Role of transthyretin in thyroxine transfer from cerebrospinal fluid to brain and choroid plexus

Abstract

The transport of125I-labeled thyroxine (T4) from the cerebrospinal fluid (CSF) into brain and choroid plexus (CP) was measured in anesthetized rabbit [0.5 mg/kg medetomidine (Domitor) and 10 mg/kg pentobarbitonal sodium (Sagatal) iv] using the ventriculocisternal (V-C) perfusion technique.125I-labeled T4contained in artificial CSF was continually perfused into the lateral ventricles for up to 4 h and recovered from the cisterna magna. The %recovery of125I-labeled T4from the aCSF was 47.2 ± 5.6% ( n = 10), indicating removal of125I-labeled T4from the CSF. The recovery increased to 53.2 ± 6.3% ( n = 4) and 57.8 ± 14.8% ( n = 3), in the presence of 100 and 200 μM unlabeled-T4, respectively ( P < 0.05), indicating a saturable component to T4removal from CSF. There was a large accumulation of125I-labeled T4in the CP, and this was reduced by 80% in the presence of 200 μM unlabeled T4, showing saturation. In the presence of the thyroid-binding protein transthyretin (TTR), more125I-labeled T4was recovered from CSF, indicating that the binding protein acted to retain T4in CSF. However,125I-labeled T4uptake into the ependymal region (ER) of the frontal cortex also increased by 13 times compared with control conditions. Elevation was also seen in the hippocampus (HC) and brain stem. Uptake was significantly inhibited by the presence of endocytosis inhibitors nocodazole and monensin by > 50%. These data suggest that the distribution of T4from CSF into brain and CP is carrier mediated, TTR dependent, and via RME. These results support a role for TTR in the distribution of T4from CSF into brain sites around the ventricular system, indicating those areas involved in neurogenesis (ER and HC).