Brain capillary endothelium and choroid plexus epithelium regulate transport of transferrin-bound and free iron into the rat brain

Abstract

Iron transport into the CNS is still not completely understood. Using a brain perfusion technique in rats, we have shown a significant brain capillary uptake of circulating transferrin (Tf)-bound and free 59Fe (1 nm) at rates of 136 +/- 26 and 182 +/- 23 microL/g/min, respectively, while their respective transport rates into brain parenchyma were 1.68 +/- 0.56 and 1.52 +/- 0.48 microL/g/min. Regional Tf receptor density (Bmax) in brain endothelium determined with 125I-holo-Tf correlated well with 59Fe-Tf regional brain uptake rates reflecting significant vascular association of iron. Tf-bound and free circulating 59Fe were sequestered by the choroid plexus and transported into the CSF at low rates of 0.17 +/- 0.01 and 0.09 +/- 0.02 microL/min/g, respectively, consistent with a 10-fold brain-CSF concentration gradient for 59Fe, Tf-bound or free. We conclude that transport of circulating Tf-bound and free iron could be equally important for its delivery to the CNS. Moreover, data suggest that entry of Tf-bound and free iron into the CNS is determined by (i) its initial sequestration by brain capillaries and choroid plexus, and (ii) subsequent controlled and slow release from vascular structures into brain interstitial fluid and CSF.

Fig. 1

⁵⁹Fe uptake (as a distributing volume, mL/g) into isolated cerebral capillaries (a) and capillary-depleted brain (b), after brain perfusion, at different time periods, with (Fe-Tf, square) and without transferrin (Fe-only, circle). Values are mean ± SEM, n = 3–5 for each time point.

Fig. 2

A typical one-class receptor binding curve of bound ¹²⁵I-holo-transferrin to transferrin receptor on isolated brain capillaries from hippocampus at different concentrations of holo-transferrin. Data were best fitted to one-site competitive binding equation using Prism 3.0 software.

Fig. 3

Comparison of ⁵⁹Fe uptake (mL/g) into capillary-depleted brain (filled column) and cerebrospinal fluid (open column), after 15 min brain perfusion with and without transferrin. Values are mean ± SEM, n = 3–5. *p < 0.001.