Prolyl hydroxylase domain inhibitors: a route to HIF activation and neuroprotection.
Abstract Ischemic stroke is a major cause of death worldwide, and current therapeutic options are very limited. Preconditioning with an ischemic or hypoxic insult is beneficial in experimental models of ischemic stroke. Ischemia/hypoxia results in activation of numerous transcription factors, including hypoxia inducible factor (HIF), which is a master regulator of oxygen homeostasis. HIF activation induces a diverse range of target genes, encompassing a wide variety of cellular processes; including angiogenesis, energy metabolism, cell survival, radical production/scavenging, iron metabolism, stem cell homing, and differentiation. Inhibition of HIF prolyl hydroxylase domain (PHD) enzymes results in activation of HIF and is likely to mimic, at least in part, the effects of hypoxia preconditioning. A caveat is that not all consequences of HIF activation will be beneficial and some could even be deleterious. Nevertheless, PHD inhibitors may be therapeutically useful in the treatment of stroke. Prototype PHD inhibitors have shown promising results in preclinical models.
Harten
Sarah K
SK
Division of Medicine, Rayne Institute, University College London, University Street, London, United Kingdom. s.harten@ucl.ac.uk
Ashcroft
Margaret
M
Maxwell
Patrick H
PH
D000818:Animals; D001812:Blood-Brain Barrier / Q000201:enzymology; D001921:Brain / Q000098:blood supply; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D019610:Cytoprotection; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000819:agonists*; D019194:Ischemic Preconditioning; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D051793:Hypoxia-Inducible Factor 1; D018696:Neuroprotective Agents; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D011393:Procollagen-Proline Dioxygenase