We examined the kinetics and distribution of [Fe-59-I-125] rat Tf and unlabelled human Tf injected into a lateral cerebral ventricle (i.c.v. injection) in the rat. [Fe-56-I-131]Tf injected intravenously served as a control of blood-brain barrier (BBB) integrity. In CSF of adult rats, Fe-59 and [I-125]Tf decreased to only 2.5% of the dose injected after 4 h. In brain parenchyma, [I-125]Tf had disappeared after 24 h, whereas approximately 18% of i.c.v.-injected Fe-59 was retained even after 72 h. The elimination pattern of [I-125]Tf from the CSF corresponded to that of [I-131]albumin injected i.c.v., suggesting a nonselective washout of CSF proteins. [I-131]Tf was hardly detectable in the brain, reflecting an unimpaired BBB during the experiments. Morphologically, Fe-59 and i.c.v. injected human Tf were confined to the ventricular surface and meningeal areas, whereas grey matter regions at distances more than 2-3 mm from the ventricles and the subarachnoid space were unlabelled. However, accumulation of Fe-59 was observed in the anterior thalamic and the medial habenular nuclei, and in brain regions with synaptic communications to these areas. In the newborn rats aged 7 days (P7) injected i.c.v. with [Fe-59-I-125]Tf and examined after 24 h, the amounts of [I-125]Tf in CSF were approximately 3.5 times higher than in adult rats collected after the same time interval, whereas the amounts of Fe-59 in CSF were at the same level in P7 and adult rats. In the brain tissue of the i.c.v. injected P7 rats, both [I-125]Tf and Fe-59 were retained to a significantly higher degree compared to that seen in adult brains. The rapid washout and lack of capability for i.c.v. injected [I-125]Tf to penetrate deeply into the brain parenchyma of the adult brain question the importance of Tf of the CSF, and choroid plexus-derived Tf, for Fe neutralization and delivery of Fe-Tf to TfR-containing neurons and other cells in the CNS. However, it may serve these functions in young animals due to a lower rate of turnover of CSF. (C) 1998 Elsevier Science B.V.