RT Journal Article
T1 Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage
A1 DeGregorio Rocasolano, Nuria
A1 Martí Sistac, Octavi
A1 Ponce, Jovita
A1 Castelló Ruiz, María
A1 Millán, Mònica
A1 Guirao, Verónica
A1 García Yébenes, Isaac
A1 Salom, Juan B.
A1 Ramos Cabrer, Pedro
A1 Alborch, Enrique
A1 Lizasoain, Ignacio
A1 Castillo Sánchez, José Antonio
A1 Dávalos, Antoni
A1 Gasull, Teresa
K1 Experimental stroke
K1 Brain damage
K1 Neuroprotection
K1 Apotransferrin
K1 Blood transferrin saturation (TSAT)
K1 Reactive oxygen species (ROS)
AB 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.
PB Elsevier
SN 2213-2317
YR 2018
FD 2018
LK http://hdl.handle.net/10347/22963
UL http://hdl.handle.net/10347/22963
LA eng
NO DeGregorio-Rocasolano, N., Martí-Sistac, O., Ponce, J., Castelló-Ruiz, M., Millán, M., Guirao, V., ... & Lizasoain, I. (2018). Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage. Redox biology, 15, 143-158.
NO This study was supported by the following grants: Instituto de SaludCarlos III (ISCIII) PI11/00191 and PI12/00145, ISCIII RETICSINVICTUS RD12/0014 and INVICTUS PLUS RD16/0019 that weresusceptible to be cofinanced by FEDER funds, Ministerio de Ciencia eInnovación (MICINN) SAF2010-22122, and Ministerio de Economíay Competitividad SAF2014-52225R, Centre d’Innovaciói Desenvolupament Empresarial RDITSCON 07-1-0006, and Agència deGestió d’Ajuts Universitaris i de Recerca 2014SGR1670. V.G. was supported by a contract from the FPI programme of the MICINN. J.P. andP.R.-C. were supported by ‘Sara Borrell’ and ‘Miguel Servet’ contracts ofthe ISCIII, respectively. This project has received funding from“la Caixa” Foundation CI15-00009 and from the European Institute ofInnovation and Technology (EIT) PoC-2016-SPAIN-04. EIT receivessupport from the European Union’s Horizon 2020 research and innovation programe
DS Minerva
RD 25 abr 2026