RESUMEN
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.
Asunto(s)
Factor de Transcripción Activador 4/metabolismo , Encéfalo/patología , Hemorragias Intracraneales/patología , Terapia Molecular Dirigida , Neuronas/patología , Oxígeno/metabolismo , Procolágeno-Prolina Dioxigenasa/antagonistas & inhibidores , Animales , Muerte Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Genes Reporteros , Hemina/toxicidad , Subunidad alfa del Factor 1 Inducible por Hipoxia/química , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Hemorragias Intracraneales/fisiopatología , Hierro/farmacología , Quelantes del Hierro/farmacología , Ratones , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Procolágeno-Prolina Dioxigenasa/metabolismo , Dominios Proteicos , Isoformas de Proteínas/metabolismo , Ratas , Recuperación de la Función/efectos de los fármacosRESUMEN
Neurologic conditions including stroke, Alzheimer disease, Parkinson disease, and Huntington disease are leading causes of death and long-term disability in the United States, and efforts to develop novel therapeutics for these conditions have historically had poor success in translating from bench to bedside. Hypoxia-inducible factor (HIF)-1α mediates a broad, evolutionarily conserved, endogenous adaptive program to hypoxia, and manipulation of components of the HIF pathway is neuroprotective in a number of human neurological diseases and experimental models. In this review, we discuss molecular components of one aspect of hypoxic adaptation in detail and provide perspective on which targets within this pathway seem to be ripest for preventing and repairing neurodegeneration. Further, we highlight the role of HIF prolyl hydroxylases as emerging targets for the salutary effects of metal chelators on ferroptosis in vitro as well in animal models of neurological diseases.