models (Gao et al., 2015; Li et al., 2017; Linkermann et al., 2014).”
Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke. (2019, neutral): “Recent studies demonstrate that secondary cell death in ICH is not the result of random destruction of macromolecules by iron-catalyzed oxidants, but rather by ferroptosis, a nonapoptotic, programmed cell death pathway (Karuppagounder et al., 2016; Li et al., 2017; Zille et al., 2017).”