Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage.

Abstract

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.

• Authors: Nuria DeGregorio-Rocasolano, Octavi Martí-Sistac, Jovita Ponce, María Castelló-Ruiz, Mònica Millán, Verónica Guirao, Isaac García-Yébenes, Juan B Salom, Pedro Ramos-Cabrer, Enrique Alborch, Ignacio Lizasoain, José Castillo, Antoni Dávalos, Teresa Gasull
• Journal: Redox biology (Redox Biol) Vol. 15 Pg. 143-158 (05 2018) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 29248829 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Apoproteins
• Reactive Oxygen Species
• Receptors, Transferrin
• Transferrin
• apotransferrin
• holotransferrin
• Iron
• Deferoxamine

Topics

• Animals
• Apoproteins (administration & dosage, blood)
• Brain Ischemia (blood, diagnostic imaging, drug therapy, pathology)
• Deferoxamine (administration & dosage)
• Female
• Humans
• Iron (blood)
• Iron Overload (blood, drug therapy, pathology)
• Lipid Peroxidation (drug effects)
• Male
• Neurons (metabolism, pathology)
• Rats
• Reactive Oxygen Species (blood)
• Receptors, Transferrin (blood)
• Stroke (blood, diagnostic imaging, drug therapy, pathology)
• Transferrin (administration & dosage, metabolism)