Evidence map›Paper›PMID 26936506›Full record

ArticleScience translational medicine2016

Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models.

Saravanan S Karuppagounder, Ishraq Alim, Soah J Khim, Megan W Bourassa, Sama F Sleiman, Roseleen John, Cyrille C Thinnes, Tzu-Lan Yeh, Marina Demetriades, Sandra Neitemeier and 22 more

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In one paragraph

Article in Science translational medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 88 papers.

0numbers the graph read from it
0cells of the map it votes in
88citing papers in PubMed
5.6field-weighted citation impact, top 3% 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

88 citing papers in PubMed, 139 citations in OpenAlex.

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28 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

32 authors at 10 institutions in 3 countries.

Saravanan S KaruppagounderSperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
Ishraq AlimSperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
Soah J KhimSperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
Megan W BourassaSperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
Sama F SleimanSperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
Roseleen JohnDepartment of Psychology, University of Alberta, Edmonton, Alberta T6G 2E9, Canada.
Cyrille C ThinnesDepartment of Chemistry, University of Oxford, OX1 3TA Oxford, UK.
Tzu-Lan YehDepartment of Chemistry, University of Oxford, OX1 3TA Oxford, UK.
Marina DemetriadesDepartment of Chemistry, University of Oxford, OX1 3TA Oxford, UK.
Sandra NeitemeierInstitut fuer Pharmakologie and Klinische Pharmazie, Phillips-Universitaet Marburg, D 35032 Marburg, Germany.
Dana CruzDepartment of Biochemistry, Weill Medical College of Cornell University, New York, NY 10065, USA.
Irina GazaryanSperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
David W KillileaChildren's Hospital of Oakland, Oakland, CA 94609, USA.
Lewis MorgensternDepartment of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
Guohua XiDepartment of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, USA.
Richard F KeepDepartment of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, USA.
Timothy SchallertDepartment of Psychology, University of Texas at Austin, Austin, TX 78712, USA.
Ryan V TapperoPhoton Sciences Directorate, Brookhaven National Laboratory, Upton, NY 11973, USA.
Jian ZhongSperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
Sunghee ChoSperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
Frederick R MaxfieldDepartment of Biochemistry, Weill Medical College of Cornell University, New York, NY 10065, USA.
Theodore R HolmanChemistry and Biochemistry, Department, University of California at Santa Cruz, Santa Cruz, CA 95064, USA.
Carsten CulmseeInstitut fuer Pharmakologie and Klinische Pharmazie, Phillips-Universitaet Marburg, D 35032 Marburg, Germany.
Guo-Hua FongCenter for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Yijing SuInstitute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Guo-li MingInstitute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Hongjun SongInstitute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
John W CaveSperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
Christopher J SchofieldDepartment of Chemistry, University of Oxford, OX1 3TA Oxford, UK.
Frederick ColbourneDepartment of Psychology, University of Alberta, Edmonton, Alberta T6G 2E9, Canada.
Giovanni CoppolaDepartment of Psychiatry, University of California at Los Angeles, CA 90095, USA.
Rajiv R RatanSperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA. rrr2001@med.cornell.edu.
MIND Research Institute · USCornell University · USUniversity of Oxford · GBUniversity of Michigan–Ann Arbor · USJohns Hopkins University · USUniversity of Alberta · CABrookhaven National Laboratory · USJohns Hopkins Medicine · USThe University of Texas at Austin · USUConn Health · US

Funding

TRANSCRIPTIONAL RESPONSES TO MITOCHONDRIAL DYSFUNCTIONP01AG014930 · NIA · WINIFRED MASTERSON BURKE MED RES INST · PI GIBSON, GARY E · 1999 to 2020
$30.7M
Integrative Center for Neurogenetics and Neurogenomics - OverallP30NS062691 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI COPPOLA, GIOVANNI · 2009 to 2018
$7.4M
B-RAF drives regenerative axon growth in the optic nerve in vivoR01EY022409 · NEI · WINIFRED MASTERSON BURKE MED RES INST · PI ZHONG, JIAN · 2012 to 2016
$2.4M
Biotechnology and Biological Sciences Research Council BBS/B/07683British Heart Foundation PG/12/33/29546NEI NIH HHS R01 EY022409NIA NIH HHS P01 AG014930NIA NIH HHS P01 NIA AG014930NINDS NIH HHS P30 NS062691Wellcome Trust
6 · The paper itself

Abstract

Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models.

Indexed as

Molecular Targeted TherapyActivating Transcription Factor 4AnimalsBrainCell DeathCells, CulturedDisease Models, AnimalGene Expression RegulationGenes, ReporterHeminHypoxia-Inducible Factor 1, alpha SubunitIntracranial HemorrhagesIronIron Chelating AgentsMiceNeuronsActivating Transcription Factor 4HeminHypoxia-Inducible Factor 1, alpha SubunitIronIron Chelating AgentsNeuroprotective AgentsOxygenProcollagen-Proline DioxygenaseProtein Isoforms

Identifiers

PMID26936506
PMCPMC5341138
OpenAlexW2290683813

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Registered trials

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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.