Abstract
Whether iron formulations used therapeutically for a variety of conditions involving iron deficiency can deliver iron to the brain is a significant clinical question given the impact that iron loading has on the brain in neurodegenerative diseases. In this study, we examine the ability of 5 pharmaceutical iron formulations that are given intravenously for treatment of iron deficiency to cross an in vitro model of the blood-brain barrier. The model uses human brain endothelial cells derived from induced pluripotent stem cells. We report that, compared to the natural iron delivery proteins, transferrin and H-ferritin, the pharmaceutical iron formulations neither cross the blood-brain barrier model nor significantly load the endothelial cells with iron. Furthermore, we report that mimicking brain iron sufficiency or deficiency by exposing the endothelial cells to apo- or holo-transferrin does not alter the amount of iron compound transported by or loaded into the cells. Coupled with previous studies, we propose that pharmaceutical iron formulations must first be processed in macrophages to make iron bioavailable. The results of this study have significant clinical and mechanistic implications for the use of therapeutic iron formulations.
Highlights
Iron is a crucial micronutrient serving as a cofactor in various cellular processes such as myelination, oxygen transport, and DNA synthesis [1]
Using an in vitro model of the blood-brain barrier (BBB), we first examined the ability of transferrin, H-ferritin, or the iron formulations to promote iron transport across the Human brain endothelial cells (huECs)
The total iron transport at 24 hours for each of five iron formulations represented less than 0.02% of the total iron formulation (Fig 1)
Summary
Iron is a crucial micronutrient serving as a cofactor in various cellular processes such as myelination, oxygen transport, and DNA synthesis [1]. As a transition element, it has properties enabling generation of oxygen free radicals and oxidative stress through the Fenton reaction [2]. Iron levels are tightly regulated because both too much iron as well as a deficiency in iron can be detrimental to biological function and health [3,4,5,6,7]. Iron deficiency (ID) is the most common and widespread nutritional disorder with over 2 billion people suffering significant negative health effects worldwide [8].
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