title: Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models.
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.
authors.affiliation: Sperling 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.
authors.forename: Saravanan S
authors.initials: SS
authors.lastname: Karuppagounder
authors.affiliation: Sperling 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.
authors.forename: Ishraq
authors.initials: I
authors.lastname: Alim
authors.affiliation: Sperling 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.
authors.forename: Soah J
authors.initials: SJ
authors.lastname: Khim
authors.affiliation: Sperling 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.
authors.forename: Megan W
authors.initials: MW
authors.lastname: Bourassa
authors.affiliation: Sperling 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.
authors.forename: Sama F
authors.initials: SF
authors.lastname: Sleiman
authors.affiliation: Department of Psychology, University of Alberta, Edmonton, Alberta T6G 2E9, Canada.
authors.forename: Roseleen
authors.initials: R
authors.lastname: John
authors.affiliation: Department of Chemistry, University of Oxford, OX1 3TA Oxford, UK.
authors.forename: Cyrille C
authors.initials: CC
authors.lastname: Thinnes
authors.affiliation: Department of Chemistry, University of Oxford, OX1 3TA Oxford, UK.
authors.forename: Tzu-Lan
authors.initials: TL
authors.lastname: Yeh
authors.affiliation: Department of Chemistry, University of Oxford, OX1 3TA Oxford, UK.
authors.forename: Marina
authors.initials: M
authors.lastname: Demetriades
authors.affiliation: Institut fuer Pharmakologie and Klinische Pharmazie, Phillips-Universitaet Marburg, D 35032 Marburg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Neitemeier
authors.affiliation: Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Cruz
authors.affiliation: Sperling 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.
authors.forename: Irina
authors.initials: I
authors.lastname: Gazaryan
authors.affiliation: Children's Hospital of Oakland, Oakland, CA 94609, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Killilea
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Lewis
authors.initials: L
authors.lastname: Morgenstern
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Guohua
authors.initials: G
authors.lastname: Xi
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Keep
authors.affiliation: Department of Psychology, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Schallert
authors.affiliation: Photon Sciences Directorate, Brookhaven National Laboratory, Upton, NY 11973, USA.
authors.forename: Ryan V
authors.initials: RV
authors.lastname: Tappero
authors.affiliation: Sperling 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Sperling 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.
authors.forename: Sunghee
authors.initials: S
authors.lastname: Cho
authors.affiliation: Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Maxfield
authors.affiliation: Chemistry and Biochemistry, Department, University of California at Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Holman
authors.affiliation: Institut fuer Pharmakologie and Klinische Pharmazie, Phillips-Universitaet Marburg, D 35032 Marburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Culmsee
authors.affiliation: Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Fong
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Yijing
authors.initials: Y
authors.lastname: Su
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Guo-li
authors.initials: GL
authors.lastname: Ming
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Song
authors.affiliation: Sperling 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.
authors.forename: John W
authors.initials: JW
authors.lastname: Cave
authors.affiliation: Department of Chemistry, University of Oxford, OX1 3TA Oxford, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: Department of Psychology, University of Alberta, Edmonton, Alberta T6G 2E9, Canada.
authors.forename: Frederick
authors.initials: F
authors.lastname: Colbourne
authors.affiliation: Department of Psychiatry, University of California at Los Angeles, CA 90095, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Sperling 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.
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Ratan
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006427:Hemin / Q000633:toxicity; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000378:metabolism; D020300:Intracranial Hemorrhages / Q000473:pathology* / Q000503:physiopathology; D007501:Iron / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D051379:Mice; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072417:Protein Domains; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D020033:Protein Isoforms; D051701:Activating Transcription Factor 4; D006427:Hemin; D007501:Iron; D011393:Procollagen-Proline Dioxygenase; D010100:Oxygen