ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2009
Selective inhibition of hypoxia-inducible factor (HIF) prolyl-hydroxylase 1 mediates neuroprotection against normoxic oxidative death via HIF- and CREB-independent pathways.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 125 citations in OpenAlex.
- Luteolin Attenuates Hypoxia-Induced Ferroptosis in Human Brain Microvascular Endothelial Cells Through Modulation of the PPARγ/FABP5/ALOX15 Signaling Pathway.Biomedicines · 2026Article
- Morphological Changes in the Rat Brain in the Early Post-Resuscitation Period: The Relationship Between Hypoxia-Sensitive Immunohistochemical Markers, Hemodynamic and Acid-Base Status.International journal of molecular sciences · 2026Article
- Exploring the role of HIF-1α in pathogenesis of parkinson's disease and its potential as a therapeutic target.Molecular biology reports · 2025Review
- Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.Signal transduction and targeted therapy · 2025Review
- Cannabidiol effectively prevents oxidative stress and stabilizes hypoxia-inducible factor-1 alpha (HIF-1α) in an animal model of global hypoxia.Scientific reports · 2024Article
- Recent Advances and Therapeutic Implications of 2-Oxoglutarate-Dependent Dioxygenases in Ischemic Stroke.Molecular neurobiology · 2024Review
- Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke.Journal of translational medicine · 2024Article
- Out of the core: the impact of focal ischemia in regions beyond the penumbra.Frontiers in cellular neuroscience · 2024Review
- A critical appraisal of ferroptosis in Alzheimer's and Parkinson's disease: new insights into emerging mechanisms and therapeutic targets.Frontiers in pharmacology · 2024Review
- Deciphering the link: ferroptosis and its role in glioma.Frontiers in immunology · 2024Review
- Effects of DNA, RNA, and Protein Methylation on the Regulation of Ferroptosis.International journal of biological sciences · 2023Review
- Exploring the natural products chemical space through a molecular search to discover potential inhibitors that target the hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD).Frontiers in pharmacology · 2023Article
- Article
- Unlocking mammalian regeneration through hypoxia inducible factor one alpha signaling.Biomaterials · 2021Review
- Mechanisms of Intranasal Deferoxamine in Neurodegenerative and Neurovascular Disease.Pharmaceuticals (Basel, Switzerland) · 2021Review
- CD73 alleviates GSDMD-mediated microglia pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling.Clinical and translational medicine · 2021Article
- Epigenetic regulators of neuronal ferroptosis identify novel therapeutics for neurological diseases: HDACs, transglutaminases, and HIF prolyl hydroxylases.Neurobiology of disease · 2021Review
- The not-so-sweet side of sugar: Influence of the microenvironment on the processes that unleash cancer.Biochimica et biophysica acta. Molecular basis of disease · 2020Review
- Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation.PLoS pathogens · 2020Article
- Neuroprotective Effect of HIF Prolyl Hydroxylase Inhibition in an In Vitro Hypoxia Model.Antioxidants (Basel, Switzerland) · 2020Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 5 institutions in 2 countries.
Funding
Abstract
Oxidative stress contributes to tissue injury in conditions ranging from cardiovascular disease to stroke, spinal cord injury, neurodegeneration, and perhaps even aging. Yet the efficacy of antioxidants in human disease has been mixed at best. We need a better understanding of the mechanisms by which established antioxidants combat oxidative stress. Iron chelators are well established inhibitors of oxidative death in both neural and non-neural tissues, but their precise mechanism of action remains elusive. The prevailing but not completely substantiated view is that iron chelators prevent oxidative injury by suppressing Fenton chemistry and the formation of highly reactive hydroxyl radicals. Here, we show that iron chelation protects, rather unexpectedly, by inhibiting the hypoxia-inducible factor prolyl 4-hydroxylase isoform 1 (PHD1), an iron and 2-oxoglutarate-dependent dioxygenase. PHD1 and its isoforms 2 and 3 are best known for stabilizing transcriptional regulators involved in hypoxic adaptation, such as HIF-1alpha and cAMP response element-binding protein (CREB). Yet we find that global hypoxia-inducible factor (HIF)-PHD inhibition protects neurons even when HIF-1alpha and CREB are directly suppressed. Moreover, two global HIF-PHD inhibitors continued to be neuroprotective even in the presence of diminished HIF-2alpha levels, which itself increases neuronal susceptibility to oxidative stress. Finally, RNA interference to PHD1 but not isoforms PHD2 or PHD3 prevents oxidative death, independent of HIF activation. Together, these studies suggest that iron chelators can prevent normoxic oxidative neuronal death through selective inhibition of PHD1 but independent of HIF-1alpha and CREB; and that HIF-2alpha, not HIF-1alpha, regulates susceptibility to normoxic oxidative neuronal death.
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Registered trials
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.