Submitted on November 9, 2005
Accepted on June 27, 2006
Role of transthyretin in thyroxine transfer from cerebrospinal fluid to brain and choroid plexus
Nouhad A Kassem1*, Rashid Deane2, Malcolm B Segal1, and Jane E Preston1
1 Institute of Gerontology, King's College London, London, United Kingdom; Frank P. Smith Laboratories for Neuroscience and Neurosurgical Research, University of Rochester, Rochester, United States
2 King's College London, Institute of Gerontology; Frank P. Smith Laboratories for Neuroscience and Neurosurgical Research, University of Rochester, Rochester, United States
* To whom correspondence should be addressed. E-mail: nouhad.kassem{at}kcl.ac.uk.
The transport of 125I-T4 from the cerebrospinal fluid (CSF) into brain and choroid plexus (CP) was measured in anaesthetized rabbit (0.5 mg.kg-1 medetomidine [Domitor] and 10 mg.kg-1 pentobarbitone [Sagatal] i.v.) using the ventriculo-cisternal (V-C) perfusion technique. 125I-T4 contained in artificial CSF was continually perfused into the lateral ventricles for up to 4 hours, and recovered from the cisterna magna. The % recovery of 125I-T4 from the aCSF was 47.2±5.6 % (n=10), indicating removal of 125I-T4 from 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 unlabelled-thyroxine (T4) respectively, (p<0.05), indicating a saturable component to T4 removal from CSF. There was a large accumulation of 125I-T4 in the CP, and this was reduced by 80% in the presence of 200 µM unlabelled T4, showing saturation. In the presence of transthyretin (TTR), more 125I-T4 was recovered from CSF indicating that TTR acted to retain T4 in CSF. However, 125I-T4 uptake into the ependymal region (ER) also increased by 13 times compared to control. Elevation was also seen in hippocampus (HC) and brain stem (BS). Uptake was significantly inhibited by the presence of endocytosis inhibitors nocodazole and monensin by >50%. These data suggest that the distribution of T4 from CSF into brain and CP is carrier- mediated, TTR dependent, and via receptor- mediated endocytosis. These results support a role for TTR in the distribution of T4 from CSF into brain sites around the ventricular system, indicating those areas involved in neurogenesis (ER and HC).
