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

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

  • Sci Transl Med. 2016 Mar 2;8(328):328ra29. doi: 10.1126/scitranslmed.aac6008.
Saravanan S Karuppagounder 1,  Ishraq Alim 1,  Soah J Khim 1,  Megan W Bourassa 1,  Sama F Sleiman 1,  Roseleen John 2,  Cyrille C Thinnes 3,  Tzu-Lan Yeh 3,  Marina Demetriades 3,  Sandra Neitemeier 4,  Dana Cruz 5,  Irina Gazaryan 1,  David W Killilea 6,  Lewis Morgenstern 7,  Guohua Xi 8,  Richard F Keep 8,  Timothy Schallert 9,  Ryan V Tappero 10,  Jian Zhong 1,  Sunghee Cho 1,  Frederick R Maxfield 5,  Theodore R Holman 11,  Carsten Culmsee 4,  Guo-Hua Fong 12,  Yijing Su 13,  Guo-li Ming 13,  Hongjun Song 13,  John W Cave 1,  Christopher J Schofield 3,  Frederick Colbourne 2,  Giovanni Coppola 14,  Rajiv R Ratan 15
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Psychology, University of Alberta, Edmonton, Alberta T6G 2E9, Canada.
  • 3 Department of Chemistry, University of Oxford, OX1 3TA Oxford, UK.
  • 4 Institut fuer Pharmakologie and Klinische Pharmazie, Phillips-Universitaet Marburg, D 35032 Marburg, Germany.
  • 5 Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10065, USA.
  • 6 Children's Hospital of Oakland, Oakland, CA 94609, USA.
  • 7 Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 8 Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, USA.
  • 9 Department of Psychology, University of Texas at Austin, Austin, TX 78712, USA.
  • 10 Photon Sciences Directorate, Brookhaven National Laboratory, Upton, NY 11973, USA.
  • 11 Chemistry and Biochemistry, Department, University of California at Santa Cruz, Santa Cruz, CA 95064, USA.
  • 12 Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
  • 13 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 14 Department of Psychiatry, University of California at Los Angeles, CA 90095, USA.
  • 15 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.
PMID: 26936506 DOI: 10.1126/scitranslmed.aac6008
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.

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