Web of Science: 20 cites, Scopus: 21 cites, Google Scholar: cites,
Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage
Gregorio-Rocasolano Barbany, Núria de (Institut Germans Trias i Pujol)
Martí Sistac, Octavi (Universitat Autònoma de Barcelona)
Ponce, Jovita (Institut Germans Trias i Pujol)
Castelló Ruiz, María (Institut d'Investigació Sanitària La Fe)
Millán Torné, Mònica (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Guirao, Verónica (Institut Germans Trias i Pujol)
García Yébenes, Isaac (Universidad Complutense de Madrid. Departamento de Farmacología)
Salom, Juan B. (Institut d'Investigació Sanitària La Fe)
Ramos Cabrer, Pedro (Hospital Clínico Universitario (Santiago de Compostela, Galícia))
Alborch, Enrique (Institut d'Investigació Sanitària La Fe)
Lizasoain, Ignacio (Universidad Complutense de Madrid. Departamento de Farmacología)
Castillo, José (Hospital Clínico Universitario (Santiago de Compostela, Galícia))
Dávalos, Antoni (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Gasull Dalmau, Teresa (Institut Germans Trias i Pujol)

Data: 2018
Resum: Despite transferrin being the main circulating carrier of iron in body fluids, and iron overload conditions being known to worsen stroke outcome through reactive oxygen species (ROS)-induced damage, the contribution of blood transferrin saturation (TSAT) to stroke brain damage is unknown. The objective of this study was to obtain evidence on whether TSAT determines the impact of experimental ischemic stroke on brain damage and whether iron-free transferrin (apotransferrin, ATf)-induced reduction of TSAT is neuroprotective. We found that experimental ischemic stroke promoted an early extravasation of circulating iron-loaded transferrin (holotransferrin, HTf) to the ischemic brain parenchyma. In vitro, HTf was found to boost ROS production and to be harmful to primary neuronal cultures exposed to oxygen and glucose deprivation. In stroked rats, whereas increasing TSAT with exogenous HTf was detrimental, administration of exogenous ATf and the subsequent reduction of TSAT was neuroprotective. Mechanistically, ATf did not prevent extravasation of HTf to the brain parenchyma in rats exposed to ischemic stroke. However, ATf in vitro reduced NMDA-induced neuronal uptake of HTf and also both the NMDA-mediated lipid peroxidation derived 4-HNE and the resulting neuronal death without altering Ca²⁺ -calcineurin signaling downstream the NMDA receptor. Removal of transferrin from the culture media or blockade of transferrin receptors reduced neuronal death. Together, our data establish that blood TSAT exerts a critical role in experimental stroke-induced brain damage. In addition, our findings suggest that the protective effect of ATf at the neuronal level resides in preventing NMDA-induced HTf uptake and ROS production, which in turn reduces neuronal damage.
Ajuts: Instituto de Salud Carlos III PI11/00191
Instituto de Salud Carlos III PI12/00145
Ministerio de Economía y Competitividad SAF2014-52225R
Ministerio de Ciencia e Innovación SAF2010-22122
Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-1670
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades. Creative Commons
Llengua: Anglès
Document: Article ; recerca ; Versió publicada
Matèria: Experimental stroke ; Brain damage ; Neuroprotection ; Apotransferrin ; Blood transferrin saturation (TSAT) ; Reactive oxygen species (ROS)
Publicat a: Redox biology, Vol. 15 (May 2018) , p. 143-158, ISSN 2213-2317

DOI: 10.1016/j.redox.2017.11.026
PMID: 29248829

16 p, 2.3 MB

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