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APPETITE, OBESITY, DIGESTION, AND METABOLISM

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

King's College London, Institute of Gerontology and Wolfson Centre for Age-Related Diseases, Guy's Hospital Campus, London, United Kingdom

Submitted 11 November 2005 ; accepted in final form 27 June 2006

The transport of ¹²⁵I-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 T₄ contained in artificial CSF was continually perfused into the lateral ventricles for up to 4 h and recovered from the cisterna magna. The %recovery of ¹²⁵I-labeled T₄ from the aCSF was 47.2 ± 5.6% (n = 10), indicating removal of ¹²⁵I-labeled T₄ from 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 T₄ removal from CSF. There was a large accumulation of ¹²⁵I-labeled T₄ in 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), more ¹²⁵I-labeled T₄ was recovered from CSF, indicating that the binding protein acted to retain T₄ in CSF. However, ¹²⁵I-labeled T₄ uptake 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 T₄ from CSF into brain and CP is carrier mediated, TTR dependent, and via RME. 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).

hippocampus; ependymal region; blood-brain barrier