Targeting Pro-Oxidant Iron with Exogenously Administered Apotransferrin Provides Benefits Associated with Changes in Crucial Cellular Iron Gate Protein TfR in a Model of Intracerebral Hemorrhagic Stroke in Mice

Alexia García-Serran, Jesús Ordoño, Núria DeGregorio-Rocasolano, Marc Melià-Sorolla, Karla Odendaal, Octavi Martí-Sistac* and Teresa Gasull*. Antioxidants 2023, 12, 1945.

Abstract: We have previously demonstrated that the post-stroke administration of iron-free transferrin (apotransferrin, ATf) is beneficial in different models of ischemic stroke (IS) through the inhibitionof the neuronal uptake of pro-oxidant iron. In the present study, we asked whether ATf is safeand also beneficial when given after the induction of intracerebral hemorrhage (ICH) in mice, and investigated the underlying mechanisms. We first compared the main iron actors in the brain of IS- or collagenase-induced ICH mice and then obtained insight into these iron-related proteins in ICH 72 h after the administration of ATf. The infarct size of the IS mice was double that of hemorrhage in ICH mice, but both groups showed similar body weight loss, edema, and increased ferritin and transferrin levels in the ipsilateral brain hemisphere. Although the administration of human ATf (hATf) to ICH mice did not alter the hemorrhage volume or levels of the classical ferroptosis GPX4/system xcpathways, hATf induced better neurobehavioral performance, decreased 4-hydroxynonenal levels and those of the second-generation ferroptosis marker transferrin receptor (TfR), and restored the mRNA levels of the recently recognized cytosolic iron chaperone poly(RC) binding protein 2. In addition, hATf treatment lowered the ICH-induced increase in both endogenous mouse transferrin mRNA levels and the activation of caspase-2. In conclusion, hATf treatment provides neurobehavioral benefits post-ICH associated with the modulation of iron/oxidative players.

Funding: This study was supported by grants from the Agency for Management of University and Research Grants (AGAUR) Catalan Research Group (SGR) 2021SGR00925 and 2019PROD00120, and by the Fondo de Investigaciones Sanitarias-Instituto de Salud Carlos III projects PI18/01813 and PI21/01925, RICORS RD21/0006/0024, that were susceptible to be co-financed by FEDER/FSE funds. MMS was supported by a PFIS contract from the ISCIII (FI19/00174), and AGS was supported by contracts associated with 2019PROD00120 and PI18/01813. The IGTP is a Research Center of Catalonia of the CERCA Program/Government of Catalonia. The group has received funding from “la Caixa” CI15-00009 from the European Institute of Innovation and Technology (EIT) PoC-2016- SPAIN-04, which receives support from the European Union’s Horizon 2020 research and innovation program; and from the Fundación para la Innovación y la Prospectiva en Salud en España (FIPSE) program 3594-18.