Evidence map›Paper›PMID 28250197›Full record

ArticleStroke2017

Neuronal Death After Hemorrhagic Stroke In Vitro and In Vivo Shares Features of Ferroptosis and Necroptosis.

Marietta Zille, Saravanan S Karuppagounder, Yingxin Chen, Peter J Gough, John Bertin, Joshua Finger, Teresa A Milner, Elizabeth A Jonas, Rajiv R Ratan

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Stroke, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 325 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
325citing papers in PubMed, 2 pooled it
27.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

325 citing papers in PubMed, 2 syntheses or guidelines pooled it, 509 citations in OpenAlex.

  1. Pooled it
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  12. The CaCell reports. Medicine · 2026
    Article
  13. Ironing out mechanisms of ferroptotic death to tailor new stroke therapies.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026
    Review
  14. Non-canonical cell death in neurodegeneration: emerging mechanisms and therapeutic Frontiers.Apoptosis : an international journal on programmed cell death · 2026
    Review
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265 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 4 institutions in 1 country.

Marietta ZilleFrom the Burke Medical Research Institute, White Plains, New York (M.Z., S.S.K., Y.C., R.R.R.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York (M.Z., S.S.K., Y.C., T.A.M., R.R.R.); Host Defense Discovery Performance Unit, Infectious Diseases Therapy Area Unit (P.J.G.) and Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area (J.B., J.F.), GlaxoSmithKline, Collegeville, PA; Laboratory of Neuroendocrinology, The Rockefeller University, New York (T.A.M.); and Department of Internal Medicine, Section of Endocrinology, Yale University, New Haven, CT (E.A.J.).
Saravanan S KaruppagounderFrom the Burke Medical Research Institute, White Plains, New York (M.Z., S.S.K., Y.C., R.R.R.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York (M.Z., S.S.K., Y.C., T.A.M., R.R.R.); Host Defense Discovery Performance Unit, Infectious Diseases Therapy Area Unit (P.J.G.) and Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area (J.B., J.F.), GlaxoSmithKline, Collegeville, PA; Laboratory of Neuroendocrinology, The Rockefeller University, New York (T.A.M.); and Department of Internal Medicine, Section of Endocrinology, Yale University, New Haven, CT (E.A.J.).
Yingxin ChenFrom the Burke Medical Research Institute, White Plains, New York (M.Z., S.S.K., Y.C., R.R.R.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York (M.Z., S.S.K., Y.C., T.A.M., R.R.R.); Host Defense Discovery Performance Unit, Infectious Diseases Therapy Area Unit (P.J.G.) and Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area (J.B., J.F.), GlaxoSmithKline, Collegeville, PA; Laboratory of Neuroendocrinology, The Rockefeller University, New York (T.A.M.); and Department of Internal Medicine, Section of Endocrinology, Yale University, New Haven, CT (E.A.J.).
Peter J GoughFrom the Burke Medical Research Institute, White Plains, New York (M.Z., S.S.K., Y.C., R.R.R.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York (M.Z., S.S.K., Y.C., T.A.M., R.R.R.); Host Defense Discovery Performance Unit, Infectious Diseases Therapy Area Unit (P.J.G.) and Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area (J.B., J.F.), GlaxoSmithKline, Collegeville, PA; Laboratory of Neuroendocrinology, The Rockefeller University, New York (T.A.M.); and Department of Internal Medicine, Section of Endocrinology, Yale University, New Haven, CT (E.A.J.).
John BertinFrom the Burke Medical Research Institute, White Plains, New York (M.Z., S.S.K., Y.C., R.R.R.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York (M.Z., S.S.K., Y.C., T.A.M., R.R.R.); Host Defense Discovery Performance Unit, Infectious Diseases Therapy Area Unit (P.J.G.) and Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area (J.B., J.F.), GlaxoSmithKline, Collegeville, PA; Laboratory of Neuroendocrinology, The Rockefeller University, New York (T.A.M.); and Department of Internal Medicine, Section of Endocrinology, Yale University, New Haven, CT (E.A.J.).
Joshua FingerFrom the Burke Medical Research Institute, White Plains, New York (M.Z., S.S.K., Y.C., R.R.R.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York (M.Z., S.S.K., Y.C., T.A.M., R.R.R.); Host Defense Discovery Performance Unit, Infectious Diseases Therapy Area Unit (P.J.G.) and Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area (J.B., J.F.), GlaxoSmithKline, Collegeville, PA; Laboratory of Neuroendocrinology, The Rockefeller University, New York (T.A.M.); and Department of Internal Medicine, Section of Endocrinology, Yale University, New Haven, CT (E.A.J.).
Teresa A MilnerFrom the Burke Medical Research Institute, White Plains, New York (M.Z., S.S.K., Y.C., R.R.R.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York (M.Z., S.S.K., Y.C., T.A.M., R.R.R.); Host Defense Discovery Performance Unit, Infectious Diseases Therapy Area Unit (P.J.G.) and Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area (J.B., J.F.), GlaxoSmithKline, Collegeville, PA; Laboratory of Neuroendocrinology, The Rockefeller University, New York (T.A.M.); and Department of Internal Medicine, Section of Endocrinology, Yale University, New Haven, CT (E.A.J.).
Elizabeth A JonasFrom the Burke Medical Research Institute, White Plains, New York (M.Z., S.S.K., Y.C., R.R.R.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York (M.Z., S.S.K., Y.C., T.A.M., R.R.R.); Host Defense Discovery Performance Unit, Infectious Diseases Therapy Area Unit (P.J.G.) and Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area (J.B., J.F.), GlaxoSmithKline, Collegeville, PA; Laboratory of Neuroendocrinology, The Rockefeller University, New York (T.A.M.); and Department of Internal Medicine, Section of Endocrinology, Yale University, New Haven, CT (E.A.J.).
Rajiv R RatanFrom the Burke Medical Research Institute, White Plains, New York (M.Z., S.S.K., Y.C., R.R.R.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York (M.Z., S.S.K., Y.C., T.A.M., R.R.R.); Host Defense Discovery Performance Unit, Infectious Diseases Therapy Area Unit (P.J.G.) and Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area (J.B., J.F.), GlaxoSmithKline, Collegeville, PA; Laboratory of Neuroendocrinology, The Rockefeller University, New York (T.A.M.); and Department of Internal Medicine, Section of Endocrinology, Yale University, New Haven, CT (E.A.J.). rrr2001@med.cornell.edu.
Burke Medical Research Institute · USCornell University · USMIND Research Institute · USRockefeller University · US

Funding

TRANSCRIPTIONAL RESPONSES TO MITOCHONDRIAL DYSFUNCTIONP01AG014930 · NIA · WINIFRED MASTERSON BURKE MED RES INST · PI GIBSON, GARY E · 1999 to 2020
$30.7M
ULTRASTRUCTURAL INTERACTIONS OF OPIOIDS IN HIPPOCAMPUSR01DA008259 · NIDA · WEILL MEDICAL COLL OF CORNELL UNIV · PI MILNER, TERESA A · 1993 to 2019
$6.4M
Mitochondrial Ion Channels in Hypoxic NeuronsR37NS045876 · NINDS · YALE UNIVERSITY · PI Elizabeth Ann Jonas · 2014 to 2026
$4.9M
Mitochondrial ion channels in hypoxic neuronsR01NS045876 · NINDS · YALE UNIVERSITY · PI JONAS, ELIZABETH ANN · 2004 to 2013
$3.3M
MENOPAUSAL CHANGES IN HYPOTHALAMUS AND HYPERTENSION SUSCEPTIBILITYR01HL098351 · NHLBI · WEILL MEDICAL COLL OF CORNELL UNIV · PI MILNER, TERESA A · 2011 to 2014
$1.7M
NHLBI NIH HHS R01 HL098351NIA NIH HHS P01 AG014930NIDA NIH HHS R01 DA008259NINDS NIH HHS R01 NS045876NINDS NIH HHS R37 NS045876
6 · The paper itself

Abstract

background and purposeIntracerebral hemorrhage leads to disability or death with few established treatments. Adverse outcomes after intracerebral hemorrhage result from irreversible damage to neurons resulting from primary and secondary injury. Secondary injury has been attributed to hemoglobin and its oxidized product hemin from lysed red blood cells. The aim of this study was to identify the underlying cell death mechanisms attributable to secondary injury by hemoglobin and hemin to broaden treatment options.

methodsWe investigated cell death mechanisms in cultured neurons exposed to hemoglobin or hemin. Chemical inhibitors implicated in all known cell death pathways were used. Identified cell death mechanisms were confirmed using molecular markers and electron microscopy.

resultsChemical inhibitors of ferroptosis and necroptosis protected against hemoglobin- and hemin-induced toxicity. By contrast, inhibitors of caspase-dependent apoptosis, protein or mRNA synthesis, autophagy, mitophagy, or parthanatos had no effect. Accordingly, molecular markers of ferroptosis and necroptosis were increased after intracerebral hemorrhage in vitro and in vivo. Electron microscopy showed that hemin induced a necrotic phenotype. Necroptosis and ferroptosis inhibitors each abrogated death by >80% and had similar therapeutic windows in vitro.

conclusionsExperimental intracerebral hemorrhage shares features of ferroptotic and necroptotic cell death, but not caspase-dependent apoptosis or autophagy. We propose that ferroptosis or necroptotic signaling induced by lysed blood is sufficient to reach a threshold of death that leads to neuronal necrosis and that inhibition of either of these pathways can bring cells below that threshold to survival.

Indexed as

ApoptosisAnimalsCells, CulturedCerebral HemorrhageDisease Models, AnimalHeminHemoglobinsMaleMiceMice, Inbred C57BLNecrosisNeuronsHeminHemoglobinsapoptosiscell deathferroptosisintracerebral hemorrhagenecrosis

Identifiers

PMID28250197
PMCPMC5613764
OpenAlexW2593130667

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.